Mapping the Morphological Landscape of Oligomeric Di-block Peptide-Polymer Amphiphiles.

Peptide-polymer amphiphiles (PPAs) are tunable hybrid materials that achieve complex assembly landscapes by combining the sequence-dependent properties of peptides with the structural diversity of polymers. Despite their promise as biomimetic materials, determining how polymer and peptide properties simultaneously affect PPA self-assembly remains challenging. We herein present a systematic study of PPA structure-assembly relationships. PPAs containing oligo(ethyl acrylate) and random-coil peptides were used to determine the role of oligomer molecular weight, dispersity, peptide length, and charge density on self-assembly. We observed that PPAs predominantly formed spheres rather than anisotropic particles. Oligomer molecular weight and peptide hydrophilicity dictated morphology, while dispersity and peptide charge affected particle size. These key benchmarks will facilitate the rational design of PPAs that expand the scope of biomimetic functionality within assembled soft materials.

Bioactive, Ion-Releasing PMMA Bone Cement Filled with Functional Graphenic Materials.

Graphene oxide and functionalized graphenic materials (FGMs) have promise as platforms for imparting programmable bioactivity to poly(methyl methacrylate) (PMMA)-based bone cement. To date, however, graphenic fillers have only been feasible in PMMA cements at extremely low loadings, limiting the bioactive effects. At higher loadings, graphenic fillers decrease cement strength by aggregating and interfering with curing process. Here, these challenges are addressed by combining bioactive FGM fillers with a custom cement formulation. These cements contain an order of magnitude more graphenic filler than previous reports. Even at 1 wt% FGM, these cements have compressive strengths of 78- 88 MPa, flexural strengths of 74-81 MPa, and flexural stiffnesses of 1.8-1.9 GPa, surpassing the ASTM requirements for bone cement and competing with traditional PMMA cement. Further, by utilizing designer FGMs with programmed bioactivity, these cements demonstrate controlled release of osteogenic calcium ions (releasing a total of 5 ± 2 µmol of Ca2+ per gram of cement over 28 d) and stimulate a 290% increase in expression of alkaline phosphatase in human mesenchymal stem cells in vitro. Also, design criteria are described to guide creation of future generations of bone cements that utilize FGMs as platforms to achieve dynamic biological activity.

Injectable amine functionalized graphene and chondroitin sulfate hydrogel with potential for cartilage regeneration.

Damaged cartilage does not readily heal and often requires surgical intervention that only modestly improves outcomes. A synthetic material that could be injected and covalently crosslinked in situ to form a bioactive, mechanically robust scaffold that promotes stem cell chondrogenic differentiation holds promise for next-generation treatment of cartilage lesions. Here, Johnson-Claisen rearrangement chemistry was performed on graphene oxide (GO) to enable functionalization with a primary amine covalently bound to the graphenic backbone through a chemically stable linker. The primary amines are used to form covalent crosslinks with chondroitin sulfate, an important component of cartilage that promotes regeneration, to form a hydrogel (EDAG-CS). The EDAG-CS system gels in situ within 10 min, and the graphenic component imparts improved mechanical properties, including stiffness (320% increase) and toughness (70% increase). EDAG-CS hydrogels are highly porous, resistant to degradation, and enable the growth of human mesenchymal stem cells and their deposition of collagen matrix. This system has potential to improve clinical outcomes of patients with cartilage damage.

Covalently-controlled drug delivery via therapeutic methacrylic tissue adhesives.

Medical cyanoacrylate adhesives have the potential to eliminate the need for sutures but face challenges to widespread implementation due to their brittleness and release of formaldehyde upon degradation. To overcome these limitations, we used molecular design to create therapeutic methacrylic (TMA) monomers to impart tunable mechanical properties, decreased formaldehyde release, and covalently-controlled bioactivity to commercial cyanoacrylate adhesives. The small molecule therapeutics ibuprofen, acetaminophen, and benzocaine were covalently tethered to the carbonyl of methacrylate using anhydride, ester, and amide bonds. When these TMAs were incorporated into n-butyl cyanoacrylate (BCA) tissue adhesives, the resulting TMA-BCA materials provided release of the therapeutics across a range of time scales according to the reactivity of the tether bond to hydrolysis. The anhydride-tether TMA-BCA adhesive delivered ibuprofen on the same order of magnitude and time scale as topical medications (12 ± 6 mg per g adhesive after 3.4 h). TMA-BCA adhesives also produced less formaldehyde than standard BCA adhesive, showed promising cytocompatibility, and adhered effectively to porcine skin. Further, the anhydride, ester, and amide tether TMA-BCA adhesives exhibited a range of shear moduli, with those containing rigid aromatic amide groups being stiffer, and those with flexible alkyl segments being less stiff, which could enable these adhesives to be tailored to match the mechanical properties of target tissues. The amide-tether TMA-BCA adhesive also showed a 219% increase in toughness compared to BCA. Overall, TMAs represent a platform technology that can be used to build adaptable and bioactive tissue adhesives.

