The present and future of biologically inspired adhesive interfaces and materials.

The natural world provides many examples of robust, permanent adhesive platforms. Synthetic adhesive interfaces and materials inspired by mussels of genus Mytulis have been extensively applied, and it is expected that characterization and adaptation of several other biological adhesive strategies will follow the Mytilus edulis model. These candidate species will be introduced, along with a discussion of the adhesive behaviors that make them attractive for synthetic adaptation. While significant progress has been made in the development of biologically inspired adhesive interfaces and materials, persistent questions, current challenges, and emergent areas of research will be also be discussed.

Enzymatically degradable mussel-inspired adhesive hydrogel.

Mussel-inspired adhesive hydrogels represent innovative candidate medical sealants or glues. In the present work, we describe an enzyme-degradable mussel-inspired adhesive hydrogel formulation, achieved by incorporating minimal elastase substrate peptide Ala-Ala into the branched poly(ethylene glycol) (PEG) macromonomer structure. The system takes advantage of neutrophil elastase expression upregulation and secretion from neutrophils upon recruitment to wounded or inflamed tissue. By integrating adhesive degradation behaviors that respond to cellular cues, we expand the functional range of our mussel-inspired adhesive hydrogel platforms. Rapid (<1 min) and simultaneous gelation and adhesion of the proteolytically active, catechol-terminated precursor macromonomer was achieved by addition of sodium periodate oxidant. Rheological analysis and equilibrium swelling studies demonstrated that the hydrogel is appropriate for soft tissue-contacting applications. Notably, hydrogel storage modulus (G') achieved values on the order of 10 kPa, and strain at failure exceeded 200% strain. Lap shear testing confirmed the material's adhesive behavior (shear strength: 30.4 ± 3.39 kPa). Although adhesive hydrogel degradation was not observed during short-term (27 h) in vitro treatment with neutrophil elastase, in vivo degradation proceeded over several months following dorsal subcutaneous implantation in mice. This work represents the first example of an enzymatically degradable mussel-inspired adhesive and expands the potential biomedical applications of this family of materials.

A Cationic Micelle Complex Improves CD8+ T Cell Responses in Vaccination Against Unmodified Protein Antigen.

Nanoscale carrier platforms promote immune responses to vaccination by facilitating delivery of vaccine components to immunologically relevant sites. The technique is particularly valuable for subunit vaccination, in which coadministration of immunostimulatory adjuvant is known to enhance immune responses to protein antigen. The fabrication of polymer-based nanoparticle vaccines commonly requires covalent attachment of vaccine components to the carrier surface. In contrast, we here describe a cationic micelle vaccination platform in which antigen and adjuvant loading is mediated by noncovalent molecular encapsulation and electrostatic complexation. Cationic micelles were generated through self-assembly of a polyarginine-conjugated poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-PPS) diblock copolymer amphiphile, with or without encapsulation of monophosphoryl lipid A (MPLA), an amphiphilic experimental vaccine adjuvant. Micelle complexes were subsequently formed by complexation of ovalbumin (OVA) and CpG-B oligodeoxynucleotide (a second experimental adjuvant) to the cationic micelles. In a 35-day study in mouse, micelle-mediated codelivery of OVA antigen and CpG-B enhanced cellular and humoral responses to vaccination. These outcomes were highlighted in spleen and lymph node CD8+ T cells, with significantly increased populations of IFNγ+, TNFα+, and polyfunctional IFNγ+ TNFα+ cells. Elevated cytokine production is a hallmark of robust cytotoxic T lymphocyte (CTL) responses sought in next-generation vaccine technologies. Increased production of OVA-specific IgG1, IgG2c, and IgG3 also confirmed micelle enhancement of humoral responses. In a subsequent 35-day study, we explored micelle-mediated vaccination against OVA antigen coadministered with MPLA and CpG-B adjuvants. A synergistic effect of adjuvant coadministration was observed in micelle-free vaccination but not in groups immunized with micelle complexes. This outcome underlines the advantage of the micelle carrier: we achieved optimal cellular and humoral responses to vaccination by use of this nanoparticle platform with a single adjuvant. In particular, enhanced CTL responses support future development of the cationic micelle platform in experimental cancer vaccines and for vaccination against reticent viral pathogens.

One-step synthesis of low polydispersity, biotinylated poly(N-isopropylacrylamide) by ATRP.

Low polydispersity poly(N-isopropylacrylamide) with a biotin end-group was obtained in one step from a biotinylated initiator for atom transfer radical polymerization and interacted with streptavidin to generate the thermosensitive polymer-protein conjugate.

Crystalline Oligo(ethylene sulfide) Domains Define Highly Stable Supramolecular Block Copolymer Assemblies.

With proper control over copolymer design and solvation conditions, self-assembled materials display impressive morphological variety that encompasses nanoscale colloids as well as bulk three-dimensional architectures. Here we take advantage of both hydrophobicity and crystallinity to mediate supramolecular self-assembly of spherical micellar, linear fibrillar, or hydrogel structures by a family of highly asymmetric poly(ethylene glycol)-b-oligo(ethylene sulfide) (PEG-OES) copolymers. Assembly structural polymorphism was achieved with modification of PEG-OES topology (linear versus multiarm) and with precise, monomer-by-monomer control of OES length. Notably, all three morphologies were accessed utilizing OES oligomers with degrees of polymerization as short as three. These exceptionally small assembly forming blocks represent the first application of ethylene sulfide oligomers in supramolecular materials. While the assemblies demonstrated robust aqueous stability over time, oxidation by hydrogen peroxide progressively converted ethylene sulfide residues to increasingly hydrophilic and amorphous sulfoxides and sulfones, causing morphological changes and permanent disassembly. We utilized complementary microscopic and spectroscopic techniques to confirm this chemical stimulus-responsive behavior in self-assembled PEG-OES colloidal dispersions and physical gels. In addition to inherent stimulus-responsive behavior, fibrillar assemblies demonstrated biologically relevant molecular delivery, as confirmed by the dose-dependent activation of murine bone marrow-derived dendritic cells following fibril-mediated delivery of the immunological adjuvant monophosphoryl lipid A. In physical gels composed of either linear or multiarm PEG-OES precursors, rheologic analysis also identified mechanical stimulus-responsive shear thinning behavior. Thanks to the facile preparation, user-defined morphology, aqueous stability, carrier functionality, and stimuli-responsive behaviors of PEG-OES supramolecular assemblies, our findings support a future role for these materials as injectable or implantable biomaterials.

Biological performance of mussel-inspired adhesive in extrahepatic islet transplantation.

There is significant need for effective medical adhesives that function reliably on wet tissue surfaces with minimal inflammatory insult. To address these performance characteristics, we have generated a synthetic adhesive biomaterial inspired by the protein glues of marine mussels. In-vivo performance was interrogated in a murine model of extrahepatic syngeneic islet transplantation, as an alternative to standard portal administration. The adhesive precursor polymer consisted of a branched poly(ethylene glycol) (PEG) core, whose endgroups were derivatized with catechol, a functional group abundant in mussel adhesive proteins. Under oxidizing conditions, adhesive hydrogels formed in less than 1 min from catechol-derivatized PEG (cPEG) solutions. Upon implantation, the cPEG adhesive elicited minimal acute or chronic inflammatory response in C57BL6 mice, and maintained an intact interface with supporting tissue for up to one year. In-situ cPEG adhesive formation was shown to efficiently immobilize transplanted islets at the epididymal fat pad and external liver surfaces, permitting normoglycemic recovery and graft revascularization. These findings establish the use of synthetic, biologically-inspired adhesives for islet transplantation at extrahepatic sites.