Precise Microscale Polymeric Networks through Piezoelectronic Inkjet

Article pubs.acs.org/journal/abseba

Precise Microscale Polymeric Networks through Piezoelectronic Inkjet Printing Benjamin R. Spears,† Michael A. Marin,†,‡ Anisse N. Chaker,† Michael W. Lampley,† and Eva Harth*,†,‡ †

Department of Chemistry and ‡Department of Chemical and Biomolecular Engineering, Vanderbilt University, 7665 Stevenson Center, Nashville, Tennessee 37235, United States S Supporting Information *

ABSTRACT: Microsized particles are versatile drug delivery systems with applications as inhalants, implants, and vaccines. An ideal fabrication technique is envisioned to provide particles with controlled size dimensions and is facile, without excessive loss of drug during incorporation, modulated morphologies and release kinetics. In this work, we report on the utilization of a set of polymeric building blocks such as allyl- functionalized polycarbonates, semibranched poly(glycidol allylglycidyl ether)s, and dithiol-PEG cross-linkers to form microsized networks in controlled size dimensions of 18−12 μm, 12−8 μm, and 1−2 μm with modulated morphologies and hydrophilicity based on the ratio of the polycarbonate or polyglycidol building blocks. Piezoelectric ink jet printing allows for the direct printing of these polymeric structures onto substrates, after which the printed droplet is cross-linked via UV light using thiol−ene click reactions. By varying the ratio of the allyl-functionalized building block droplets from being purely prepared either from polycarbonate (PC), polyglycidol (PG) backbones or in a ratio of 70/30 of functionalized polycarbonates and polyglycidols, the droplets can be either printed in DMSO or water. Preliminary studies to control the particle sizes not only through the droplet volume but also by reducing the polymer concentration by 20%, resulted in another set of 70/30 polycarbonate/polyglycidol micron sized networks with an observed corresponding size reduction of 20%. With this, we have developed a facile technique to prepare microsized hydrogel particles with homogeneous and attractive size dimensions that can be directly prepared without using lithography methodologies. The strength of the approach is the set of unique polymeric building blocks that in combination with the new technique allows for a modulation of hydrophilicity and morphologies to form promising drug delivery candidates to carry and release synthetic as well as biological cargo. KEYWORDS: ink jet printing, microsized particles, hydrophilic particles, control of micrometer-sized particles and morphologies

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INTRODUCTION Microsized particles have been developed alongside nanosized objects and impressive examples exist as inhalants and materials for adjuvant reagents and find applications in cancer treatments,1 diabetes1d and tuberculosis.2 Chronic pulmonary disease and cancer of trachea and lung are, together with diabetes, the most deadly diseases worldwide. Popular preparation methods for microsized particles are emulsion3 and emulsion polymerization methods,4 photolithography,5 and microfluidic6 and spray drying techniques.7 Some of these methods have severe drawbacks, with particles of high polydispersity or the method being expensive or not practical. For example, lithography techniques require masks and molds and smaller size dimensions below 100 μm are rather difficult to achieve. Spray drying methods are working exceptionally well for resorbable formulations of drugs intended to be administered orally, in which a precise size dimension of the © XXXX American Chemical Society

particle is not required. Emulsion methodologies suffer from the need to incorporate drugs during the emulsion process and are not ideal if precious drugs are involved or a dual combination delivery system consisting of a small molecule drug and a biological component such as a protein is desired. One of the most successful inhalants are made from poly(lacticco-glycolic acid) PLGA microsized particles. Kim1a and coworkers emphasized, that the size dimension of around 14 μm is thought to be ideal for an even distribution throughout the bronchi, trachea and alveoli. In vivo experiments documented the capability for a sustained drug release and the released doxorubicin could still be detected after a period of 2 weeks. Although quite successful, the further optimization of inhalants Received: April 6, 2016 Accepted: May 26, 2016

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DOI: 10.1021/acsbiomaterials.6b00175 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

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ACS Biomaterials Science & Engineering Scheme 1. Illustration of the Invented Piezoelectronic Ink Jet Process for the Preparation of Microsized Particles

