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1.  Patterning discrete stem cell culture environments via localized SAM replacement 
Self-assembled monolayers (SAMs) of alkanethiolates on gold have become an important tool for probing cell-material interactions. Emerging studies in stem cell biology are particularly reliant on well-defined model substrates, and rapid and highly controllable fabrication methods may be necessary to characterize the wide array of stem cell-material interactions. Therefore, this study describes a rapid method to create SAM cell culture substrates with multiple discrete regions of controlled peptide identity and density. The approach uses an NaBH4 solution to selectively remove regions of bio-inert, hydroxyl-terminated oligo(ethylene glycol) alkanethiolate SAM, then locally replace them with mixed SAMs of hydroxyl- and carboxylic acid-terminated oligo(ethylene glycol) alkanethiolates. The cell adhesion peptide Arg-Gly-Asp-Ser-Pro (RGDSP) was then covalently linked to carboxylic acid-terminated mixed SAM regions to create cell adhesive environments within a bio-inert background. SAM preparation and peptide immobilization were characterized using polarization modulation–infrared reflection-absorption spectroscopy (PMIRRAS), as well as assays to monitor conjugation of a fluorescently-labeled peptide. This “localized SAM replacement” method was achieved using an array of microchannels, which facilitated rapid and simple processing. Results indicate that immobilized RGDSP promoted spatially localized attachment of human mesenchymal stem cells (hMSCs) within specified regions, while maintaining a stable, bio-inert background in serum-containing cell culture conditions for up to 14 days. Cell attachment to patterned regions presenting a range of cell adhesion peptide densities demonstrated that peptide identity and density strongly influence hMSC spreading and focal adhesion density. These substrates contain discrete, well-defined microenvironments for stem cell culture, which could ultimately enable high-throughput screening for the effects of immobilized signals on stem cell phenotype.
doi:10.1021/la901938e
PMCID: PMC2769026  PMID: 19856996
2.  Solid-State Densification of Spun-Cast Self-Assembled Monolayers for Use in Ultra-Thin Hybrid Dielectrics 
Applied surface science  2012;261:10.1016/j.apsusc.2012.09.013.
Ultra-thin self-assembled monolayer (SAM)-oxide hybrid dielectrics have gained significant interest for their application in low-voltage organic thin film transistors (OTFTs). A [8-(11-phenoxy-undecyloxy)-octyl]phosphonic acid (PhO-19-PA) SAM on ultrathin AlOx (2.5 nm) has been developed to significantly enhance the dielectric performance of inorganic oxides through reduction of leakage current while maintaining similar capacitance to the underlying oxide structure. Rapid processing of this SAM in ambient conditions is achieved by spin coating, however, as-cast monolayer density is not sufficient for dielectric applications. Thermal annealing of a bulk spun-cast PhO-19-PA molecular film is explored as a mechanism for SAM densification. SAM density, or surface coverage, and order are examined as a function of annealing temperature. These SAM characteristics are probed through atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and near edge X-ray absorption fine structure spectroscopy (NEXAFS). It is found that at temperatures sufficient to melt the as-cast bulk molecular film, SAM densification is achieved; leading to a rapid processing technique for high performance SAM-oxide hybrid dielectric systems utilizing a single wet processing step. To demonstrate low-voltage devices based on this hybrid dielectric (with leakage current density of 7.7×10−8 A cm−2 and capacitance density of 0.62 µF cm−2 at 3 V), pentacene thin-film transistors (OTFTs) are fabricated and yield sub 2 V operation and charge carrier mobilites of up to 1.1 cm2 V−1 s−1.
doi:10.1016/j.apsusc.2012.09.013
PMCID: PMC3840438  PMID: 24288423
Self Assembled Monolayer (SAM); SAM Dielectric; Hybrid Dielectric; SAM Processing; Organic Field Effect Transistor (OFET); Organic Thin Film Transistor (OTFT)
3.  Fabrication and in vitro deployment of a laser-activated shape memory polymer vascular stent 
Background
Vascular stents are small tubular scaffolds used in the treatment of arterial stenosis (narrowing of the vessel). Most vascular stents are metallic and are deployed either by balloon expansion or by self-expansion. A shape memory polymer (SMP) stent may enhance flexibility, compliance, and drug elution compared to its current metallic counterparts. The purpose of this study was to describe the fabrication of a laser-activated SMP stent and demonstrate photothermal expansion of the stent in an in vitro artery model.
Methods
A novel SMP stent was fabricated from thermoplastic polyurethane. A solid SMP tube formed by dip coating a stainless steel pin was laser-etched to create the mesh pattern of the finished stent. The stent was crimped over a fiber-optic cylindrical light diffuser coupled to an infrared diode laser. Photothermal actuation of the stent was performed in a water-filled mock artery.
Results
At a physiological flow rate, the stent did not fully expand at the maximum laser power (8.6 W) due to convective cooling. However, under zero flow, simulating the technique of endovascular flow occlusion, complete laser actuation was achieved in the mock artery at a laser power of ~8 W.
