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Wound closure in surgeries is traditionally achieved using invasive methods such as sutures and staples. Adhesion-based wound closure methods such as tissue adhesives, sealants, and hemostats are slowly replacing these methods due to their ease of application. Although several chemistries have been developed and used commercially for wound closure, there is still a need for better tissue adhesives from the point of view of toxicity, wet-adhesion strength, and long-term bonding. Catechol chemistry has shown great promise in developing wet-set adhesives that meet these criteria. Herein, we have studied the biocompatibility of a catechol-based copolymer adhesive, poly([dopamine methacrylamide]-co-[methyl methacrylate]-co-[poly(ethylene glycol) methyl ether methacrylate]) or poly(catechol-MMA-OEG), which is soluble in water. The adhesive was injected subcutaneously in a mouse model on its own and in combination with a sodium periodate crosslinker. After 72 h, 4 weeks, and 12 weeks, the mice were euthanized and subjected to histopathological analysis. Both adhesives were present and still palpable at the end of 12 weeks. The moderate inflammation observed for the poly(catechol-MMA-OEG) cohort at 72 h had reduced to mild inflammation at the end of 12 weeks. However, the moderate inflammatory response observed for the poly(catechol-MMA-OEG) + crosslinker cohort at 72 h had not subsided at 12 weeks.
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Achieving robust underwater adhesion remains challenging. Through generations of evolution, marine mussels have developed an adhesive system that allows them to anchor onto wet surfaces. Scientists have taken varied approaches to developing mussel-inspired adhesives. Mussel foot proteins are rich in lysine residues, which may play a role in the removal of salts from surfaces. Displacement of water and ions on substrates could then enable molecular contact with surfaces. The necessity of cations for underwater adhesion is still in debate. Here, we examined the performance of a methacrylate polymer containing quaternary ammonium and catechol groups. Varying amounts of charge in the polymers were studied. As opposed to protonated amines such as lysine, quaternary ammonium groups offer a nonreactive cation for isolating effects from only charge. Results shown for dry bonding demonstrated that cations tended to decrease bulk cohesion while increasing surface interactions. Stronger interactions at surfaces, along with weaker bulk bonding, indicate that cations decreased the cohesive forces. When under salt water, overall bulk adhesion also dropped with higher cation loadings. Surface attachment under salt water also dropped, indicating that the polymer cations could not displace surface waters or sodium ions. Salt did, however, appear to shield bulk cation-cation repulsions. These studies help to distinguish influences upon bulk cohesion from attachment at surfaces. The roles of cations in adhesion are complex, with both cohesive and surface bonding being relevant in different ways, sometimes even working in opposite directions.
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BACKGROUND: Ex vivo lung perfusion (EVLP) has expanded the donor pool for lung transplantation. Pulmonary Staphylococcus aureus infection, especially that caused by multidrug-resistant strains, is a severe threat to posttransplantation outcomes. Sphingosine is a lipid compound that exhibits broad-spectrum antibacterial activity. Therefore, we aimed to evaluate the effects of S aureus infection on EVLP and whether sphingosine administration during EVLP prevents infection with S aureus. METHODS: Eighteen pigs were randomly assigned to 3 groups: uninfected, infected with S aureus with NaCl treatment, or infected with sphingosine treatment. Bacterial numbers were determined before and after treatment. Sphingosine concentrations in the lung tissues were determined using biochemical assays. Lung histology, lung physiological parameters, perfusate content, lung weight, and cell death were measured to analyze the effects of infection and sphingosine administration on EVLP. RESULTS: Sphingosine administration significantly reduced the bacterial load. The concentration of sphingosine in the bronchial epithelium was elevated after sphingosine administration. S aureus infection increased pulmonary artery pressure and pulmonary vascular resistance. Lung edema, histology scores, lactate and lactate dehydrogenase levels in the perfusate, ΔPO2 in the perfusate, static lung compliance, and lung peak airway pressure did not differ among the groups. CONCLUSIONS: Infection of S aureus did not affect the lung function during EVLP but induced higher pulmonary artery pressure and pulmonary vascular resistance. Administration of sphingosine effectively eliminated S aureus without side effects in isolated, perfused, and ventilated pig lungs.
