Multiplexed Biomolecular Arrays Generated via Parallel Dip-Pen

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Biological and Medical Applications of Materials and Interfaces

Multiplexed Biomolecular Arrays Generated via Parallel Dip-Pen Nanolithography Hui Ma, Zhang Jiang, Xiaoji Xie, Ling Huang, and Wei Huang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b07369 • Publication Date (Web): 09 Jul 2018 Downloaded from http://pubs.acs.org on July 18, 2018

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ACS Applied Materials & Interfaces

Multiplexed Biomolecular Arrays Generated via Parallel Dip-Pen Nanolithography Hui Ma,† Zhang Jiang,† Xiaoji Xie,† Ling Huang*,† Wei Huang*,† †

Institute of Advanced Materials (IAM), Jiangsu National Synergistic Innovation Center for

Advanced Materials (SICAM), Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816 China

KEYWORDS: Parallel · Dip-Pen Nanolithography · Patterning · Multiplexed · Biomolecules

ABSTRACT: The capabilities of transferring target materials, especially functionality-reliable biomolecules into specific locations and with arbitrarily designed patterns are of critical importance for high throughput disease diagnosis, multiplexing, and drug screening. Herein we report the simultaneous patterning of two types of biomolecules using the parallel dip-pen nanolithography technology where an array of the atomic force microscope (AFM) tips can be selectively and alternately coated with target biomolecules via a specially designed inkwell array. Moreover, mixing target biomolecules at proper volumetric ratio with polyethyleneglycol dissolved in PBS buffer solution that works as an ink carrier can not only facilitate the smooth transfer of ink materials from the AFM tip to the substrate, it can also help to adjust the ink diffusion constant of different biomolecules to highly similar so that the multiplexed biofunctional dot and/or line arrays at similar sizes can be reliably generated.

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The rapid development of nanoscience and nanotechnology has provided a powerful platform allowing unprecedented studies on a wide variety of functional nanomaterials towards different applications such as energy storage, solar cells, optoelectronics, disease diagnosis, and theranostics.1-5 Some of them can even be studied at the individual unit level such as single nanodevices where greatly improved performance was obtained compared with their counterparts at the bulk scale.6-10 However, the above investigations are usually limited within the proof-ofconcept stage while the lack of a rapid generation of massive products remains an obstacle that has severely delayed large-scale production of nanoarrays containing target materials.11 Thus, feasible methods for precise patterning and arrangement of those nanomaterials are highly desired.12-14 Indeed, several issues has remained as bottlenecks preventing the further application of nanomaterials. For example, being able to pattern and arrange interested nanomaterials with expected functionalities in a controlled manner such as arbitrarily designed multiplexed patterns with varying dimensions, delivery of certain materials into a specific location with the nanoscale precision, and general applicability to different type of materials and ease of operation at low-cost and high-efficiency.15,16 To tackle such circumstances, various patterning and assembly methods have been developed, which include but not limited to, photolithography for large-area patterning and with the microscale resolution, electron beam lithography with the nanoscale resolution but low throughput for pattern generation, scanning probe microscope (SPM)-based scratching, selfassembly, Langmuir-Blodgett, micro-contact printing, dip-pen nanolithography (DPN), and their combinations have been developed.17-26 However, both the optical and electron beam lithography involve harmful UV light and electron beam exposure, as well as the sequential treatment of samples with organic solvents which can easily cause defunctionalization of biomolecules, while the SPM-based scratching requires reliable and specific chemical interaction between targets and


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substrates. Unfortunately, such newly formed chemical bond might also result in malfunction of target materials especially when biomolecules are to be patterned.27 Technologies of self-assembly and Langmuir-Blodgett are good at large-scale arrangement of massive individual molecules or nano building blocks with high uniformity, but are lack of nanoscale resolution and specific pattern-designing flexibility so that they are usually combined with other lithographic methods. As a high resolution, high registration, and direct writing method, DPN can work in laboratory environment where organic solvent or harmful exposure of high-energy beam are avoided. Moreover, the mechanism that drives the DPN process, that is, the ink transfer from the tip of the atomic force microscope (AFM) to the substrate has imparted this technology good compatibility with both soft and hard matters as long as the target materials can be dissolved, and a wide variety of chemical molecules have been successfully patterned by DPN.28-34 Later on, the use of polyethyleneglycol (PEG) as ink carriers has greatly widened the scope of target materials so that various nanomaterials such as Au nanoparticles, iron oxide nanoparticles, fullerene, and especially biomolecules have been successfully patterned by DPN.35-43 However, the above cases are studied as a single ink material, and a new challenge for DPN would come if more than one type of multiplexed ink materials need to be patterned where repeated operation of the patterning process would be usually required.44 What is more, when patterning the second target materials, subsequent precise registration process is needed in order to set the location relative to the pre-