Conclusion
We have shown the design and fabrication of an SMP stent and a means of light delivery for photothermal actuation. Though further studies are required to optimize the device and assess thermal tissue damage, photothermal actuation of the SMP stent was demonstrated.
doi:10.1186/1475-925X-6-43
PMCID: PMC2211751  PMID: 18042294
4.  Assessing the plasmonics of gold nano-triangles with higher order laser modes 
Summary
Regular arrays of metallic nano-triangles – so called Fischer patterns – are fabricated by nano-sphere lithography. We studied such gold nano-triangle arrays on silicon or glass substrates. A series of different samples was investigated with a parabolic mirror based confocal microscope where the sample is scanned through the laser focus. By employing higher order laser modes (azimuthally and radially polarised laser beams), we can excite the Fischer patterns using either a pure in-plane (x,y) electric field or a strongly z-directional (optical axis of the optical microscope) electric field. We collected and evaluated the emitted luminescence and thereby investigated the respectively excited plasmonic modes. These varied considerably: firstly with the light polarisation in the focus, secondly with the aspect ratio of the triangles and thirdly with the employed substrate. Moreover, we obtained strongly enhanced Raman spectra of an adenine (sub-)monolayer on gold Fischer patterns on glass. We thus showed that gold Fischer patterns are promising surface-enhanced Raman scattering (SERS) substrates.
doi:10.3762/bjnano.3.77
PMCID: PMC3512117  PMID: 23213631
Fischer pattern; higher order laser modes; localised surface plasmons; near field; surface-enhanced Raman scattering
5.  Patterned Self-Assembled Monolayers: Efficient, Chemically Defined Tools for Cell Biology 
Self-assembled monolayers (SAMs) of alkanethiolates on gold can be used to carefully probe immobilized biomolecule interactions with cell-surface receptors. However, due to a lack of experimental throughput associated with labor-intensive production, specialized fabrication apparatus, and other practical challenges, alkanethiolate SAMs have not had widespread use by biological researchers. In this Minireview, we investigate a range of techniques that could enhance the throughput of SAM-based approaches by patterning substrates with arrays of different conditions. Here we highlight microfluidic, photochemical, localized removal, and backfilling techniques to locally pattern SAM substrates with biomolecules and also describe how these approaches have been applied in SAM-based screening systems. Furthermore we provide perspectives on several crucial barriers that need to be overcome to enable widespread use of SAM chemistry in biological applications.
doi:10.1002/cbic.201200226
PMCID: PMC3995495  PMID: 22807236
alkanethiolates; arrays; patterning; peptides; self-assembled monolayers
6.  Microwave-Accelerated Surface Modification of Plasmonic Gold Thin Films with Self-Assembled Monolayers of Alkanethiols 
A rapid surface modification technique for the formation of self-assembled monolayers (SAMs) of alkanethiols on gold thin films using microwave heating in less than 10 min is reported. In this regard, SAMs of two model alkanethiols, 11-mercaptoundecanoic acid (11-MUDA, to generate a hydrophilic surface) and undecanethiol (UDET, a hydrophobic surface), were successfully formed on gold thin films using selective microwave heating in 1) a semi-continuous and 2) a continuous fashion and at room temperature (24 hours, control experiment, no microwave heating). The formation of SAMs of 11-MUDA and UDET were confirmed by contact angle measurements, Fourier–transform infrared (FT-IR) spectroscopy and X-ray photoelectron spectroscopy (XPS). The contact angles for water on SAMs formed by the selective microwave heating and conventional room temperature incubation technique (24 hours) were measured to be similar for 11-MUDA and UDET. FT-IR spectroscopy results confirmed that the internal structure of SAMs prepared using both microwave heating and at room temperature were similar. XPS results revealed that the organic and sulfate contaminants found on bare gold thin films were replaced by SAMs after the surface modification process was carried out using both microwave heating and at room temperature.
doi:10.1021/la402455x
PMCID: PMC3863588  PMID: 24083414
Alkanethiols; self-assembled monolayers; gold thin films; surface plasmon resonance; surface plasmon fluorescence spectroscopy; microwave-induced temperature gradients
7.  In vitro and in vivo mapping of drug release after laser ablation thermal therapy with doxorubicin-loaded hollow gold nanoshells using fluorescence and photoacoustic imaging 
Doxorubicin-loaded hollow nanoshells (Dox@PEG-HAuNS) increases the efficacy of photothermal ablation (PTA) by not only mediating efficient PTA but also through chemotherapy, and therefore have potential utility for local anticancer therapy. However, in vivo real-time monitoring of Dox release and temperature achieved during the laser ablation technique has not been previously demonstrated before. In this study, we used fluorescence optical imaging to map the release of Dox from Dox@PEG-HAuNS and photoacoustic imaging to monitor the tumor temperature achieved during near-infrared laser–induced photothermal heating in vitro and in vivo. In vitro, treatment with a 3-W laser was sufficient to initiate the release of Dox from Dox@PEG-HAuNS (1:3:1 wt/wt, 1.32×1012 particles/mL). Laser powers of 3 and 6 W achieved ablative temperatures of more than 50 °C. In 4T1 tumor–bearing nude mice that received intratumoral or intravenous injections of Dox@PEG-HAuNS, fluorescence optical imaging (emission wavelength = 600 nm, excitation wavelength = 500 nm) revealed that the fluorescence intensity in surface laser–treated tumors 24 h after treatment was significantly higher than that in untreated tumors (p=0.015 for intratumoral, p=0.008 for intravenous). Similar results were obtained using an interstitial laser to irradiate tumors following the intravenous injection of Dox@PEG-HAuNS (p=0.002 at t=24h). Photoacoustic imaging (acquisition wavelength = 800 nm) revealed that laser treatment caused a substantial increase in tumor temperature, from 37 °C to ablative temperatures of more than 50 °C. Ex vivo analysis revealed that the fluorescence intensity of laser-treated tumors was twice as high as that of untreated tumors (p=0.009). Histological analysis confirmed that intratumoral injection of Dox@PEG-HAuNS and laser treatment caused significantly more tumor necrosis compared to tumors that were not treated with laser (p<0.001). On the basis of these findings, we conclude that fluorescence optical imaging and photoacoustic imaging are promising approaches to assessing Dox release and monitoring temperature, respectively, after Dox@PEG-HAuNS–mediated thermal ablation therapy.
