Redox-triggered debonding of mussel-inspired pressure sensitive adhesives: Improving efficiency through functional design.

Debondable pressure-sensitive adhesives (PSAs) promise access to recyclability in microelectronics in the transition toward a circular economy. Two PSAs were synthesized from a tetravalent thiol star-polyester forming thiol-catechol-connectivities (TCC) with either biorelated DiDopa-bisquinone (BY*Q) or fossil-based bisquinone A (BQA). The PSAs enable debonding by oxidation of TCC-catechols to quinones. The extent of debonding efficiency depends on the interaction modes, which are determined by the chemical structure differences of both TCC-motifs. BY*Q-TCC-PSA debonds with exceptional loss of 99% of its approx. 2 MPa shear strength. For BQA-TCC-PSA, a debonding efficiency of only approx. 60% was found, irrespective of its initial shear strength, which could be tuned up to approx. 7 MPa. The efficiency of debonding for BY*Q-TCC-PSA after TCC-oxidation is linked to the loss of synergistic interactions without strongly affecting the bulk glue properties, outperforming the purely catechol-based BQA-analogue.

Statistical Copolymers that Mimic Aspects of Mussel Adhesive Proteins: Access to Robust Adhesive-Domains for Non-Covalent Surface PEGylation.

Reconstructing functional sequence motifs of proteins, using statistical copolymers greatly reduces the information content, but simplifies synthesis significantly. Key amino acid residues involved in the adhesion of mussel foot proteins are identified. The side-chain functionalities of Dopa, lysine, and arginine are abstracted and incorporated into acrylate monomers to allow controlled radical polymerization. The resulting Dopa-acrylate (Y*-acr), arginine-acrylate (R-acr), and lysine-acrylate (K-acr) monomers are polymerized in different monomer ratios and compositions by reversible addition fragmentation transfer polymerization with a poly(ethylene glycol) (PEG) macrochain transfer agent. This results in two sets of PEG-block-copolymers with statistical mixtures and different monomer ratios of catechol/primary amine and catechol/guanidine side-chain functionalities, both important pairs for mimicking π-cation interactions. The coating behavior of these PEG-block-copolymers is evaluated using quartz crystal microbalance with dissipation energy monitoring (QCM-D), leading to non-covalent PEGylation of the substrates with clear compositional optima in the coating stability and antifouling properties. The coatings prevent non-reversible albumin or serum adsorption, as well as reduce cellular adhesion and fungal spore attachment.

Information-Based Design of Polymeric Drug Formulation Additives.

Tailor-made copolymers are designed based on a peptide-poly(ethylene glycol) (QFFLFFQ-PEG) conjugate as a blueprint, to solubilize the photosensitizer meta-tetra(hydroxyphenyl)chlorin (m-THPC). The relevant functionalities of the parent peptide-PEG are mimicked by employing monomer pairs that copolymerize in a strictly alternating manner. While styrene (S) or 4-vinylbenzyl-phthalimide (VBP) provide aromatic moieties like Phe, the aliphatic isobutyl side chain of Leu4 is mimicked by maleic anhydride (MA) that reacts after polymerization with isobutylamine to give the isobutylamide-carboxyl functional unit (iBuMA). A set of copolymer-PEG solubilizers is synthesized by controlled radical polymerization, systematically altering the length of the functional segment (DPn = 2, 4, 6) and the side chain functionalization (iBuMA, iPrMA, MeMA). The m-THPC hosting and release properties of P[S-alt-iBuMA]6-PEG reached higher payload capacities and more favored release rates than the parent peptide-PEG conjugate. Interestingly, P[S-alt-RMA]n-PEG mimics the sensitivity of the peptide-PEG solubilizer well, where the exchange of Leu4 residue by Val and Ala significantly reduces the drug loading by 92%. A similar trend is found with P[S-alt-RMA]n-PEG as the exchange of iBu → iPr → Me reduces the payload capacity up to 78%.

Implementing Zn2+ ion and pH-value control into artificial mussel glue proteins by abstracting a His-rich domain from preCollagen.

A His-rich domain of preCollagen-D found in byssal threads is derivatized with Cys and Dopa flanks to allow for mussel-inspired polymerization. Artificial mussel glue proteins are accessed that combine cysteinyldopa for adhesion with sequences for pH or Zn2+ induced ß-sheet formation. The artificial constructs show strong adsorption to Al2O3, the resulting coatings tolerate hypersaline conditions and cohesion is improved by activating the ß-sheet formation, that enhances E-modulus up to 60%.

Accessing the Next Generation of Synthetic Mussel-Glue Polymers via Mussel-Inspired Polymerization.