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Transplante de Pulmão , Esfingosina , Suínos , Animais , Esfingosina/farmacologia , Staphylococcus aureus , Perfusão , Pulmão , Circulação ExtracorpóreaRESUMO
Sea squirts' or tunicates' bodies are composed of cellulose nanofibers and gallol- functionalized proteins. These sea creatures are known to heal their injuries under seawater by forming crosslinks between gallols and functional groups from other proteins in their bodies. Inspired by their wound healing mechanism, herein, we have developed a tissue sealant using zein (a plant-based protein) and tannic acid (gallol-containing polyphenol). Except for fibrin- based sealants, most commercial surgical adhesives, and sealants available today are derived from petroleum products that compromise their biodegradability. They often have complicated and multi-step synthesis processes that ultimately affect their affordability. To overcome this challenge, we ensured that these sea squirt-inspired tissue sealants are bio-based, easily synthesized, and low-cost. The sealants were studied on their own and with a food-grade enzyme transglutaminase. The adhesion performances of the sealants were found to be higher than physiological pressures in seven out of nine different tissue substrates studied here. Their performance was also better than or on par with the FDA-approved fibrin sealant Tisseel. Ex vivo models demonstrate instant sealing of leaking wounds in less than a minute. The sealants were not only cytocompatible but also showed complete wound healing on par with sutures and Tisseel when applied in vivo on skin incisions in rats. Overall, these sea squirt-inspired bio-based sealants show great potential to replace currently available wound closure methods.
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Nearly all adhesives1,2 are derived from petroleum, create permanent bonds3, frustrate materials separation for recycling4,5 and prevent degradation in landfills. When trying to shift from petroleum feedstocks to a sustainable materials ecosystem, available options suffer from low performance, high cost or lack of availability at the required scales. Here we present a sustainably sourced adhesive system, made from epoxidized soy oil, malic acid and tannic acid, with performance comparable to that of current industrial products. Joints can be cured under conditions ranging from use of a hair dryer for 5 min to an oven at 180 °C for 24 h. Adhesion between metal substrates up to around 18 MPa is achieved, and, in the best cases, performance exceeds that of a classic epoxy, the strongest modern adhesive. All components are biomass derived, low cost and already available in large quantities. Manufacturing at scale can be a simple matter of mixing and heating, suggesting that this new adhesive may contribute towards the sustainable bonding of materials.
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Herein are presented several adhesive formulations made from zein protein and tannic acid that can bind to a wide range of surfaces underwater. Higher performance comes from more tannic acid than zein, whereas dry bonding required the opposite case of more zein than tannic acid. Each adhesive works best in the environment that it was designed and optimized for. We show underwater adhesion experiments done on different substrates and in different waters (sea water, saline solution, tap water, deionized water). Surprisingly, the water type does not influence the performance to a great deal but the substrate type does. An additional unexpected result was bond strength increasing over time when exposed to water, contradicting general experiments of working with glues. Initial adhesion underwater was stronger compared to benchtop adhesion, suggesting that water helps to make the glue stick. Temperature effects were determined, indicating maximum bonding at about 30 °C and then another increase at higher temperatures. Once the adhesive was placed underwater, a protective skin formed on the surface, keeping water from entering the rest of the material immediately. The shape of the adhesive could be manipulated easily and, once in place, the skin could be broken to induce faster bond formation. Data indicated that underwater adhesion was predominantly induced by tannic acid, cross-linking within the bulk for adhesion and to the substrate surfaces. The zein protein provided a less polar matrix that helped to keep the tannic acid molecules in place. These studies provide new plant-based adhesives for working underwater and for creating a more sustainable environment.