doi:10.1016/j.jconrel.2013.07.020
PMCID: PMC3853126  PMID: 23920038
targeted hollow gold nanoshells; magnetic resonance temperature imaging; photoacoustic imaging; near-infrared optical imaging; molecular imaging
8.  Near-Infrared Light Modulated Photothermal Effect Increases Vascular Perfusion and Enhances Polymeric Drug Delivery 
Hyperthermia, which is heating of the tumors above 43 °C for about 30 min, has been known to modulate vascular permeability for enhanced chemotherapy. However, it is not clear whether similar effects exists when temperature at tumor sites is elevated above 43 °C, such as temperature achieved in laser-induced photothermal ablation (PTA) therapy. Also, the effect of timing of chemotherapeutic drug administration following heating in the efficiency of drug delivery is not established. In this study, we investigated the impact of near infrared (NIR) laser irradiated anti-EGFR monoclonal antibody C225-conjugated hollow gold nanospheres (C225-HAuNS)on vascular permeability and subsequent tumor uptake of a water-soluble polymer using combined MRI, ultrasound and optical imaging approaches. Magnetic temperature imaging showed a maximum temperature of 65.2 ± 0.10 °C in A431 tumor xenograft of mice treated with C225-HAuNS plus laser and 47.0 ± 0.33 °C in tumors of mice treated with saline plus laser at 4W/cm2 for 3 min (control) at 2 mm from the light incident surface. Dynamic contrast enhanced (DCE) MRI demonstrated greater than 2-fold increase of DTPA-Gd in the initial area under the curve (IAUC90) in mice injected with C225-HAuNS and exposed to NIR laser compared with control mice at 3 min after laser treatment. Similarly, Power Doppler (PD) ultrasound revealed a 4- to 6-fold increase in percentage vascularization in mice treated with C225-HAuNS plus NIR laser compared to control mice and confirmed increased vascular perfusion immediately after laser treatment. Twenty-four hours later, the blood perfusion was shut down. On optical imaging, tumor uptake of PG-Gd-NIR813, which is the model polymeric drug used, was significantly higher (p-value < 0.05) in mice injected with PG-Gd-NIR813 at 5 min after laser treatment than in mice injected with PG-Gd-NIR813 at 24 h after laser treatment and the saline-treated mice. In conclusion, laser irradiation of tumors after intravenous injection of C255-HAuNS induces a thermally mediated modulation of the vascular perfusion, which enhances the delivery of polymeric drugs to the tumors at the time phototherapy is initiated.
doi:10.1016/j.jconrel.2011.06.030
PMCID: PMC3203335  PMID: 21763373
targeted hollow gold nanoshells; magnetic resonance temperature imaging; ultrasonography; near-infrared optical imaging; molecular imaging
9.  Polymer blend lithography: A versatile method to fabricate nanopatterned self-assembled monolayers 
Summary
A rapid and cost-effective lithographic method, polymer blend lithography (PBL), is reported to produce patterned self-assembled monolayers (SAM) on solid substrates featuring two or three different chemical functionalities. For the pattern generation we use the phase separation of two immiscible polymers in a blend solution during a spin-coating process. By controlling the spin-coating parameters and conditions, including the ambient atmosphere (humidity), the molar mass of the polystyrene (PS) and poly(methyl methacrylate) (PMMA), and the mass ratio between the two polymers in the blend solution, the formation of a purely lateral morphology (PS islands standing on the substrate while isolated in the PMMA matrix) can be reproducibly induced. Either of the formed phases (PS or PMMA) can be selectively dissolved afterwards, and the remaining phase can be used as a lift-off mask for the formation of a nanopatterned functional silane monolayer. This “monolayer copy” of the polymer phase morphology has a topographic contrast of about 1.3 nm. A demonstration of tuning of the PS island diameter is given by changing the molar mass of PS. Moreover, polymer blend lithography can provide the possibility of fabricating a surface with three different chemical components: This is demonstrated by inducing breath figures (evaporated condensed entity) at higher humidity during the spin-coating process. Here we demonstrate the formation of a lateral pattern consisting of regions covered with 1H,1H,2H,2H-perfluorodecyltrichlorosilane (FDTS) and (3-aminopropyl)triethoxysilane (APTES), and at the same time featuring regions of bare SiOx. The patterning process could be applied even on meter-sized substrates with various functional SAM molecules, making this process suitable for the rapid preparation of quasi two-dimensional nanopatterned functional substrates, e.g., for the template-controlled growth of ZnO nanostructures [1].
doi:10.3762/bjnano.3.71
PMCID: PMC3458608  PMID: 23019558
breath figure; nanopatterned template; polymer blend lithography (PBL); self-assembled monolayer (SAM); self assembly; spin coating; vapor phase
10.  The Design, Fabrication and Characterization of a Transparent Atom Chip 
Sensors (Basel, Switzerland)  2014;14(6):10292-10305.
This study describes the design and fabrication of transparent atom chips for atomic physics experiments. A fabrication process was developed to define the wire patterns on a transparent glass substrate to create the desired magnetic field for atom trapping experiments. An area on the chip was reserved for the optical access, so that the laser light can penetrate directly through the glass substrate for the laser cooling process. Furthermore, since the thermal conductivity of the glass substrate is poorer than other common materials for atom chip substrate, for example silicon, silicon carbide, aluminum nitride. Thus, heat dissipation copper blocks are designed on the front and back of the glass substrate to improve the electrical current conduction. The testing results showed that a maximum burnout current of 2 A was measured from the wire pattern (with a width of 100 μm and a height of 20 μm) without any heat dissipation design and it can increase to 2.5 A with a heat dissipation design on the front side of the atom chips. Therefore, heat dissipation copper blocks were designed and fabricated on the back of the glass substrate just under the wire patterns which increases the maximum burnout current to 4.5 A. Moreover, a maximum burnout current of 6 A was achieved when the entire backside glass substrate was recessed and a thicker copper block was electroplated, which meets most requirements of atomic physics experiments.
