Peptides that comprise the functional subunits of proteins have been conjugated to versatile materials (biomolecules, polymers, surfaces and nanoparticles) in an effort to modulate cell responses, specific binding affinity and/or self-assembly behavior. However, the efficient and convenient synthesis of peptide-conjugates, especially the constructs with multiple types of peptide functionality remains challenging. In this critical review, we focus on "click" reactions that have been used to synthesis peptide-functionalized conjugates, introducing their reaction conditions, specifically elucidating parameters that influence reaction kinetics and total conversion, and highlighting examples that have been completed recently. Moreover, orthogonal "click" reactions that synthesize multi-functional biomaterials in a one-pot or sequential manner are noted. Through this review, a comprehensive understanding of "click" reactions aims to provide insight on how one might choose suitable "click" reactions to constitute peptide-functionalized molecules/surfaces/matrices for the development of advanced biomaterials.

Approximately 1.7 million new cases of cancer will be diagnosed this year in the United States leading to 600 000 deaths. Patient survival rates are highly correlated with the stage of cancer diagnosis, with localized and regional remission rates that are much higher than for metastatic cancer. The current standard of care for many solid tumors includes imaging and biopsy with histological assessment. In many cases, after tomographical imaging modalities have identified abnormal morphology consistent with cancer, surgery is performed to remove the primary tumor and evaluate the surrounding lymph nodes. Accurate identification of tumor margins and staging are critical for selecting optimal treatments to minimize recurrence. Visible, fluorescent, and radiolabeled small molecules have been used as contrast agents to improve detection during real-time intraoperative imaging. Unfortunately, current dyes lack the tissue specificity, stability, and signal penetration needed for optimal performance. Quantum dots (QDs) represent an exciting class of fluorescent probes for optical imaging with tunable optical properties, high stability, and the ability to target tumors or lymph nodes based on surface functionalization. Here, state-of-the-art biocompatible QDs are compared with current Food and Drug Administration approved fluorophores used in cancer imaging and a perspective on the pathway to clinical translation is provided.

Accurate medical recordkeeping is a major challenge in many low-resource settings where well-maintained centralized databases do not exist, contributing to 1.5 million vaccine-preventable deaths annually. Here, we present an approach to encode medical history on a patient using the spatial distribution of biocompatible, near-infrared quantum dots (NIR QDs) in the dermis. QDs are invisible to the naked eye yet detectable when exposed to NIR light. QDs with a copper indium selenide core and aluminum-doped zinc sulfide shell were tuned to emit in the NIR spectrum by controlling stoichiometry and shelling time. The formulation showing the greatest resistance to photobleaching after simulated sunlight exposure (5-year equivalence) through pigmented human skin was encapsulated in microparticles for use in vivo. In parallel, microneedle geometry was optimized in silico and validated ex vivo using porcine and synthetic human skin. QD-containing microparticles were then embedded in dissolvable microneedles and administered to rats with or without a vaccine. Longitudinal in vivo imaging using a smartphone adapted to detect NIR light demonstrated that microneedle-delivered QD patterns remained bright and could be accurately identified using a machine learning algorithm 9 months after application. In addition, codelivery with inactivated poliovirus vaccine produced neutralizing antibody titers above the threshold considered protective. These findings suggest that intradermal QDs can be used to reliably encode information and can be delivered with a vaccine, which may be particularly valuable in the developing world and open up new avenues for decentralized data storage and biosensing.

We demonstrate the formation of polyethylene glycol (PEG) based hydrogels via oxime ligation and the photo-initiated thiol-ene 3D patterning of peptides within the hydrogel matrix post-gelation. The gelation process and final mechanical strength of hydrogels can be tuned using pH and the catalyst concentration. The time scale to reach the gel point and complete gelation can be shortened from hours to seconds using both pH and aniline catalyst, which facilitates the tuning of the storage modulus from 0.3 kPa to over 15 kPa. Azide and alkene functionalized hydrogels were also synthesized and we have shown the post gelation “click” type Husigen 1,3 cycloaddition and thiolene-based radical reactions for spatially defined peptide incorporation. These materials are the initial demonstration for translationally relevant hydrogel materials that possess tunable mechanical regimes attractive to soft tissue engineering and possess atom neutral chemistries attractive for post gelation patterning in the presence or absence of cells.