The formation of cysteinyldopa as biogenic connectivity in proteins is used to inspire a chemical pathway toward mussel-adhesive mimics. The mussel-inspired polymerization (MIPoly) exploits the chemically diverse family of bisphenol monomers that is oxidizable with 2-iodoxybenzoic acid to give bisquinones. Those react at room temperature with dithiols in Michael-type polyadditions, which leads to polymers with thiol-catechol connectivities (TCC). A set of TCC polymers proved adhesive behavior even on challenging poly(propylene) substrates, where they compete with commercial epoxy resins in dry adhesive strength. MIPoly promises facile scale up and exhibits high modularity to tailor adhesives, as proven on a small library where one candidate showed wet adhesion on aluminum substrates in both water and sea water models.

Combining Phage Display and Next-Generation Sequencing for Materials Sciences: A Case Study on Probing Polypropylene Surfaces.

Phage display biopanning with Illumina next-generation sequencing (NGS) is applied to reveal insights into peptide-based adhesion domains for polypropylene (PP). One biopanning round followed by NGS selects robust PP-binding peptides that are not evident by Sanger sequencing. NGS provides a significant statistical base that enables motif analysis, statistics on positional residue depletion/enrichment, and data analysis to suppress false-positive sequences from amplification bias. The selected sequences are employed as water-based primers for PP-metal adhesion to condition PP surfaces and increase adhesive strength by 100% relative to nonprimed PP.

Mussel-Inspired Polymerization of Peptides: The Chemical Activation Route as Key to Broaden the Sequential Space of Artificial Mussel-Glue Proteins.

A previously introduced tyrosinase-activated polymerization of Tyr- and Cys-bearing peptides yielding artificial mussel-glue proteins is realized without the need of the specific enzyme by a chemical activation route. This decouples the sequence of polymerizable peptides (unimers) from the constraints of tyrosinase substrates and enables the polymerization of minimal motifs such as Dopa-Lys-Cys (Umini *KC ) or Dopa-Gly-Cys (Umini *GC ). In the polymerization procedure, sodium periodate is used to oxidize Dopa residues of the unimers to Dopa-quinones to which the thiol of a Cys residue is added in a Michael-type reaction. The resulting polyUmini *KC and polyUmini *GC exhibit a thiol-catechol connectivity as a potent adhesive functionality at each repeat unit. QCM-D experiments show the excellent substrate adsorption properties of the products from the chemically activated polymerization. On aluminum oxide surfaces, polyUmini *KC rapidly forms a coating, even under seawater model conditions and the coating resists rinsing with hypersaline solution of 4.2 M salt mixtures. While the sodium periodate oxidation is less specific than the tyrosinase reaction and requires the implementation of Dopa instead of Tyr residues into the polymerizable unimers, the chemical route makes scale-up more easily accessible.

Toward Artificial Mussel-Glue Proteins: Differentiating Sequence Modules for Adhesion and Switchable Cohesion.

Artificial mussel-glue proteins with pH-triggered cohesion control were synthesized by extending the tyrosinase activated polymerization of peptides to sequences with specific modules for cohesion control. The high propensity of these sequence sections to adopt ß-sheets is suppressed by switch defects. This allows enzymatic activation and polymerization to proceed undisturbed. The ß-sheet formation is regained after polymerization by changing the pH from 5.5 to 6.8, thereby triggering O→N acyl transfer rearrangements that activate the cohesion mechanism. The resulting artificial mussel glue proteins exhibit rapid adsorption on alumina surfaces. The coatings resist harsh hypersaline conditions, and reach remarkable adhesive energies of 2.64 mJ m-2 on silica at pH 6.8. In in situ switch experiments, the minor pH change increases the adhesive properties of a coating by 300 % and nanoindentation confirms the cohesion mechanism to improve bulk stiffness by around 200 %.

Specific Decoration of a Discrete Bismuth Oxido Cluster by Selected Peptides towards the Design of Metal Tags.

Metal tags find application in a multitude of biomedical systems and the combination with laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) offers an opportunity for multiplexing. To lay the foundation for an increase of the signal intensities in such processes, we herein present a general approach for efficient functionalization of a well-defined metal oxido cluster [Bi6 O4 (OH)4 (SO3 CF3 )6 (CH3 CN)6 ]⋅2 CH3 CN (1), which can be realized by selecting 7mer peptide sequences via combinatorial means from large one-bead one-compound peptide libraries. Selective cluster-binding peptide sequences (CBS) for 1 were discriminated from non-binders by treatment with H2 S gas to form the reduction product Bi2 S3 , clearly visible to the naked eye. Interactions were further confirmed by NMR experiments. Extension of a binding peptide with a maleimide linker (Mal) introduces the possibility to covalently attach thiol-bearing moieties such as biological probes and for their analysis the presence of the cluster instead of mononuclear entities should lead to an increase of signal intensities in LA-ICP-MS measurements. To prove this, CBS-Mal was covalently bound onto thiol-presenting glass substrates, which then captured 1 effectively, so that LA-ICP-MS measurements demonstrated drastic signal amplification compared to single lanthanide tags.