doi:10.3390/s140610292
PMCID: PMC4118404  PMID: 24922456
glass substrate; transparent atom chip; heat dissipation
11.  Monolayer-directed Assembly and Magnetic Properties of FePt Nanoparticles on Patterned Aluminum Oxide 
FePt nanoparticles (NPs) were assembled on aluminum oxide substrates, and their ferromagnetic properties were studied before and after thermal annealing. For the first time, phosph(on)ates were used as an adsorbate to form self-assembled monolayers (SAMs) on alumina to direct the assembly of NPs onto the surface. The Al2O3 substrates were functionalized with aminobutylphosphonic acid (ABP) or phosphonoundecanoic acid (PNDA) SAMs or with poly(ethyleneimine) (PEI) as a reference. FePt NPs assembled on all of these monolayers, but much less on unmodified Al2O3, which shows that ligand exchange at the NPs is the most likely mechanism of attachment. Proper modification of the Al2O3 surface and controlling the immersion time of the modified Al2O3 substrates into the FePt NP solution resulted in FePt NPs assembly with controlled NP density. Alumina substrates were patterned by microcontact printing using aminobutylphosphonic acid as the ink, allowing local NP assembly. Thermal annealing under reducing conditions (96%N2/4%H2) led to a phase change of the FePt NPs from the disordered FCC phase to the ordered FCT phase. This resulted in ferromagnetic behavior at room temperature. Such a process can potentially be applied in the fabrication of spintronic devices.
doi:10.3390/iijms11031162
PMCID: PMC2869229  PMID: 20480007
SAM; Al2O3; FePt; ferromagnetic; nanoparticle
12.  Immobilization of peptides with distinct biological activities onto stem cell culture substrates using orthogonal chemistries 
We have used the orthogonal carbodiimide condensation and Copper-catalyzed azide-alkyne “click” cycloaddition (CuAAC) reactions to prepare self-assembled monolayers that present distinct peptides to stem cells in a bio-inert background. The approach involved first forming mixed SAMs with three components: i) an azide-terminated hexaethylene glycol alkanethiolate (HS---EG6---N3), ii) a carboxylate-terminated hexaethylene glycol alkanethiolate (HS---EG6---COOH), and iii) a triethylene glycol alkanethiolate (HS---EG3). An acetylene-bearing peptide and an amine-terminated peptide were then immobilized to these substrates using a “click” CuAAC reaction and a carbodiimide condensation reaction, respectively. Polarization-modulated infrared reflectance-absorbance spectroscopic analysis demonstrated formation of well-ordered, close-packed SAMs, chemoselective conjugation of amine-terminated peptides to surface carboxylate groups, and subsequent conjugation of acetylene-terminated peptides to the azide groups on SAMs. Varying the mole fraction of HS---EG6---N3, HS---EG6---COOH, and HS---EG3 during SAM formation allowed for control over the densities of each peptide on the substrate. Substrates presenting varying surface densities of RGESP (a non-functional peptide), RGDSP (a cell adhesion peptide) or TYRSRKY (a heparin/heparan sulfate-binding peptide) were then used to characterize the relationship between peptide surface density and human mesenchymal stem cell (hMSC) adhesion. Results demonstrate that RGESP does not influence RGDSP-mediated adhesion of hMSCs, which indicates that a second peptide with distinct bio-activity can be immobilized alongside RGDSP to characterize the influence of two peptides on hMSC behavior. Our results also demonstrate that RGDSP and TYRSRKY act synergistically to promote hMSC adhesion in the absence of serum. Interestingly, heparin sequestered by TYRSRKY inhibits cell adhesion on substrates presenting RGDSP = 0.1% and > 0.1% TYRSRKY or RGDSP = 1% and > 0.5% TYRSRKY. Taken together, these results indicate that two peptides can be controllably presented to stem cells on the same otherwise bio-inert SAM substrate, and that multiple, distinct extracellular moieties act in concert to regulate hMSC adhesion.
doi:10.1021/la1008208
PMCID: PMC2860651  PMID: 20353153
13.  Role of Surface Chemistry in Protein Remodeling at the Cell-Material Interface 
PLoS ONE  2011;6(5):e19610.
Background
The cell-material interaction is a complex bi-directional and dynamic process that mimics to a certain extent the natural interactions of cells with the extracellular matrix. Cells tend to adhere and rearrange adsorbed extracellular matrix (ECM) proteins on the material surface in a fibril-like pattern. Afterwards, the ECM undergoes proteolytic degradation, which is a mechanism for the removal of the excess ECM usually approximated with remodeling. ECM remodeling is a dynamic process that consists of two opposite events: assembly and degradation.
Methodology/Principal Findings
This work investigates matrix protein dynamics on mixed self-assembled monolayers (SAMs) of –OH and –CH3 terminated alkanethiols. SAMs assembled on gold are highly ordered organic surfaces able to provide different chemical functionalities and well-controlled surface properties. Fibronectin (FN) was adsorbed on the different surfaces and quantified in terms of the adsorbed surface density, distribution and conformation. Initial cell adhesion and signaling on FN-coated SAMs were characterized via the formation of focal adhesions, integrin expression and phosphorylation of FAKs. Afterwards, the reorganization and secretion of FN was assessed. Finally, matrix degradation was followed via the expression of matrix metalloproteinases MMP2 and MMP9 and correlated with Runx2 levels. We show that matrix degradation at the cell material interface depends on surface chemistry in MMP-dependent way.
