A Photoresponsive Hyaluronan Hydrogel Nanocomposite for Dynamic Macrophage Immunomodulation

Abstract

Macrophages are a predominant immune cell population that drive inflammatory responses and exhibit transitions in phenotype and function during tissue remodeling in disease and repair. Thus, engineering an immunomodulatory biomaterial has significant implications for resolving inflammation. Here, a biomimetic and photoresponsive hyaluronan (HA) hydrogel nanocomposite with tunable 3D extracellular matrix (ECM) adhesion sites for dynamic macrophage immunomodulation is engineered. Photodegradative alkoxylphenacyl‐based polycarbonate (APP) nanocomposites are exploited to permit user‐controlled Arg–Gly–Asp (RGD) adhesive peptide release and conjugation to a HA‐based ECM for real‐time integrin activation of macrophages encapsulated in 3D HA–APP nanocomposite hydrogels. It is demonstrated that photocontrolled 3D ECM–RGD peptide conjugation can activate αvβ3 integrin of macrophages, and periodic αvβ3 integrin activation can enhance anti‐inflammatory M2 macrophage polarization. Altogether, an emerging use of biomimetic, photoresponsive, and bioactive HA–APP nanocomposite hydrogel is highlighted to command 3D cell–ECM interactions for modulating macrophage polarization, which may shed light on cell–ECM interactions in innate immunity and inspire new biomaterial‐based immunomodulatory therapies.

Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy

“…To dissect the heterogeneity of anti-PD-1 immunotherapy responses in molecularly distinct GBM cohort of PN , CL , and MES subtypes, we developed a microfluidics-based 3D ‘GBM-on-a-Chip’ microphysiological system ( Figure 2 and Figure 2—figure supplement 1 ) mimicking the subtype-specific in vivo GBM tumor niche. In this organotypic system, we housed a 3D brain microvessel ( Figure 2A–C , yellow ) derived from human brain microvascular endothelial cells (hBMVECs), TAMs derived from human macrophages ( Figure 2—figure supplement 2A and B ), patient-derived and molecularly-distinct GBM cells ( Figure 2A–C , red ), and sorted allogeneic human CD8+ T-cells ( Figure 2A–C , green ) from primary peripheral blood mononuclear cells (PBMCs) within a 3D brain-mimicking hyaluronan (HA)-rich Matrigel extracellular matrix (ECM) ( Figure 2—figure supplement 2 ; Wang et al, 2019 ) (details see Materials and methods). Specifically, ‘GBM-on-a-Chip’ culture was compartmentalized by a peripheral channel designated for patterning 3D brain microvessels (outer ring), an intermediate tumor stromal area (middle ring), and a core media region (center region) for long-term media supply ( Figure 2A and Figure 2—figure supplement 1 ).…”

Injectable Gelatin Hydrogel Suppresses Inflammation and Enhances Functional Recovery in a Mouse Model of Intracerebral Hemorrhage

“…The mechanism by which biomaterials enable microglia/macrophages polarization into the anti-inflammatory phenotype remains largely unknown. Gelatin retains the cell adhesive motifs-RGD, which has been reported to elicit anti-inflammatory effects from macrophages in vitro as well as increase cellular adhesion ( Lynn et al, 2010 ; Zaveri et al, 2014 ; Cha et al, 2017 ; Wang et al, 2018 ; Kang et al, 2019 ). Besides, osteopontin containing RGD can significantly suppress the inductions of iNOS in postischemic brains, demonstrating anti-inflammatory effects ( Jin et al, 2016 ).…”

“…In this regard, hydrogels based on natural proteins, such as collagen and gelatin or decellularized membranes, have the advantage of generally possessing the ligands necessary for cell adhesion. Gelatin derived from denatured and partly degraded collagen, and was widely used in the tissue engineering for its good biodegradability and biocompatibility, as well as adhesion to cells and lack of antigenicity ( Lin et al, 2017 ; Mobaraki et al, 2019 ; Shi et al, 2019a , b ; Zhang et al, 2019 ), and often used for cell encapsulation ( Barthes et al, 2018 ), More importantly, gelatin retains cell adhesive motifs of RGD ( Echave et al, 2017 ), a key biological functional sequence that could be used as an active target ( Ge et al, 2018 ), promote angiogenesis and nerve regeneration ( Li et al, 2017 ; Dursun et al, 2019 ; Samadian et al, 2020 ; Wu et al, 2020 ), reduce gliosis and accelerate neural progenitor cell migration ( Nih et al, 2017 ; Motamed et al, 2019 ), influent inflammation ( Zaveri et al, 2014 ; Nguyen et al, 2016 ), and elicit M2 polarization from macrophages in vitro ( Cha et al, 2017 ; Wang et al, 2018 ; Kang et al, 2019 ) when binds to integrin receptor through ligand-receptor specific interactions. However, in vivo , we know that the interaction between host immunity and the implant depends on the microenvironment of adjacent tissue, resulting in a tissue-specific response to biomaterials ( Taraballi et al, 2018 ; Feng et al, 2019 ; Wang Y. et al, 2019 ).…”

pH-dependent nanodiamonds enhance the mechanical properties of 3D-printed hyaluronic acid nanocomposite hydrogels

“…Nanocomposite hydrogels that incorporate diverse nanophase inorganic particles are challenging because metastatic materials mimicking biological tissues require a variety of considerations including softness, biocompatibility, strength, and structurally compatible elasticity. The specific functionality granted by nanocomposite hydrogels with inorganic materials would lead to improved electrical conductivity [27,28], energy absorbance [29][30][31], as well as cellular [18,26,32,33] and protein interactions [2], in addition to mechanical enhancement.…”