Figure 1. Polymer ink 1, (a) printed onto polyglycidol coated surface, (b) washed off into water, and (c) imaged via confocal microscopy; see the Supporting Information. The average size dimension of the polycarbonate-based particles are around 13−14 μm containing Nile Red as small molecule dye.

structural ceramics are known to be printed and collected as droplets that are sintered in a sequential step. To the best of our knowledge, the only structures printed for the purpose of drug delivery employed the solvent evaporation method for particle formation and the droplet was not postmodified or cross-linked.10 The entire payload was released within the first 6 h. In this work, we present a developed piezoelectric ink jet printing technique to prepare microsized particles in precise size dimensions, adjusted morphologies and network density. It is the result of combining and cross-linking a unique set of macromolecular building blocks, consisting of linear degradable, functionalized polycarbonates, semibranched polyglycidols and linear difunctionalized cross-linkers. In this unique method, polymer droplets are printed and cross-linked in a postmodification process to be transformed into a microsized network. We will demonstrate that not only the technique is practical to give precise microparticles but also gives the opportunity to easily tune the softness, or hydrophilicity by including the desired ratios of linear polymers and hydrophilic semibranched units. Moreover, with the approach to incorporate all components into individual droplets, it gives

suggests that a higher degree of hydrophilicity or softness is advantageous. With the increasing integration of automated technologies into the field of polymer science,8 we sought a more facile, versatile approach to prepare polymeric microparticles with tuned morphologies and size ranges. Piezoelectric ink jet printing techniques have shown the potential for the formation of thin films as well as depositing polymers in droplet form. This technique benefits greatly from its inherent ability to easily change the composition of the ink being used, affording an extremely tunable system with seemingly nonexistent limitations on the compositions that can be formed. The utilization of an automated and machined fabrication also implies that the scalability is not limited by reaction conditions but by the printing capacity at a given time. Finally, by tuning the instrument settings, such as nozzle size, accelerating voltage, and/or the voltage waveform used, one can direct the size of the formed droplets. Examples for some of the more sophisticated materials are printed layer-by-layer circuits, sol− gel materials or patterned conducting polymers.9 In many of these applications, the deposited particles and layers are intended to be permanently placed on the substrate. Although, B


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ACS Biomaterials Science & Engineering

functional groups relative to the molecular weight of the polyglycidol copolymer. In general, commercially available hydrophilic cross-linkers are mostly available in varieties in which the multi- arm polymers have rather high molecular weights paired with a few functionalities, giving hydrogels with large mesh sizes and corresponding fast release rates of biological structures. The branching and the low molecular weight of the prepared poly(GLY AGE) will give the opportunity to produce tighter networks by adding hydrophilic character. With these key structures in hand, we started to explore the possibility of preparing microscopic networks with the ink jet printing technique. To exploit the boundaries for the most diverse network characteristics, we chose three droplet compositions. The first system, ink 1, is composed from poly(MEC MAC) as the only allyl containing polymeric building block and represents the particle in this series with the highest hydrophobic character. The second system, ink 2, is composed of a 70/30 wt % mixture of poly(MEC MAC) and poly(GLY AGE) which is expected to give a network with mostly hydrophobic character but will have some increased hydrophilicity and softness due to the polyglycidol component. The final system in this series would be comprised purely of the polyglycidol copolymer, as the only allyl carrying unit, to achieve a completely hydrophilic species. To test the feasibility of our approach we prepared macroscale hydrogels from the individual compositions with the intent to optimize ratios for the most ideal droplet for an application in cross-linking reactions using the thiol−ene click reaction. The thiol−ene cross-linking technique was chosen because of the ability to be initiated by light. It will be critical to accomplish the printing process with the droplet containing polymer and cross-linker components in their native, nonreacted state, which then upon controlled initiation with light form a microgel. In a general procedure for sample 1 (ink 1) and sample 2 (ink 2), the allyl-functionalized polymers, poly(MEC MAC) and poly(GLY AGE) were solubilized in DMSO before the addition of the DMPA initiator and adding the dithiol 3,6-dioxa-1,8-octanedithiol. The order of the addition of the various components was varied in the watersoluble, sample 3 (ink 3). Here, we added to the poly(GLY AGE) solid dithiol-PEG (1.5KDa) together with half of the desired amount of water until completely dissolved, followed by the second half of water containing the water-soluble photoinitiator (VA-044). Once the solutions with the various droplet/ink compositions had been completely solubilized, the samples were irradiated with long wave UV light (365 nm) for 5 min to induce gelation. In order to determine the yields from the gelation, dry masses were compared to the total mass of the unreacted starting materials, with typical yields exceeding 90%. Determination of Limiting Polymer Concentration in Droplet Compositions. After we explored representative droplet compositions and their preparation, we needed to examine polymer/solvent ratios that allow a successful ejection from the printer head together with a subsequent postprinting cross-linking reaction. In a dilution study we determined for each of the three polymer systems concentration limits below which a hydrogel cannot be formed. In other words, it was the goal to determine the most dilute concentration while still affording a hydrogel. To determine this concentration, we performed a dilution assay on all three hydrogel samples wherein the dilution was increased from 1:1 w/v (mg polymer:μL solvent) to 1:15 w/v. The ratios are expressed as weight to volume ratios in milligram and microliter scales. It has