Conclusions/Significance
This work provides a broad overview of matrix remodeling at the cell-material interface, establishing correlations between surface chemistry, FN adsorption, cell adhesion and signaling, matrix reorganization and degradation. The reported findings improve our understanding of the role of surface chemistry as a key parameter in the design of new biomaterials. It demonstrates the ability of surface chemistry to direct proteolytic routes at the cell-material interface, which gains a distinct bioengineering interest as a new tool to trigger matrix degradation in different biomedical applications.
doi:10.1371/journal.pone.0019610
PMCID: PMC3090403  PMID: 21573010
14.  Using “click” chemistry to prepare SAM substrates to study stem cell adhesion 
We have used a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) “click” reaction to prepare self-assembled monolayers (SAMs) presenting the cell adhesion peptide Arg-Gly-Asp-Ser-Pro (RGDSP) in a bio-inert background. The surface preparation approach involved first forming mixed SAMs with an azide-terminated hexaethylene glycol alkanethiolate (HS---EG6---N3) and a triethylene glycol alkanethiolate (HS---EG3), then using the CuAAC reaction to immobilize an alkyne-terminated peptide. The mixed SAMs were classified as bio-inert, as SAMs comprised of 10 mole percent HS---EG6---N3 and 90 mole percent HS---EG3 showed minimal non-specific protein adsorption in solutions of 1 mg/ml lysozyme or 10% fetal bovine serum. The reaction between an acetylene-terminated peptide and an azide-terminated SAM proceeded rapidly and quantitatively in the presence of a Cu(I)-TBTA complex, displaying pseudo-first order kinetics with a rate constant of ∼ 0.2 min−1. Varying the ratio of HS---EG6---N3 to HS---EG3 during SAM formation allowed for control over the density of azide and, in turn, the density of RGDSP on the substrates. These substrates were therefore used to study the detailed relationship between RGDSP surface density and human mesenchymal stem cell (hMSC) adhesion, spreading, and focal adhesion complex formation, without interference from non-specifically adsorbed serum proteins. Results indicate that an RGDSP intermolecular spacing of 36 nm or less (≥ 0.01 mole percent on the surface) is sufficient for hMSC adhesion and a spacing of 11 nm or less (≥ 0.05 mole percent on the surface) is sufficient for cell spreading and focal adhesion complex formation. In total, our results demonstrate that CuAAC is a suitable mechanism for conjugating peptides to otherwise bio-inert SAMs, and that the resulting SAMs can be used to study the dependence of peptide density on stem cell behavior.
doi:10.1021/la804077t
PMCID: PMC2694954  PMID: 19326875
15.  A study of photothermal laser ablation of various polymers on microsecond time scales 
SpringerPlus  2014;3:489.
To analyze the photothermal ablation of polymers, we designed a temperature measurement setup based on spectral pyrometry. The setup allows to acquire 2D temperature distributions with 1 μm size and 1 μs time resolution and therefore the determination of the center temperature of a laser heating process. Finite element simulations were used to verify and understand the heat conversion and heat flow in the process. With this setup, the photothermal ablation of polystyrene, poly(α-methylstyrene), a polyimide and a triazene polymer was investigated. The thermal stability, the glass transition temperature Tg and the viscosity above Tg were governing the ablation process. Thermal decomposition for the applied laser pulse of about 10 μs started at temperatures similar to the start of decomposition in thermogravimetry. Furthermore, for polystyrene and poly(α-methylstyrene), both with a Tg in the range between room and decomposition temperature, ablation already occurred at temperatures well below the decomposition temperature, only at 30–40 K above Tg. The mechanism was photomechanical, i.e. a stress due to the thermal expansion of the polymer was responsible for ablation. Low molecular weight polymers showed differences in photomechanical ablation, corresponding to their lower Tg and lower viscosity above the glass transition. However, the difference in ablated volume was only significant at higher temperatures in the temperature regime for thermal decomposition at quasi-equilibrium time scales.
doi:10.1186/2193-1801-3-489
PMCID: PMC4162890  PMID: 25279287
Temperature measurement; Laser heating; Finite element simulation; Polystyrene; Molecular weight; Poly(α-methylstyrene); Polyimide; Triazene polymer; Ablation threshold
16.  Regio- and Chemoselective Immobilization of Proteins on Gold Surfaces 
Bioconjugate Chemistry  2014;25(2):269-275.
Protein chips are powerful tools as analytical and diagnostic devices for detection of biomolecular interactions, where the proteins are covalently or noncovalently attached to biosensing surfaces to capture and detect target molecules or biomarkers. Thus, fabrication of biosensing surfaces for regio- and chemoselective immobilization of biomolecules is a crucial step for better biosensor performance. In our previous studies, a regio- and chemoselective immobilization strategy was demonstrated on glass surfaces. This strategy is now used to regioselectively attach proteins to self-assembled monolayers (SAMs) on gold surfaces. Recombinant green fluorescent protein (GFP), glutathione S-transferase (GST), and antibody-binding protein G, bearing a C-terminal CVIA motif, were prepared and a farnesyl analogue with an ω-alkyne moiety was attached to the sulfhydryl moiety in the cysteine side chain by protein farnesyltransferase. The proteins, modified with the bioorthogonal alkyne functional group, were covalently and regioselectively immobilized on thiol or dithiocarbamate (DTC) SAMs on a gold surface by a Huigsen [3 + 2] cycloaddition reaction with minimal nonspecific binding. A concentration-dependent increase of fluorescence intensity was observed in wells treated with GFP on both thiol- and DTC-SAMs. The highly ordered, densely packed layer allowed for a high loading of immobilized protein, with a concomitant increase in substrate binding capacity. The DTC-SAMs were substantially more resistant to displacement of the immobilized proteins from the gold surface by β-mercaptoethanol than alkane-thiol SAMs.
doi:10.1021/bc400413d
PMCID: PMC3983139  PMID: 24437976
17.  Inhibition of Escherichia coli Biofilm Formation by Self-Assembled Monolayers of Functional Alkanethiols on Gold▿ † 
Applied and Environmental Microbiology  2007;73(13):4300-4307.