Graphene oxide as a scaffold for bone regeneration.

Graphene oxide (GO), the oxidized form of graphene, holds great potential as a component of biomedical devices, deriving utility from its ability to support a broad range of chemical functionalities and its exceptional mechanical, electronic, and thermal properties. GO composites can be tuned chemically to be biomimetic, and mechanically to be stiff yet strong. These unique properties make GO-based materials promising candidates as a scaffold for bone regeneration. However, questions still exist as to the compatibility and long-term toxicity of nanocarbon materials. Unlike other nanocarbons, GO is meta-stable, water dispersible, and autodegrades in water on the timescale of months to humic acid-like materials, the degradation products of all organic matter. Thus, GO offers better prospects for biological compatibility over other nanocarbons. Recently, many publications have demonstrated enhanced osteogenic performance of GO-containing composites. Ongoing work toward surface modification or coating strategies could be useful to minimize the inflammatory response and improve compatibility of GO as a component of medical devices. Furthermore, biomimetic modifications could offer mechanical and chemical environments that encourage osteogenesis. So long as care is given to assure their safety, GO-based materials may be poised to become the next generation scaffold for bone regeneration. WIREs Nanomed Nanobiotechnol 2017, 9:e1437. doi: 10.1002/wnan.1437 For further resources related to this article, please visit the WIREs website.

Further evaluation of quantitative structure--activity relationship models for the prediction of the skin sensitization potency of selected fragrance allergens.

Fragrance substances represent a very diverse group of chemicals; a proportion of them are associated with the ability to cause allergic reactions in the skin. Efforts to find substitute materials are hindered by the need to undertake animal testing for determining both skin sensitization hazard and potency. One strategy to avoid such testing is through an understanding of the relationships between chemical structure and skin sensitization, so-called structure-activity relationships. In recent work, we evaluated 2 groups of fragrance chemicals -- saturated aldehydes and alpha,beta-unsaturated aldehydes. Simple quantitative structure-activity relationship (QSAR) models relating the EC3 values [derived from the local lymph node assay (LLNA)] to physicochemical properties were developed for both sets of aldehydes. In the current study, we evaluated an additional group of carbonyl-containing compounds to test the predictive power of the developed QSARs and to extend their scope. The QSAR models were used to predict EC3 values of 10 newly selected compounds. Local lymph node assay data generated for these compounds demonstrated that the original QSARs were fairly accurate, but still required improvement. Development of these QSAR models has provided us with a better understanding of the potential mechanisms of action for aldehydes, and hence how to avoid or limit allergy. Knowledge generated from this work is being incorporated into new/improved rules for sensitization in the expert toxicity prediction system, deductive estimation of risk from existing knowledge (DEREK).

Investigation of the skin sensitizing activity of linalool.

An increasing range of chemicals appears to be capable of causing skin sensitization as a result of their capacity to undergo air oxidation (autoxidation) with the consequent formation of reactive species such as epoxides and hydroperoxides. In this small investigation, the ability of linalool, a common fragrance ingredient, to cause such effects was quantified using the local lymph node assay before and after careful purification by vacuum distillation. The commercially available grade of linalool (97% purity) was shown to be a weak skin sensitizer. Various impurities, including linalool oxide, dihydrolinalool, epoxylinalool, 3-hexenyl butyrate and 3,7-dimethyl-1,7-octadiene-3,6-diol were identified and were completely removed (except for the dihydrolinalool remaining at 1.4%) and the re-purified linalool retested. Neither linalool or dihydrolinalool are protein-reactive compounds. The sensitization potency of the re-purified linalool sample was considerably reduced, but not entirely eliminated, suggesting either that an allergenic impurity could be very quickly reformed by mechanisms of activation or that certain potent undetectable allergens remained. Both possibilities are consistent with what is understood of the chemistry and composition of commercially available linalool.