rise not only to incorporate molecules for imaging purposes but also drug molecules toward the application as biomedical devices.

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RESULTS AND DISCUSSION With the intent to deliver a range of cargo with varied solubility and size, the availability of a diverse set of polymeric networks

Figure 2. Confocal Z-stack analysis of polymer ink 1. The scale bar is 10 μm. See also the Supporting Information.

from tailored building blocks would be of advantage. First, we selected a polycarbonate copolymer prepared from 5-methyl-5ethyloxycarbonyl-1,3-dioxane-2-one (MEC) and 5-methyl-5allyloxycarbonyl-1,3- dioxane-2-one (MAC) as previously described by our group,11 see the Supporting Information. This highly hydrophobic polymer with an MAC incorporation of 20% has shown the ability to form hydrogel structures with a tunable sustained release of small molecule drugs. 11b Furthermore, degradation products from polycarbonates are less acidic than from corresponding polyesters and are ideal for an application as inhalants. As the second polymer, we synthesized a branched hydrophilic polyglycidol-based copolymer containing integrated allyl functionalities to the same degree as the polycarbonate, poly(GLY AGE). The copolymerization of glycidol (GLY) and allylglycidol ether (AGE) was performed under the same ring-opening polymerization conditions as we have described for the cationic homopolymerization of glycidol using Sn(OTf)2 as catalyst with a feed ratio of 75/25 achieving a 20% incorporation.12 The degree of branching (DB) is 0.21, which we describe as semibranched, was calculated according to Frey (see the Supporting Information) to describe more accurately branching in hyperbranched polymers in which a perfect dendrimer would have the value 1. The low branching of this novel macromolecular building block is preferred over a highly hyperbranched structure as it provides an increased ratio of C


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Figure 3. Polymer ink 2, (a) printed onto polyglycidol coated surface, scale bar (100 μm); (b) washed off into water; and (c) imaged via confocal microscopy; see the Supporting Information. The average size dimension of the polycarbonate/polyglycidol (70/30) based particles are around 10− 12 μm containing Coumarin as small molecule dye.