Bacterial biofilms cause serious problems, such as antibiotic resistance and medical device-related infections. To further understand bacterium-surface interactions and to develop efficient control strategies, self-assembled monolayers (SAMs) of alkanethiols presenting different functional groups on gold films were analyzed to determine their resistance to biofilm formation. Escherichia coli was labeled with green florescence protein, and its biofilm formation on SAM-modified surfaces was monitored by confocal laser scanning microscopy. The three-dimensional structures of biofilms were analyzed with the COMSTAT software to obtain information about biofilm thickness and surface coverage. SAMs presenting methyl, l-gulonamide (a sugar alcohol tethered with an amide bond), and tri(ethylene glycol) (TEG) groups were tested. Among these, the TEG-terminated SAM was the most resistant to E. coli biofilm formation; e.g., it repressed biofilm formation by E. coli DH5α by 99.5% ± 0.1% for 1 day compared to the biofilm formation on a bare gold surface. When surfaces were patterned with regions consisting of methyl-terminated SAMs surrounded by TEG-terminated SAMs, E. coli formed biofilms only on methyl-terminated patterns. Addition of TEG as a free molecule to growth medium at concentrations of 0.1 and 1.0% also inhibited biofilm formation, while TEG at concentrations up to 1.5% did not have any noticeable effects on cell growth. The results of this study suggest that the reduction in biofilm formation on surfaces modified with TEG-terminated SAMs is a result of multiple factors, including the solvent structure at the interface, the chemorepellent nature of TEG, and the inhibitory effect of TEG on cell motility.
doi:10.1128/AEM.02633-06
PMCID: PMC1932777  PMID: 17483274
18.  Soft Lithographic Functionalization and Patterning Oxide-free Silicon and Germanium 
The development of hybrid electronic devices relies in large part on the integration of (bio)organic materials and inorganic semiconductors through a stable interface that permits efficient electron transport and protects underlying substrates from oxidative degradation. Group IV semiconductors can be effectively protected with highly-ordered self-assembled monolayers (SAMs) composed of simple alkyl chains that act as impervious barriers to both organic and aqueous solutions. Simple alkyl SAMs, however, are inert and not amenable to traditional patterning techniques. The motivation for immobilizing organic molecular systems on semiconductors is to impart new functionality to the surface that can provide optical, electronic, and mechanical function, as well as chemical and biological activity.
Microcontact printing (μCP) is a soft-lithographic technique for patterning SAMs on myriad surfaces.1-9 Despite its simplicity and versatility, the approach has been largely limited to noble metal surfaces and has not been well developed for pattern transfer to technologically important substrates such as oxide-free silicon and germanium. Furthermore, because this technique relies on the ink diffusion to transfer pattern from the elastomer to substrate, the resolution of such traditional printing is essentially limited to near 1 μm.10-16
In contrast to traditional printing, inkless μCP patterning relies on a specific reaction between a surface-immobilized substrate and a stamp-bound catalyst. Because the technique does not rely on diffusive SAM formation, it significantly expands the diversity of patternable surfaces. In addition, the inkless technique obviates the feature size limitations imposed by molecular diffusion, facilitating replication of very small (<200 nm) features.17-23 However, up till now, inkless μCP has been mainly used for patterning relatively disordered molecular systems, which do not protect underlying surfaces from degradation.
Here, we report a simple, reliable high-throughput method for patterning passivated silicon and germanium with reactive organic monolayers and demonstrate selective functionalization of the patterned substrates with both small molecules and proteins. The technique utilizes a preformed NHS-reactive bilayered system on oxide-free silicon and germanium. The NHS moiety is hydrolyzed in a pattern-specific manner with a sulfonic acid-modified acrylate stamp to produce chemically distinct patterns of NHS-activated and free carboxylic acids. A significant limitation to the resolution of many μCP techniques is the use of PDMS material which lacks the mechanical rigidity necessary for high fidelity transfer. To alleviate this limitation we utilized a polyurethane acrylate polymer, a relatively rigid material that can be easily functionalized with different organic moieties. Our patterning approach completely protects both silicon and germanium from chemical oxidation, provides precise control over the shape and size of the patterned features, and gives ready access to chemically discriminated patterns that can be further functionalized with both organic and biological molecules. The approach is general and applicable to other technologically-relevant surfaces.
doi:10.3791/3478
PMCID: PMC3369651  PMID: 22214997
Bioengineering;  Issue 58;  Soft lithography;  microcontact printing;  protein arrays;  catalytic printing;  oxide-free silicon
19.  Photoacoustic imaging and temperature measurement for photothermal cancer therapy 
Journal of biomedical optics  2008;13(3):034024.
Photothermal therapy is a noninvasive, targeted, laser-based technique for cancer treatment. During photothermal therapy, light energy is converted to heat by tumor-specific photoabsorbers. The corresponding temperature rise causes localized cancer destruction. For effective treatment, however, the presence of photoabsorbers in the tumor must be ascertained before therapy and thermal imaging must be performed during therapy. This study investigates the feasibility of guiding photothermal therapy by using photoacoustic imaging to detect photoabsorbers and to monitor temperature elevation. Photothermal therapy is carried out by utilizing a continuous wave laser and metal nanocomposites broadly absorbing in the near-infrared optical range. A linear array-based ultrasound imaging system is interfaced with a nanosecond pulsed laser to image tissue-mimicking phantoms and ex-vivo animal tissue before and during photothermal therapy. Before commencing therapy, photoacoustic imaging identifies the presence and spatial location of nanoparticles. Thermal maps are computed by monitoring temperature-induced changes in the photoacoustic signal during the therapeutic procedure and are compared with temperature estimates obtained from ultrasound imaging. The results of our study suggest that photoacoustic imaging, augmented by ultrasound imaging, is a viable candidate to guide photoabsorber-enhanced photothermal therapy.
doi:10.1117/1.294036
PMCID: PMC2713867  PMID: 18601569
photoacoustics; optoacoustics; thermal imaging; ultrasound; photothermal therapy; treatment monitoring
20.  Photolithographic patterning of organosilane monolayer for generating large area two-dimensional B lymphocyte arrays† 
Lab on a chip  2008;8(12):2105-2112.