Hydrogels that are self-assembled by peptides have attracted great interest for biomedical applications. However, the link between chemical structures of peptides and their corresponding hydrogel properties is still unclear. Here, we showed a combinational approach to generate a structurally diverse hydrogel library with more than 2,000 peptides and evaluated their corresponding properties. We used a quantitative structure-property relationship to calculate their chemical features reflecting the topological and physicochemical properties, and applied machine learning to predict the self-assembly behavior. We observed that the stiffness of hydrogels is correlated with the diameter and cross-linking degree of the nanofiber. Importantly, we demonstrated that the hydrogels support cell proliferation in culture, suggesting the biocompatibility of the hydrogel. The combinatorial hydrogel library and the machine learning approach we developed linked the chemical structures with their self-assembly behavior and can accelerate the design of novel peptide structures for biomedical use.self-assembly | dipeptide hydrogels | machine learning H ydrogels that are cross-linked by three-dimensional networks of modified molecules can maintain a large amount of water without dissolving its own chemical structure, which is very similar to natural tissue. As a result of favorable biocompatibility, hydrogels have great potential in biomedical applications such as drug delivery, tissue engineering, sensing, and cell encapsulation (1-7). In the past few years, considerable attention has been directed toward the design of peptide-based hydrogels in particular, not only because of their favorable features such as easy synthesis, decoration, biodegradability, and high compatibility, but also due to their wide applications in the biological and medical fields (8)(9)(10)(11)(12)(13)(14). However, to the best of our knowledge, the prediction and design of peptide-based hydrogels is still challenging, which limits our research choices on peptide-based hydrogels (15,16). Therefore, the design strategy for hydrogels based on peptides is of great significance. Our aim is to reveal the relationship between molecular structure and hydrogel behavior, which can help us to predict and design peptide hydrogels with new chemical structures.There are approaches using molecular dynamics simulation to model the self-assembly behavior of peptides into different types of nanostructures, including nanofibers, which can subsequently form hydrogels (17)(18)(19). However, it is difficult to evaluate the actual prediction accuracy of the molecular dynamics simulation methods because only a few positive peptides were selected and synthesized to test whether they could form a hydrogel. Additionally, the current reported synthetic method on 9fluorenylmethyloxycarbonyl (Fmoc)-peptide is limited to the traditional peptide synthesis method, involving step-by-step protection and deprotection. Since a high-throughput peptide generation method is not available, our first ...

Hybrid systems of hydrogels and metals with tough bonding may find widespread applications. Here, a simple and universal method to obtain strong adhesion between hydrogels and diverse metal surfaces, such as titanium, steel, nickel, tantalum, argentum, and aluminum, with adhesion energy up to >1000 J m−2 is reported. To achieve such, the metal surfaces are instantly modified with a linker molecule via soaking, dip‐coating, or drop‐casting. The designed linker molecule has a carboxylic acid group to bind with a metal surface, and a methacrylic group to crosslink with a hydrogel, thus bridging the interface between them. In addition, by introducing a stimulus‐responsive disulfide bond into the linker molecule, the on‐demand debonding between toughly bonded hydrogel and metal surface, which is enabled by reductive cleavage of the disulfide chemical linkage, is also demonstrated. More interestingly, after the reductive debonding, the resulting metal surface with free thiol groups can be easily rebonded with a second hydrogel without any further surface modification. The strategy may provide unique opportunities in designing hybrid devices that are suitable for complex and dynamic environments.

A series of monodispersed oligo( p-phenyleneethynylene)s were synthesized bearing intramolecular hydrogen bonds between side chains of adjacent phenylene units in the backbone. Thus, all repeating units of the molecules are constrained in a coplanar orientation. Such planarized conformation is considered favorable for single-molecule conductance. Photophysical characterization results show narrowed bandgaps and extended conjugation lengths, consistent with a rigid, planar backbone framework as a result of intramolecular hydrogen bonding.

A series of multivalent dendrons containing a bioactive osteogenic growth peptide (OGP) domain and surface-binding catechol domains were obtained through solid phase synthesis, and their binding affinity to hydroxyapatite, TiO2, ZrO2, CeO2, Fe3O4 and gold was characterized using a quartz crystal microbalance with dissipation (QCM-d). Using the distinct difference in binding affinity of the bioconjugate to the metal oxides, TiO2-coated glass slides were selectively patterned with bioactive peptides. Cell culture studies demonstrated the bioavailability of the OGP and that OGP remained on the surface for at least 2 weeks under in vitro cell culture conditions. Bone sialoprotein (BSP) and osteocalcein (OCN) markers were upregulated 3-fold and 60-fold, respectively, relative to controls at 21 days. Similarly, 3-fold more calcium was deposited using the OGP tethered dendron compared to TiO2. These catechol-bearing dendrons provide a fast and efficient method to functionalize a wide range of inorganic materials with bioactive peptides and have the potential to be used in coating orthopaedic implants and fixation devices.