combinations showed that the polycarbonate/polyglycidol (ink 2 or here PC/PG) has similar strength and elasticity up to 20% of strain measured stress in comparison to model hydrogels derived from polyglycidol only as allyl containing component (ink 3). But with the stress exceeding 20% both the pure polyglycidol gel and the polyglycidol containing hydrogel become less elastic, however the PC/PG gel displays greater strength. The PC/PG model hydrogel has in comparison with the polycarbonate gel (PC, ink 1) similar strength as the pressure is increasing (Figure 4S). Swelling Studies of the Model Hydrogel Structures. The ability of a gel to swell while in water environments, mimicking physiological conditions, is a characteristic that can directly influence other properties such as drug release. Rapid swelling often is associated with a rapid release of cargo as well as increased rates of degradation due to the increase in surface area. The swelling capacity was investigated for all of the three hydrogel models to evaluate the increase in the mass and the influence of the covalently bound polyglycidol to the polycarbonate. As expected, the highest degree of swelling (1000 fold) was observed containing the hydrophilic polyglycidol (ink 3) only in comparison to a much smaller swelling capacity for the polycarbonate (ink 1) and polyglycidol containing polycarbonate system (ink 2). The polycarbonate gels showed only a minor weight increase of 1% after soaking in water. The PC/PG gel showed a weight increase of 38 ± 6%. In contrast to this, the polyglycidol gels displayed a much higher weight increase of 1112 ± 236% (Figure 5S). Fabrication and Characterization of Micrometer-Sized Hydrogel Structures. For the preparation of microsized hydrogel structures a Dimatix Materials printer was chosen to test the preparation of individual microgel spheres with reproducible sizes. The droplet compositions were chosen to

to be noted that these macroscale experiments were intended to give us a rough guideline to start preliminary experiments performed in the micronscale. As would be expected, the threshold concentration varied for each of the gel solutions with the addition of the branched polyglycidol structure affording gelation at even lower concentrations. The optimal dilution for samples 1,2 and 3 was found to be 1:2, 1:4, and 1:10 respectively (Table 1S), and it was also hypothesized that we would observe a decrease in size of the printed gels with the decrease in concentration as less polymer was present for gelation in each dot. Determination of the Mechanical Properties of Model Hydrogel Structures. As we planned to prepare microsized particles with tailored morphologies, we wanted to test the mechanical properties of the model bulk hydrogels to gather information for the anticipated properties of the micron sized particles. We previously investigated hydrogels formed from poly(MEC MAC), which were either doped with unfunctionalized polyglycidol, which acted as filler, or were prepared from polycarbonate copolymer only. It was determined with unconfined compression testing that the incorporation of polyglycidol as filler led to a drastic increase in deformability of the formed hydrogels for rather small amounts, whereas the use of a 1.5 kDa PEG cross-linker had a similar but less exaggerated effect.11b For the proposed microgels we sought the polyglycidol to be an integral part of the network rather than only a filler to capitalize on the polyglycidol properties. We hypothesized that the combination of the highly branched polyglycidol structure and linear polycarbonate would form a unique delivery system when once brought into a microscopic hydrogel structure and could display favorable interactions between cargo and polymer network. The compression studies of the three model hydrogels formed from the three ink D