High-density live cell array serves as a valuable tool for the development of high-throughput immunophenotyping systems and cell-based biosensors. In this paper, we have, for the first time, demonstrated a simple fabrication process to form the hexamethyldisilazane (HMDS) and poly(ethylene glycol) (PEG) binary molecular surface which can be used to effectively form high fidelity cell arrays. The HMDS self-assembled monolayer (SAM) on glass substrates was photolithographically patterned and its ability to physically adsorb proteins was characterized by contact angle measurement and fluorescence microscopy respectively. Passivation of the non-HMDS coated background by PEG was verified to have no impact on the pre-patterned HMDS and greatly inhibited the non-specific protein binding. Using the biotin–streptavidin complexation as an intermediate, uniform orientation and high bioactivity were achieved for the immobilized B lymphocyte specific anti-CD19 antibodies and therefore ensured the formation of high resolution B lymphocyte arrays. The cell–ligand interaction specificity was investigated and the anti-CD19 decorated micropatterns presented a much higher cell-capturing rate (88%) than those modified by non-specific ligands (15% for anti-CD5 and 7% for streptavidin). The approach was verified to be biocompatible and the properties of the antibody-modified surface were maintained after 12 h cell culture. The HMDS monolayer formation and patterning processes, and the universal HMDS/biotin-BSA/streptavidin template, provide a very simple and convenient process to generate high resolution micropatterns of cell-adhesive ligands and are extendable to form arrays of other types of cells as well.
doi:10.1039/b810329a
PMCID: PMC2719280  PMID: 19023473
21.  Photothermal-Chemotherapy with Doxorubicin-Loaded Hollow Gold Nanospheres: A Platform for Near-Infrared Light-Trigged Drug Release 
Photothermal ablation (PTA) is an emerging technique that uses near-infrared (NIR) laser light-generated heat to destroy tumor cells. However, complete eradication of tumor cells with PTA is difficult because of uneven heat distribution in the treatment volume. We hypothesized that combining PTA with chemotherapy using a single multifunctional nanoconstruct that mediates simultaneous photothermal cell killing and drug release (photothermal-chemotherapy) would result in enhanced antitumor activity and reduced toxicity compared to chemotherapy alone. Doxorubicin (DOX) was loaded to hollow gold nanospheres (HAuNS) coated with polyethylene glycol (PEG). The pharmacokinetics and biodistribution of both DOX and HAuNS in the resulting nanoconstruct, DOX@PEG-HAuNS having different DOX:PEG:HAuNS ratios, were evaluated using dual isotope labeling techniques. The antitumor activity of DOX@PEG-HAuNS with DOX:PEG:HAuNS weight ratio of 1:3:1 (NP3) in combination with NIR laser was studied in vitro and in vivo using human MDA-MB-231 breast cancer and A2780 ovarian cancer cells. In vitro, NP3 mediated PTA of both cancer cells and DOX release upon NIR laser treatment. In vivo, NP3 showed slower clearance in blood and greater accumulation in tumors than free DOX. NP3-plus-NIR laser demonstrated greater antitumor activity than free DOX, NP3, or liposomal DOX. Moreover, NP3 displayed significantly decreased systemic toxicity compared to free DOX or liposomal DOX. Enhanced antitumor effect with NP3-plus-laser can be attributed to both the cytotoxic effect of DOX released from NP3 and the photothermal effect mediated by HAuNS. Slow release of DOX from NP3 in normal tissues contributed to reduced systemic toxicity. Photothermal-chemotherapy exemplified by a single-agent nanoconstruct NP3 is a promising approach to anticancer therapy.
doi:10.1016/j.jconrel.2011.10.028
PMCID: PMC3463239  PMID: 22063003
Doxorubicin; Near-Infrared light; Triggered Release; Photothermal ablation therapy; Pharmacokinetics
22.  Mathematical modeling of laser lipolysis 
Background and Objectives
Liposuction continues to be one of the most popular procedures performed in cosmetic surgery. As the public's demand for body contouring continues, laser lipolysis has been proposed to improve results, minimize risk, optimize patient comfort, and reduce the recovery period. Mathematical modeling of laser lipolysis could provide a better understanding of the laser lipolysis process and could determine the optimal dosage as a function of fat volume to be removed.
Study design/Materials and Methods
An Optical-Thermal-Damage Model was formulated using finite-element modeling software (Femlab 3.1, Comsol Inc). The general model simulated light distribution using the diffusion approximation of the transport theory, temperature rise using the bioheat equation and laser-induced injury using the Arrhenius damage model. Biological tissue was represented by two homogenous regions (dermis and fat layer) with a nonlinear air-tissue boundary condition including free convection.
Video recordings were used to gain a better understanding of the back and forth movement of the cannula during laser lipolysis in order to consider them in our mathematical model. Infrared video recordings were also performed in order to compare the actual surface temperatures to our calculations. The reduction in fat volume was determined as a function of the total applied energy and subsequently compared to clinical data reported in the literature.