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Adesivos , Zeína , Adesivos/química , Zeína/química , Proteínas , Água/químicaRESUMO
Surgical adhesives can be useful in wound closure because they reduce the risk of infection and pain associated with sutures and staples. However, there are no commercially available surgical adhesives for soft tissue wound closure. To be effective, soft tissue adhesives must be soft and flexible, strongly cohesive and adhesive, biocompatible, and effective in a moist environment. To address these criteria, we draw inspiration from the elasticity and resilience of elastin proteins and the adhesive of marine mussels. We used an elastin-like polypeptide (ELP) for the backbone of our adhesive material due to its elasticity and biocompatibility. A mussel-inspired adhesive molecule, l-3,4-dihydroxyphenylalanine (DOPA), was incorporated into the adhesive to confer wet-setting adhesion. In this study, an ELP named YKV was designed to include tyrosine residues and lysine residues, which contain amine groups. A modified version of YKV, named mYKV, was created through enzymatic conversion of tyrosine residues into DOPA. The ELPs were combined with iron(III) nitrate, sodium periodate, and/or tris(hydroxymethyl)phosphine (THP) cross-linkers to investigate the effect of DOPA- and amine-based cross-linking on adhesion strength and cure time on porcine skin in a warm, humid environment. Incorporation of DOPA into the ELP increased adhesive strength by 2.5 times and reduced failure rates. Iron cross-linkers improved adhesion in the presence of DOPA. THP increased adhesion for all proteins tested even in the absence of DOPA. Using multiple cross-linkers in a single formulation did not significantly improve adhesion. The adhesives with the highest performance (iron nitrate mixed with mYKV and THP mixed with YKV or mYKV) on porcine skin had 10-18 times higher adhesion than a commercial sealant and reached appreciable adhesive strength within 10 min.
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Adesivos , Elastina , Adesivos/farmacologia , Animais , Di-Hidroxifenilalanina/química , Compostos Férricos , Ferro/química , Nitratos , Peptídeos/farmacologia , SuínosRESUMO
Incorporating catechols into polymers can provide strong adhesion even in moist environments, and these polymers show promise for use in several biomedical applications. Surgical adhesives must have strong bonds, be biocompatible, and function in a moist environment. Poly(lactic acid) (PLA) has a long history as a biocompatible material for hard tissue device fixation. By combining these concepts, catechol-containing poly(lactic acid) (cPLA) polymers are created that are strongly adhesive and degrade in physiological environments. Here, we evaluated the cytocompatibility of cPLA with iron(III) or periodate (IO4- ) cross-linkers. Fibroblasts cultured in cPLA leachate or on cPLA films generally had slower growth and lower metabolism compared with PLA controls but no differences in viability. These results demonstrated that cPLA was not cytotoxic but that including catechols reduced cell health. When cPLA was cross-linked with periodate, cells generally had reduced metabolism, slower cell growth, and poor actin fiber formation compared with PLA. These results are attributed to the cytotoxicity of periodate since cells cultured with periodate leachate had extremely low viability. Cells grown on the films of iron-cross-linked cPLA generally had high viability and metabolism but slower proliferation than PLA controls. These results indicate that the cPLA and iron-cross-linked cPLA systems are promising materials for biomedical adhesive applications.
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Adesivos , Bivalves , Adesivos/química , Animais , Bivalves/química , Compostos Férricos , Poliésteres/farmacologiaRESUMO
Mussels use microfluidic assembly and vanadium to create an adhesive that anchors them in their natural environment.
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Metais , Fenômenos FísicosRESUMO
Adhesive bonding is commonly used to replace mechanical fasteners in many applications. However, the surface chemistry of different substrates varies, making adhesion to a variety of materials difficult. Many biological adhesives are adept at sticking to multiple surfaces with a range of surface chemistries. Marine mussels utilize a catechol moiety within their adhesive proteins to bring about surface binding as well as cohesive cross-linking. Mimicking this functionality in synthetic polymers has yielded high strength adhesives that can attach to both high and low surface energy materials, although not equally well. Here, the amount of catechol within a copolymer system was varied for potential tailoring to specific surfaces. Structure-function studies revealed differing trends of optimal catechol content for high energy aluminum versus low energy polytetrafluoroethylene (TeflonTM) surfaces. Adhesion strengths were optimized with â¼10 mol% catechol for aluminum and â¼41 mol% for TeflonTM. Varying the catechol incorporation also resulted in changes to wettability, failure modes, and mechanics on these substrates. When considering performance of the entire bulk material, the different surfaces required an altered adhesive-cohesive balance. Tailoring the composition of polymeric adhesives for different surfaces may aid future manufacturing in cases where joining a variety of materials is required.