Scheme 1. Schematic illustration of the multiplexed dot arrays of two types of biomolecules generated by parallel DPN process.



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generated patterns. However, such registration is normally realized by scanning the AFM tip over the reference markers, which could easily cause cross contamination between different biomolecules. As a further development of our previous investigation on matrix assisted DPN,36,42,43 herein we report a new technology using the combination of a specially designed inkwell array (Figure S1a, S1b) and a parallel AFM tip array (Figure S1c), which allows precise coating of specific ink materials onto expected AFM tips by a one-time dipping of the tip array into the inkwell array, or by a subsequent second-time dipping if the two types of ink materials need to be alternately coated on every other AFM tips, as illustrated in Scheme 1. Ink materials can then be reliably patterned by operating the DPN process exactly the same manner as how a single-tipped DPN works, so that multiplexed ink material arrays can be routinely generated. It is worthy to mention that precise coating of interested ink material onto expected AFM tips becomes possible by using ink well with dimensional design matching that of the AFM tip array. Moreover, this parallel DPN technology has greatly simplified the patterning procedures when two or more biomolecular inks need to be simultaneously patterned, exhibiting great potential in drug screening, multiplexing, and geometric adhesion studies of single cell.45,46 It is worthy to emphasize that, since the distance between two adjacent AFM tips is 35 m (Figure S1c), a total of 840 m-wide pattern can be generated through the parallel 26 AFM tip array. Considering the fact that the theoretical area the AFM scanner can reach is 100 m x 100 m. So one-time such parallel patterning can cover roughly the area of 0.1 mm2. Taking advantage of the perfect ink carrier ability of PEG and the linear AFM tip array, we are able to coat target ink materials onto selected AFM tip so that simultaneous and parallel patterning of two types of


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biomolecules can be readily achieved. Further characterization has proved that the functionalities of the patterned biomolecules are retained. Since a certain type of ink material usually has its own constant of diffusion from the AFM tip to the substrate, which can be roughly calculated by the following equation47-49 r ≈ kt1/2

(1)

where r represents the radius of the dot generated, k is ink diffusion constant, and t is the tipsubstrate contact time. The ink diffusion constant can be calculated by plotting the radius of the patterned dots generated with the square root of the tip-substrate contact time (Scheme 2a).

Scheme 2. (a) Dot array generated by DPN at different tip-substrate contact times. (b) Diffusion constants of Ink 1 and Ink 2 change to Ink 1’ and Ink 2’, respectively, after adjustment by mixing with proper amount of PEG.

PEG has perfect solubility in both hydrophobic and hydrophilic solvents such as chloroform, hexane, toluene, ethanol, water and so on. This allows it readily mixed with many types of nanomaterials that are dispersed in different solvents, so that proper ink solutions can be prepared