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addition of a separate fluorescent dye for each droplet composition. The individual solutions were loaded into a Dimatix printer cartridge and placed within the Dimatix instrument. The substrates chosen for the printing process were initially glass slides. However, we experienced a strong attachment of the final cross-linked micrometer particles to the glass slides which circumvented a detachment and collection in water. Therefore, we sought to coat the surface of the glass slides with a watersoluble coating but which could be easily spin coated onto the glass surface as well. In search for an ideal coating we decided for a sacrificial layer of polyglycidol. This method yielded surfaces that, once printed onto, could be easily removed with water to liberate the hydrogel structures and found to be ideal for the PC (ink 1) and PC/PG (ink 2). For a deposition of polyglycidol droplets we chose Teflon sheets, which provides an excellent surface for the printed polyglycidol droplets (Scheme 1). The Dimatix program was used to create a pattern which printed individual dots, with spacing of 100 μm, in a continuous grid over the entire surface of the printing substrates. The ejection of the hydrogel solution from the printing cartridge was controlled by varying the voltages applied to the piezoelectric plate within the cartridge. A number of waveforms were tried before one was chosen which afforded the most consistent and uniform formation of drops.9a Once the desired waveform had been determined (see the Supporting Information), the hydrogel solution was printed onto the appropriate substrates. Upon completion, the substrate was carefully removed from the printing surface and irradiated with long wave UV (365 nm) for 5 min in order to form the microgel spheres. The product gels, still attached to the surface of the substrate could then be visualized using fluorescent microscopy with a Nikon AZ100 M microscope, which allowed for the determination of spatial resolution between the dots as well as confirmation of the incorporation of the fluorescent dye. Once it had been confirmed that the microdots were successfully printed onto the surface and went through the cross-linking procedure, DI water was used to rinse the gels from the surface into MakTek glass bottom culture dishes for investigation with confocal microscopy. The microgels, now suspended in water, were investigated using a Zeiss LSM Inverted Confocal Microscope to study their sizes, shapes, and, as the gels are relatively transparent, Z-stack images were obtained at a resolution of 0.05−0.25 μm. The data obtained from these cross-sectional readings for all three inks showed good integration of the fluorescent molecules throughout the hydrogel structure, meaning that any drug loaded into the system should be evenly distributed throughout the formed microgels. We will now discuss the findings using the individual gels more in detail. Polycarbonate Particles. The first printing system investigated was a pure polycarbonate based ink, ink (1) primed with dithiol cross-linker (short), DMPA initiator, and Nile red as a model hydrophobic drug in DMSO as solvent. For this composition, the polyglycidol coated glass slides were employed to give a hydrophilic surface for the hydrophobic hydrogel solution to be printed onto. The resulting printed particles were easily visualized using fluorescent microscopy because of the incorporation of Nile red, and showed a good uniformity and spacing on the polyglycidol coated surface (Figure 1). After cross-linking, the particles were washed from the surface and resuspended, and visualized using confocal microscopy. We found that the printing technique proved to be a facile particle fabrication method, and particles with an

Figure 4. Confocal analysis (top) and Z-stack of polymer ink 2 (bottom) of the same image. The scale bar is 10 μm.

Figure 5. Polymer ink 2a with a 20% reduction in polymer mass leading to smaller sizes in the 6−8 μm range.

be the optimized concentration of the polymer components as we have described for the model hydrogel materials. In this way, the droplet solutions were formed using the same methodology as was utilized for the bulk samples with the E


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Figure 6. Polymer ink 3, printed onto a Teflon sheet, washed off into water, and imaged via confocal microscopy. The average size dimension of the polyglycidol based particles are around 2−3 μm containing Cy 3 dye as small molecule dye.

average size of 12.5 μm were obtained. The size disparity among the printed particles was minimal and the Nile red dye was observed to be distributed evenly throughout the particle structure, which allows for the argument that any therapeutic loaded into the system should also exhibit this homogeneous distribution. Furthermore, the particles exhibited some signs of porosity (Figure 2) and would be highly advantageous for delivery methods such as inhalation, where the low particle density affords better aerosolization.1a,9b Furthermore, the particle size of 12.5 μm is in the size range of particles capable of accomplishing both, good nasal cavity and throat distribution, as well as dispersion into the lower portions (alveoli) of the lungs for directed delivery of therapeutic cargo. Polycarbonate/Polyglycidol Particles. The ability to form microsized hydrogel networks with both hydrophobic and hydrophilic character expands the potential for cargo delivery and tunable release. To investigate this possibility, we formed a hybrid system using a 70/30 w/w combination of polycarbonate/polyglycidol polymer chains (ink 2). The hydrogel ink for this investigation was primed with dithiol cross-linker, DMPA initiator as in the corresponding bulk hydrogel, and Coumarin 30 was added as imaging agent but also as a model hydrophobic drug. Because these gels are still mostly hydrophobic, the polyglycidol-coated slides were used as a printing surface, and the printed particles were again visualized using fluorescent microscopy. These particles appeared to be smaller in size than those formed purely from polycarbonate, with the average size of the particles of around 10 μm. These hybrid particles were seen to be much more mobile and able to bump into each other and continue moving without any perceived aggregation in water. This fact is very important when considering the utilization of these systems for intravenous delivery, where aggregation leads to potentially severe side effects. The size of the particles formed is again wellsuited for inhalation and direct injection therapies, and the formation of these hybrid systems is a representation of the