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Animals incorporate metals within the materials they manufacture, such as protective armor and teeth. Iron is an element used for adding strength and self-healing properties to load-bearing materials. Incorporation of iron is found beyond hard, brittle materials, even within the soft adhesive produced by marine mussels. Such findings suggest that the bioavailability of iron may have an influence on the properties of a biological material. Experiments were conducted using live mussels in which seawater iron levels were deficient, normal, or in excess of typical concentrations. The weakest adhesive strengths were produced in iron-deficient waters. Increasing seawater iron brought about more robust bonding. Changes in strengths correlated with varied adhesive morphology, color, and microstructural features, likely a result of variations in the degree of iron-induced protein cross-linking. This study provides the first whole animal scale data on how the manipulation of bioavailable iron influences the performance of a biological material. Changing ocean chemistries will alter the iron bioavailability when a decrease in pH shifts elemental speciation from particulate to dissolved, hindering the ability of filtering organisms to capture nutrients. These results show future implications of changing ocean chemistry as well as of the resulting abilities of marine organisms to construct essential materials.
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Mytilus edulis , Adesivos , Animais , Disponibilidade Biológica , Ferro , Metais , Água do MarRESUMO
Developing future high performance adhesives is predicated upon achieving properties including strength and ductility. However, designing tough materials that are simultaneously strong and soft is usually contradictory in nature. Biological materials including shells and wood achieve impressive toughness by using weak bonds to connect larger structures at several length scales. Here, we show that this toughness design approach can be applied to synthetic adhesives. A biomimetic adhesive polymer, poly(catechol-acrylic acid), was examined in conjunction with several compounds containing two organic functional groups. In a typical example, the diol ethylene glycol decreased the overall system modulus. Performance was seen to increase significantly. Spectroscopic and physical methods indicated that these bifunctional additives created an interpolymeric network of weak hydrogen bonds. Material toughness was enhanced when breakable bonds were available to dissipate mechanical stresses while leaving the surrounding matrix intact. These discoveries illustrate how a biological materials strategy of interplay between strength and ductility can be achieved with sacrificial bonds in an adhesive. Such an approach may be a general principle applicable to designing higher performance electronics, transportation, and aerospace systems.
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Resinas Acrílicas/química , Adesivos/química , Materiais Biomiméticos/química , Catecóis/química , Ligação de HidrogênioRESUMO
Antifouling properties of materials play crucial roles in many important applications such as biomedical implants, marine antifouling coatings, biosensing, and membranes for separation. Poly(ethylene glycol) (or PEG) containing polymers and zwitterionic polymers have been shown to be excellent antifouling materials. It is believed that their outstanding antifouling activity comes from their strong surface hydration. On the other hand, it is difficult to develop underwater glues, although adhesives with strong adhesion in a dry environment are widely available. This is related to dehydration, which is important for adhesion for many cases while water is the enemy of adhesion. In this research, we applied sum frequency generation (SFG) vibrational spectroscopy to investigate buried interfaces between mussel adhesive plaques and a variety of materials including antifouling polymers and control samples, supplemented by studies on marine animal (mussel) behavior and adhesion measurements. It was found that PEG containing polymers and zwitterionic polymers have very strong surface hydration in an aqueous environment, which is the key for their excellent antifouling performance. Because of the strong surface hydration, mussels do not settle on these surfaces even after binding to the surfaces with rubber bands. For control samples, SFG results indicate that their surface hydration is much weaker, and therefore mussels can generate adhesives to displace water to cause dehydration at the interface. Because of the dehydration, mussels can foul on the surfaces of these control materials. Our experiments also showed that if mussels were forced to deposit adhesives onto the PEG containing polymers and zwitterionic polymers, interfacial dehydration did not occur. However, even with the strong interfacial hydration, strong adhesion between mussel adhesives and antifouling polymer surfaces was detected, showing that under certain circumstances, interfacial water could enhance the interfacial bio-adhesion.