Expanding the Material Space of Biosustainable Poly(sophorolipids) by Modular Functionalization.

A general strategy to modify the structurally interesting poly(lactonic sophorolipid) (Poly(LSL)), a polymer derived from the biobased sophorolipid monomer, is presented. Effective backbone modification is achieved via a triazolinedione (TAD)-ene-reaction. This enables the straightforward introduction of various functionalities to the double bond in the fatty acid segment of the Poly(LSL). The reaction occurs quantitatively in stoichiometric ratios up to a targeted functionalization degree of 50% and complete functionalization of all double bonds is feasible when three equivalents excess of the TAD moiety with respect to the double bonds are used. It is shown that the thermal and mechanical properties of the modified polymers can be tailored via type and degree of functionalization. The exploited TAD ligation fulfills the criteria of an economic and efficient reaction, making the presented modification strategy straightforward to fine-tune the material properties and extending the applicability of Poly(LSL) as a material.

Digging into the Sequential Space of Thiolactone Precision Polymers: A Combinatorial Strategy to Identify Functional Domains.

Functional sequences of precision polymers based on thiolactone/Michael chemistry are identified from a large one-bead one-compound library. Single-bead readout by MALDI-TOF MS/MS identifies sequences that host m-THPC that is a second generation photo-sensitizer drug. The corresponding Tla/Michael-PEG conjugates make m-THPC available in solution and drug payload as well as drug release kinetics can be fine-tuned by the precision segment.

Learning from Peptides to Access Functional Precision Polymer Sequences.

Functional precision polymers based on monodisperse oligo(N-substituted acrylamide)s and oligo(2-substituted-α-hydroxy acid)s have been synthesized. The discrete sequences originate from a direct translation of side-chain functionality sequences of a peptide with well-studied properties. The peptide was previously selected to solubilize the photosensitizer meta-tetra(hydroxyphenyl)chlorin. The resulting peptidomimetic formulation additives preserve the drug solubilization and release characteristics of the parent peptide. In some cases, superior properties are obtained, reaching up to 40 % higher payloads and 27-times faster initial drug release.

Lipid-DNAs as Solubilizers of mTHPC.

Hydrophobic drug candidates require innovative formulation agents. We designed and synthesized lipid-DNA polymers containing varying numbers of hydrophobic alkyl chains. The hydrophobicity of these amphiphiles is easily tunable by introducing a defined number of alkyl chain-modified nucleotides during standard solid-phase synthesis of DNA using an automated DNA synthesizer. We observed that the resulting self-assembled micelles solubilize the poorly water-soluble drug, meta-tetra-hydroxyphenyl-chlorin (mTHPC) used in photodynamic therapy (PDT) with high loading concentrations and loading capacities. A cell viability study showed that mTHPC-loaded micelles exhibit good biocompatibility without irradiation, and high PDT efficacy upon irradiation. Lipid-DNAs provide a novel class of drug-delivery vehicle, and hybridization of DNA offers a potentially facile route for further functionalization of the drug-delivery system with, for instance, targeting or imaging moieties.

Polymerizing Like Mussels Do: Toward Synthetic Mussel Foot Proteins and Resistant Glues.

A novel strategy to generate adhesive protein analogues by enzyme-induced polymerization of peptides is reported. Peptide polymerization relies on tyrosinase oxidation of tyrosine residues to Dopaquinones, which rapidly form cysteinyldopa-moieties with free thiols from cysteine residues, thereby linking unimers and generating adhesive polymers. The resulting artificial protein analogues show strong adsorption to different surfaces, even resisting hypersaline conditions. Remarkable adhesion energies of up to 10.9 mJ m-2 are found in single adhesion events and average values are superior to those reported for mussel foot proteins that constitute the gluing interfaces.

Fine-tuning Nanocarriers Specifically toward Cargo: A Competitive Study on Solubilizing Related Photosensitizers for Photodynamic Therapy.