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at varied volumetric ratios. More importantly, due to the good diffusion capability, the diffusion constant of the mixed ink material can be further adjusted the same or highly similar for different type of nanomaterials by changing the amount of PEG. As illustrated in Scheme 2b, by varying the amount of PEG mixed with target ink solution, the pristine diffusion constant of Ink 1 and Ink 2 can be adjusted to Ink 1’ and Ink 2’, respectively, which become very similar so that both of the resulted dots could be at the same or highly similar size when patterned simultaneously (Scheme 2b). To prove the general applicability of this ink diffusion constant adjustment strategy, four biomolecules of -galactosidase, immunoglobulin G (IgG), bovine serum albumin (BSA), and anti-ubiquitin dissolved in PBS buffer were chosen as representative ink materials. A primary measurement indicates that the four ink materials, as well as PEG in buffer solution have their characteristic diffusion constants that differ obviously from each other (Figure 1a). However, by mixing with PEG buffer solution at volumetric ratios of 1:2 and 1:5, the ink diffusion constant of anti-ubiquitin could be gradually adjusted to 29.41 from 11.30, which is the diffusion constant of pure anti-ubiquitin (Figure 1b and Figure S2a, S2b). Following similar operation, after mixed with PEG buffer solution at volumetric ratios of 1:5, the diffusion constant of BSA was adjusted to 28.08 from 26.56, which is the diffusion constant of pure BSA (Figure S2c, S2d). Thus it is reasonable that by mixing with proper amount of PEG, the diffusion constants of two different ink materials can be adjusted almost the same or highly similar. Indeed, as shown in Figure 1c, the ink diffusion constant of BSA and anti-ubiquitin can be adjusted almost the same when mixed with PEG at the volumetric ratio of 1:5 and 1:5, respectively. Further results have proved that the ink diffusion constant of IgG and -galactosidase could also be adjusted highly similar by mixing with PEG buffer solution at volumetric ratios of 1:5 and 1:7.5 (Figure 1d), respectively. This way, the


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dot arrays with similar size or line arrays with similar width shall be reliably obtained when the ink pair of BSA/anti-ubiquitin or IgG/-galactosidase is simultaneously patterned by DPN, respectively. Next, the solution of IgG and -galactosidase mixed with proper amount of PEG was used as ink to generate dot arrays, respectively, and the actual suitability for simultaneous patterning was

Figure 1. (a) Ink diffusion constants of -galactosidase, IgG, BSA, anti-ubiquitin, and PEG at their pristine PBS buffer solution. (b) Changes of the ink diffusion constant of anti-ubiquitin when mixed with different amount of PEG. (c) Ink diffusion constants of BSA and anti-ubiquitin become highly similar when mixed with PEG both at volumetric ratio of 1:5. (d) Ink diffusion constants of IgG and -galactosidase become highly similar when mixed with PEG at volumetric ratio of 1:5 and 1:7.5, respectively.



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checked by measuring the dot diameters. As shown in Figure S3a, four dots of IgG at tip-substrate contact time of 32 s are 385.1, 382.5, 357.0, and 376.5 nm with the average size of 375.3 nm. The according dot size of patterned -galactosidase are 367.2, 339.4, 332.3, and 349.9 nm (Figure S3b) with the average size of 347.2 nm, which shows a dot size variation less than 8%. However, if without the ink diffusion constant adjustment, the average dot diameter for IgG and galactosidase calculated is 435.0 (Figure S3c) and 512.0 nm (Figure S3d), respectively, whereas the size variation is larger than 18%. This clearly indicates that PEG can be reliably used to make efficient adjustment of the ink diffusion constant so that two types of biomolecular dot arrays at similar sizes could be routinely obtained when simultaneously patterned by parallel DPN. Indeed, using the red dye labelled IgG as ink material, by parallelly dipping the 26 AFM-tip array into the specially designed inkwell array (Figure S1) where the distance between the adjacent inkwells matches exactly that of the adjacent AFM tips so that every AFM tip could be coated with the same amount of ink material. Then the 4x3 arrays of the “X” shaped line patterns were generated where the 14 line arrays can be seen in Figure S4a and the zoomed-in area gives more details of the patterned line array (Figure S4b). The center to center distance between the line arrays is 35 m, equaling exactly to the distance between two adjacent AFM tips. Furthermore, if the distance between the inkwell array (Figure 2a) is designed to be 70 m (Figure 2b), which shall match exactly the distance between every 3 AFM tips (Figure 2c). This means that for one-time dipping of the AFM tip array, every other AFM tip will be coated by one type of ink material and the left half of the AFM tips can be subsequently coated with another type of ink material by a second-time dipping. Finally, the whole AFM tip array will be alternately coated by two types of ink materials in a manner of “ABAB…” as shown in Figure 2d. When


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parallely aligned between the AFM tip array and the substrate, simultaneous patterning of two types of biomolecules at the nanoscale resolution can be easily realized, the process is exactly the same as that of operating one AFM tip for pattern generation. Obviously, neither the repeated DPN operation or the cross contamination caused by registration scanning that previous patterning strategy has encountered will be an issue in this parallel DPN technology.44

Figure 2. (a) Dimensional layout of the computer-aided design of the inkwells. (b) Zoomed-in details of the blue area in (a) observed under scanning electron microscope (SEM). (c) SEM image of the AFM tip-array and the distance between adjacent tips is 35 m. Inset shows schematic structure of a single AMF tip. (d) Fluorescence microscope image of AFM tip-array alternately coated with anti-ubiquitin and BSA that are labelled with red and green dyes, respectively.