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In prior generations, proteins were taken from horses and other animals to make glues. Petroleum-derived polymers including epoxies and cyanoacrylates have since replaced proteins owing to improved performance. These modern materials come at a cost of toxicity as well as being derived from limited resources. Ideally, replacement adhesives will be made from benign, cheap, and renewable feedstocks. Such a transition to biobased materials, however, will not occur until similar or improved performance can be achieved. We have discovered that coupling of proteins and sugars gives rise to strong adhesives. An unexpected connection was made between adhesion and Maillard chemistry, known to be at the heart of cooking foods. Cross-linked proteins bonded metal and wood with high strengths, in some cases showing forces exceeding those withstood by the substrates themselves. Simple cooking chemistry may provide a route to future high-performance materials derived from low-cost, environmentally benign components.
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Adesivos/química , Ácido Ascórbico/química , Soroalbumina Bovina/química , Proteínas de Soja/química , Adesividade , Adesivos/síntese química , Animais , Bovinos , Calefação , Lisina/química , Reação de Maillard , Solubilidade , Glycine max , ViscosidadeRESUMO
The cement produced by the Eastern oyster, Crassostrea virginica, may provide blueprints for waterproof biocompatible adhesives synthesized under benign conditions. The composition of this organic-inorganic composite, and of an organic extract, was characterized by 13C and 1H solid-state NMR and also compared with C. virginica shell and its organic extract. Quantification of the organic fraction by 13C and 1H NMR spectroscopy consistently showed 3 wt % organics in cement, which was higher than the 1.2 wt % in the shell. According to 13C NMR with spectral editing, the organic fraction of cement consisted of 73% protein, 25% polysaccharide, and 2% lipid. The organic acid-insoluble extract from the cement was mostly made up of protein remarkably rich in alanine and glycine. The unusual amino acid content matched the composition of silk-like proteins in the C. virginica or C. gigas genomes, including spidron-1-like and shelk2 previously found to be upregulated at the mantle edge. The corresponding extract from the shell contained 32% glycine and was also enriched in serine but not alanine, which was consistent with a previous wet-chemistry study. The 13C and 1H NMR spin-lattice relaxation in the organic component of cement and the acid-insoluble extract was 4-40 times faster than in the shell and showed pronounced nonexponentiality, indicating a high concentration of persistent radicals in the organic components of cement, in agreement with a prior EPR study. The presence of radicals in the acid-insoluble cement fraction was confirmed by observation of a paramagnetic shift anisotropy. 13C NMR corroborated prior observations that the calcium carbonate in the shell and pseudonacre was mostly calcite, whereas cement had an enhanced aragonite fraction. Surprisingly, 1H-13C NMR indicated that aragonite in cement was more distant from the organic fraction than was calcite. These results help advance our understanding of how oysters achieve adhesion within their wet environment.
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Many protein-based materials, such as soy and mussel adhesive proteins, have been the subject of scientific and commercial interest. Recently, a variety of protein adhesives have been isolated from diverse sources such as insects, frogs and squid ring teeth. Many of these adhesives have similar amino acid compositions to elastomeric proteins such as elastin. Although elastin is widely investigated for a structural biomaterial, little work has been done to assess its adhesive potential. In this study, recombinant elastin-like polypeptides were created to probe the factors affecting adhesion strength. Lap shear adhesion was used to examine the effects of both extrinsic factors (pH, concentration, cross-linker, humidity, cure time and cure temperature) and intrinsic factors (protein sequence, structure and molecular weight). Of the extrinsic factors tested, only humidity, cure time and cure temperature had a significant effect on adhesion strength. As water content was reduced, adhesion strength increased. Of the intrinsic factors tested, amino acid sequence did not significantly affect adhesion strength, but less protein structure and higher molecular weights increased adhesion strength directly. The strengths of proteins in this study (greater than 2 MPa) were comparable to or higher than those of two commercially available protein-based adhesives, hide glue and a fibrin sealant. These results may provide general rules for the design of adhesives from elastomeric proteins.