potential of this method to form covalently bound hydrogel structures with tunable hydrophilicity (Figures 3 and 4). Control of Microgel Size: Influence of Mass/Volume. The ability to tune the hydrophilicity of the hydrogel system is advantageous, but it is also desirable to be able to direct the size of the particles that are being formed so that the system can be optimized for various forms of delivery. It was hypothesized that a decrease in the weight percent of the polymer solution (ink 2a), thus decreasing the amount of polymer in each printed drop, would lead to a decrease in the size of the printed polymer structures. To investigate this proposition polycarbonate/polyglycidol hydrogel precursors were printed as before with the mass percent of the ink being decreased by 20% (Figure 5). The particles formed with the lower weight percent solution were decreased in size by almost the same amount as the decrease in weight percent, with particles an average size of around 7.75 μm. The ability to tune the size of the printed hydrogels through the polymer concentration easily manipulated parameter is a promising proposition to fine-tune particle sizes. Polyglycidol Particles. The final printing composition investigated was the pure polyglycidol ink 3. For this ink we could use water instead of DMSO, which gives the opportunity of a higher compatibility with future biological cargos. In contrast to the other inks, a higher molecular weight dithiol cross-linker was incorporated together with a water-soluble photoinitiator, in this case VA-044. Finally, the use of a Cy3 dye served as a model hydrophilic drug and readily visible fluorophore. For this formulation, the use of polyglycidolcoated slides is not possible because of mixing of the two hydrophilic systems, so Teflon sheets were tested as a printing surface. The printed particles were visualized using fluorescent microscopy, and after cross-linking, were washed from the Teflon surface and studied with confocal microscopy in the same procedure as conducted with the other two particle types. The resulting gel structures were much smaller at an average F


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ACS Biomaterials Science & Engineering size of around 2 μm (Figure 6 and Figure 9S). However, the particles maintained the high homogeneity as seen for the other inks as well.

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CONCLUSION In summary, we have demonstrated the feasibility of a developed new method for the formation of highly controlled and monodisperse micrometer-sized particles via a piezoelectric printing technique. Polymer droplets with varied compositions, and concentration can be deposited on substrates and turned into a microscopic polymer network under the influence of UV light, facilitated by a thiol−ene click reaction. The confocal analysis of three particles confirmed their spherical shape and uniformity of a small molecule/dye distribution throughout the particle. Furthermore, depending on the chosen polymer ink, sizes of the particles could be varied to be as low as 2 μm to around 14 μm. With this proof-of-concept study, we have taken the first steps toward a broader application of this technique to prepare carriers with the ability to incorporate a wide range of therapeutics into the individual micrometer gel−droplets for delivery. The optimization of this technique is currently under way and will be reported in due course.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsbiomaterials.6b00175. Experimental details and characterization of the polymer precursor and analysis of the model hydrogels together with a details on analysis and characterization of the microsized particles (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Present Address

B.R.S. is currently at Selux Diagnostics, Inc., Cambridge, MA Author Contributions

B.R.S. and M.A.M. contributed equally. 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 gratefully acknowledge the Department of Chemistry and the Juvenile Diabetes Research Foundation for supporting parts of this work.

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ABBREVIATIONS MEC, 5-methyl-5-ethyloxycarbonayl-1,3-dioxane-2-one; MAC, 5-methyl-5-allyloxycarbonyl1,3-dioxane-2-one REFERENCES

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ACS Biomaterials Science & Engineering polyglycidols as ″fillers″ in polycarbonate hydrogels to tune hydrophobic drug release. Polym. Chem. 2015, 6 (7), 1096−1102. (12) Spears, B. R.; Waksal, J.; McQuade, C.; Lanier, L.; Harth, E. Controlled branching of polyglycidol and formation of protein-glycidol bioconjugates via a graft-from approach with ″PEG-like″ arms. Chem. Commun. 2013, 49 (24), 2394−2396.

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Precise Microscale Polymeric Networks through Piezoelectronic Inkjet

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