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To further prove the generality of this patterning strategy, AFM tip arrays alternately coated with BSA and anti-ubiquitin inks (Figure 2d) that have been pre-adjusted with PEG to have highly similar ink diffusion constants (Figure 1c), were used for dot-array patterning. In order to check the dot array under fluorescent microscope, BSA and anti-ubiquitin were labelled with green and red dyes respectively, so that they can be easily visualized once patterned. Indeed, 3 groups of

Figure 3. (a) Fluorescence microscope image of simultaneously patterned dot arrays of anti-ubiquitin and BSA at tip-substrate contact times of 4, 8, 16, and 32 s, respectively. (b) Zoomed-in image of the pink square in (a) showing the dot arrays of anti-ubiquitin and BSA at tip-substrate contact time of 8 and 16 s, respectively.


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multiplexed dot arrays of BSA and anti-ubiquitin were generated via parallel DPN patterning process at tip-substrate contact times of 4, 8, 16, and 32 s, respectively, were shown in Figure 3a where 4 s tip-substrate contact time couldn’t generate continuous dot arrays while those at 8, 16, and 32 s contact times show consistent fluorescence intensity. Figure 3b gives the zoomed-in image of the BSA and anti-ubiquitin dot arrays generated at 8 and 16 s contact time, respectively. Again, such dot arrays were generated by a one-time parallel DPN process, which is superior to those two-step patterning method in terms of both operation simplicity and cross contamination avoidance. To check the viability of the patterned biomolecules, the “X” shaped line arrays generated using buffer solution of -galactosidase/PEG was used as ink material were incubated in the PBS buffer solution containing anti-β-galactosidase labelled with green dye. It is clear to see under fluorescence microscope that the 13 line arrays of the pre-patterned area became green (Figure S5a), suggesting the successful binding of anti-β-galactosidase to the line patterns of the bio-active β-galactosidase. The zoomed-in area (Figure S5b) shows more details of the lines, where only patterned area has green signal while the unpatterned area has no binding, indicating the specific recognition between these biomolecules. The control experiment by incubating pure PEG patterns in anti-β-galactosidase buffer solution has ruled out the non-specific binding possibility (Figure S6) while that of β-galactosidase has proved its good viability in the DPN generated patterns (Figure S7). In conclusion, we have realized selective coating of target ink materials onto expected AFM tip arrays under the assistance of the specially-designed inkwell arrays, so that simultaneous patterning of two types of biomolecules becomes possible. The perfect solubility and ink carrier ability of PEG dissolvable in PBS buffer solution has played a critical row in both facilitating the



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smooth transfer of ink materials from the AFM tip to the substrate and adjustment of the ink diffusion constant. Moreover, the well-retained functionality of the patterned biomolecules further enables wide applications of such biofriendly and parallel DPN technology in high throughput biomedical sample screening, such as disease diagnosis, multiplexing, new drug discovery.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Instruments, AFM images, fluorescent images, and experimental details. AUTHOR INFORMATION Corresponding Author *Ling Huang, [email protected] *Wei Huang, [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest.


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ACKNOWLEDGMENTS The authors would like to thank for the financial support from National Natural Science Foundation of China (21371095), Natural Science Foundation of Jiangsu Province (BL2014075). We would also like to thank the support of the Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM).

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Table Of Content: We report the simultaneous patterning of two types of biomolecules using parallel dip-pen nanolithography where a specially designed inkwell array allows purposed coating of target ink materials onto expected AFM tips, so that multiplexed biofunctional pattern arrays can be reliably generated via a one-time operation.


Multiplexed Biomolecular Arrays Generated via Parallel Dip-Pen

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