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Oysters construct extensive reef communities, providing food, protection from storms, and healthy coastlines. We still do not have a clear picture of how these animals attach to surfaces. Efforts described herein provide the first examination of adhesion at the transition from free swimming larvae to initial substrate attachment, through metamorphosis, and on to adulthood. Two different bonding systems were found to coexist. Larvae use an organic, hydrated glue that persists while the animal progresses into the juvenile phase, at which point a very different adhesive emerges. Juveniles bond with an organic-inorganic composite system, positioning the organic component for maximum adhesion by residing between the animal and substrate. Beyond understanding our marine environment, these insights may aid efforts in aquaculture, reef restoration, and adhesive design.
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Ostreidae , Adesivos , Envelhecimento , Animais , Cimentação , LarvaRESUMO
The development of adhesives that can be applied and create strong bonds underwater is a significant challenge for materials engineering. When the adhesive is intended for biomedical applications, further criteria, such as biocompatibility, must be met. Current biomedical adhesive technologies do not meet these needs. In response, we designed a bioinspired protein system that shows promise to achieve biocompatible underwater adhesion coupled with environmentally responsive behavior that is "smart" - that is, it can be tuned to suit a specific application. The material, ELY16, is constructed from an elastin-like polypeptide (ELP) that can be produced in high yields from Escherichia coli and can coacervate in response to environmental factors such as temperature, pH, and salinity. To confer wet adhesion, we utilized design principles from marine organisms such as mussels and sandcastle worms. When expressed, ELY16 is rich in tyrosine. Upon modification with the tyrosinase enzyme to form mELY16, the tyrosine residues are converted to 3,4-dihydroxyphenylalanine (DOPA). Both ELY16 and mELY16 exhibit cytocompatibility and significant dry adhesion strength (>2 MPa). Modification with DOPA increases protein adsorption to glass and provides moderate adhesion strength (â¼240 kPa) in a highly humid environment. Furthermore, this ELP exhibits a tunable phase transition behavior that can be formulated to coacervate in physiological conditions and provides a convenient mechanism for application underwater. Finally, mELY16 possesses significantly higher adhesion strength in dry, humid, and underwater environments compared with a commercially available fibrin sealant. To our knowledge, mELY16 provides the strongest bonds of any rationally designed protein when used completely underwater, and its high yields make it more viable for commercial application compared to natural adhesive proteins. In conclusion, this ELP shows great potential to be a new "smart" underwater adhesive.
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Adesivos/química , Materiais Biocompatíveis/química , Materiais Biomiméticos/química , Elastina/química , Proteínas de Escherichia coli/química , Água/química , Adesividade , Imersão , Teste de Materiais , Engenharia de Proteínas/métodos , Resistência à TraçãoRESUMO
When it comes to underwater adhesion, shellfish are the true experts. Mussels, barnacles, and oysters attach to rocks with apparent ease. Yet our man-made glues often fail when trying to stick in wet environments. Results described herein focus on a copolymer mimic of mussel adhesive proteins, poly(catechol-styrene). Underwater bonding was examined as a function of parameters including polymer molecular weight and composition. In doing so, several surprising results emerged. Poly(catechol-styrene) may be the strongest underwater adhesive found to date. Bonding even exceeded that of the reference biological system, live mussels. Adhesion was also found to be stronger under salt water than deionized water. Such unexpected findings may contradict an earlier proposal in which charged amino acids were suggested to be key for mussel adhesive function. Taken together, these discoveries are helping us to both understand biological adhesion as well as develop new materials with properties not accessed previously.