Results
In patients, when using cooled tumescent anesthesia, 1064 nm Nd:YAG laser or 980 nm diode laser: (6 W, back and forth motion: 100 mm/s) give similar skin surface temperature (max: 41°C). These measurements are in accordance with those obtained by mathematical modeling performed with a 1 mm cannula inserted inside the hypodermis layer at 0.8 cm below the surface. Similarly, the fat volume reduction observed in patients at 6-month follow up can be determined by mathematical modeling. This fat reduction depends on the applied energy, typically 5 cm3 for 3000 J. At last, skin retraction was observed in patients at 6-month follow up. This observation can be easily explained by mathematical modeling showing that the temperature increase inside the lower dermis is sufficient (48–50°C) to induce skin tightening
Discussion and Conclusion
Laser lipolysis can be described by a theoretical model. Fat volume reduction observed in patients is in accordance with model calculations. Due to heat diffusion, temperature elevation is also produced inside the lower reticular dermis. This interesting observation can explain remodeling of the collagenous tissue, with clinically evident skin tightening.
In conclusion, while the heat generated by interstitial laser irradiation provides stimulate lipolysis of the fat cells, the collagen and elastin are also stimulated resulting in a tightening in the skin. This mathematical model should serve as a useful tool to simulate and better understand the mechanism of action of the laser lipolysis
doi:10.1186/1475-925X-7-10
PMCID: PMC2292728  PMID: 18312643
23.  Effect of Substratum Surface Chemistry and Surface Energy on Attachment of Marine Bacteria and Algal Spores 
Two series of self-assembled monolayers (SAMs) of ω-substituted alkanethiolates on gold were used to systematically examine the effects of varying substratum surface chemistry and energy on the attachment of two model organisms of interest to the study of marine biofouling, the bacterium Cobetia marina (formerly Halomonas marina) and zoospores of the alga Ulva linza (formerly Enteromorpha linza). SAMs were formed on gold-coated glass slides from solutions containing mixtures of methyl- and carboxylic acid-terminated alkanethiols and mixtures of methyl- and hydroxyl-terminated alkanethiols. C. marina attached in increasing numbers to SAMs with decreasing advancing water contact angles (θAW), in accordance with equation-of-state models of colloidal attachment. Previous studies of Ulva zoospore attachment to a series of mixed methyl- and hydroxyl-terminated SAMs showed a similar correlation between substratum θAW and zoospore attachment. When the hydrophilic component of the SAMs was changed to carboxylate, however, the profile of attachment of Ulva was significantly different, suggesting that a more complex model of interfacial energetics is required.
doi:10.1128/AEM.70.7.4151-4157.2004
PMCID: PMC444801  PMID: 15240295
24.  Photocatalytic Nanolithography of Self-Assembled Monolayers and Proteins 
ACS Nano  2013;7(9):7610-7618.
Self-assembled monolayers of alkylthiolates on gold and alkylsilanes on silicon dioxide have been patterned photocatalytically on sub-100 nm length-scales using both apertured near-field and apertureless methods. Apertured lithography was carried out by means of an argon ion laser (364 nm) coupled to cantilever-type near-field probes with a thin film of titania deposited over the aperture. Apertureless lithography was carried out with a helium–cadmium laser (325 nm) to excite titanium-coated, contact-mode atomic force microscope (AFM) probes. This latter approach is readily implementable on any commercial AFM system. Photodegradation occurred in both cases through the localized photocatalytic degradation of the monolayer. For alkanethiols, degradation of one thiol exposed the bare substrate, enabling refunctionalization of the bare gold by a second, contrasting thiol. For alkylsilanes, degradation of the adsorbate molecule provided a facile means for protein patterning. Lines were written in a protein-resistant film formed by the adsorption of oligo(ethylene glycol)-functionalized trichlorosilanes on glass, leading to the formation of sub-100 nm adhesive, aldehyde-functionalized regions. These were derivatized with aminobutylnitrilotriacetic acid, and complexed with Ni2+, enabling the binding of histidine-labeled green fluorescent protein, which yielded bright fluorescence from 70-nm-wide lines that could be imaged clearly in a confocal microscope.
doi:10.1021/nn402063b
PMCID: PMC4327559  PMID: 23971891
nanofabrication; photocatalytic patterning; near-field lithography; local probe lithography; protein patterning; GFP; monolayers
25.  Ablation and optical third-order nonlinearities in Ag nanoparticles 
The optical damage associated with high intensity laser excitation of silver nanoparticles (NPs) was studied. In order to investigate the mechanisms of optical nonlinearity of a nanocomposite and their relation with its ablation threshold, a high-purity silica sample implanted with Ag ions was exposed to different nanosecond and picosecond laser irradiations. The magnitude and sign of picosecond refractive and absorptive nonlinearities were measured near and far from the surface plasmon resonance (SPR) of the Ag NPs with a self-diffraction technique. Saturable optical absorption and electronic polarization related to self-focusing were identified. Linear absorption is the main process involved in nanosecond laser ablation, but non-linearities are important for ultrashort picosecond pulses when the absorptive process become significantly dependent on the irradiance. We estimated that near the resonance, picosecond intraband transitions allow an expanded distribution of energy among the NPs, in comparison to the energy distribution resulting in a case of far from resonance, when the most important absorption takes place in silica. We measured important differences in the ablation threshold and we estimated that the high selectiveness of the SPR of Ag NPs as well as their corresponding optical nonlinearities can be strongly significant for laser-induced controlled explosions, with potential applications for biomedical photothermal processes.
doi:10.2147/IJN.S12463
PMCID: PMC3010154  PMID: 21187944
nonlinear optics; laser irradiation; metallic nanoparticles; Kerr effect; nonlinear optical absorption

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