Tailor-made drug solubilizers are studied based on peptide-poly(ethylene glycol) conjugates, which exhibit peptide segments constituting binding motifs for the small-molecule drugs of interest to render them water-soluble. Suitable 7mer peptides are selected via combinatorial means by screening large one-bead-one-compound (OBOC) peptide libraries. The capability of the screening method to read out structural detail of the drugs is investigated by comparing three related photosensitizers (Chlorin E6 (Ce6), Pheophorbide A (Pba) and meta-tetra(hydroxyphenyl)chlorin (m-THPC), which are applicable for photodynamic cancer therapy. The screening procedure delivers de novo solubilizers that show the best solubilization efficiency for the drug the screening is performed with. While molecular recognition events between peptide and drug are not expected to be found, significant binding capacity differences of, e.g., the Ce6-solubilizer for Pba are suggesting selectivity in drug binding, even among structurally closely related drugs. Cyro-Electron microscopy revealed the formation of colloidal aggregates between drug moieties and peptide conjugates. Insights into relevant amino acids in the identified peptide sequences are gained by studying capacities of systematic point mutations (alanine scans), enabling understanding of drug-binding motifs. These reveal the importance of sequence positioning of appropriate H-bonding between polar functional groups of the peptide and the drugs, which agrees well with computational binding studies performed on drug/peptide model complexes.

Identification of Functional Peptide Sequences to Lead the Design of Precision Polymers.

Peptide sciences developed dramatically as a result of routine use of solid-phase peptide synthesis and nowadays offer a rich set of well-established strategies to design and identify functional peptide sequences for advanced applications in materials sciences. Appropriate sequences for a wide range of interesting material targets, ranging from molecules to materials surfaces and internal interfaces, can be selected via combinatorial means, and sequence specificities within the resulting peptide-target interactions can be routinely investigated. Based on this understanding, macromolecular sciences can define new polymer structures that meet required functionalities or functional sequences with fully synthetic, nonpeptidic precision polymers to endeavor toward information-based design of next-generation, purpose-adapted macromolecules.

PEGylated Precision Segments Based on Sequence-Defined Thiolactone Oligomers.

A straightforward access route to multifunctional block copolymers, combining a poly(ethylene glycol) (PEG) block and a monodisperse segment with discrete monomer sequence based on thiolactone chemistry, is described. Exploiting an inverse conjugation strategy on a PEG preloaded poly(styrene) synthesis resin enables the convenient introduction of a predefined PEG-block at the α-terminus of thiolactone-based sequence-defined oligomers. Reaction conditions for the stepwise, submonomer synthesis at polar solid supports are optimized, using sequential synthesis on a model resin that enables to isolate and determine the purity of the oligomer segments by liquid chromatography-electrospray ionization mass spectrometry analysis. The reaction conditions are used to synthesize PEGylated 5mer precision polymers with defined monomer sequence in good yields and high purity to offer an interesting platform of macromolecules with potential for biomedical applications.

Advancing Drug Formulation Additives toward Precision Additives with Release Mediating Peptide Interlayer.

Amphiphilic drug formulation additives based on palmitic acid-modified poly(ethylene glycol) (Pal-PEG) are combined with a tailored drug binding peptide that is positioned at the hydrophobic-hydrophilic interface. The peptide originates from combinatorial selection and enables precise modulation of the drug release profiles. While Pal provides a cost-effective reservoir for drug storage, the PEG realizes solubility and shielding. The precision additives reach high payloads close to 1:1, rendering a photosensitizer water-soluble and providing adjustable drug activation kinetics by fine-tuning the peptide interface layer.

Templated CaCO3 Crystallization by Submicrometer and Nanosized Fibers.

Electrospun submicrometer-sized poly(ε-caprolactone) (PCL) meshes and nanosized multiwalled carbon nanotubes (MWCNTs) were used as a template for preparing porous and interconnected inorganic-organic hybrid materials composed of CaCO3. Herein, we describe the proportion and incorporation method of submicrometer-sized plasma-treated PCL meshes over areas >1 mm(2) with CaCO3 using three crystallization methods including the use of poly(acrylic acid) (PAA). We found that flexible and rigid acid-functionalized MWCNTs showed a clear capacity and effects to penetrate calcite particles. MWCNTs interacted differently with the individual growth planes of CaCO3, indicating that fibers can undergo changes depending on sulfonate or carboxylate groups, adopt different orientations in solution, and thereby elicit changes in CaCO3 morphology. In summary, the use of PCL and acidic MWCNT fibers as an additive for substrate templates and experimental crystallization provides a viable approach for studying various aspects of biomineralization, including the production of controlled particles, control of porosities, and defined morphologies at microscale and nanoscale levels.

Easy Access to Functional Patterns on Cellulose Paper by Combining Laser Printing and Material-Specific Peptide Adsorption.

Phage display biopanning is used to identify peptides that show material-selective adsorption, effectively distinguishing between the cellulose of paper and the printed toner of standard office laser printers. These genetically selected 12mer peptides can selectively coat either non-printed cellulose or printed toner patterns. Furthermore, triazolindione ligation chemistry is exploited to introduce, for example, dyes or functional peptides selectively to the coatings. The strategy offers an easy access towards the patterned functionalization of paper-based materials, which potentially is of relevance for low-cost diagnostics or biomedical devices.