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Colloidal Mesoporous Silica Nanoparticles as Strong Adhesives for Hydrogels and Biological Tissues Joo-Hyung Kim, Hodae Kim, Youngjin Choi, Doo Sung Lee, Jaeyun Kim, and Gi-Ra Yi ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b09083 • Publication Date (Web): 24 Aug 2017 Downloaded from http://pubs.acs.org on August 25, 2017

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ACS Applied Materials & Interfaces

Colloidal Mesoporous Silica Nanoparticles as Strong Adhesives for Hydrogels and Biological Tissues Joo-Hyung Kim,†,# Hodae Kim,†,# Youngjin Choi,† Doo Sung Lee,† Jaeyun Kim,†,§, ‡ * and GiRa Yi†,*

†

School of Chemical Engineering, §Department of Health Sciences and Technology, Samsung

Advanced Institute for Health Science & Technology (SAIHST) and ‡Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, Republic of Korea

*Email: [email protected] (G.-R.Y.), [email protected] (J.K.)

KEYWORDS: mesoporous, silica nanoparticle, adhesive, biological, wound healing

ACS Paragon Plus Environment


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ABSTRACT Sub-100-nm colloidal mesoporous silica (CMS) nanoparticles are evaluated as an adhesive for hydrogels or biological tissues. Since the adhesion energy is proportional to the surface area of nanoparticles, CMS nanoparticles could provide a stronger adhesion between two hydrogels than nonporous silica nanoparticles. In the case of 50-nm CMS nanoparticles with 6.45 nm of pore diameter, maximum adhesion energy was approximately 35.0 J/m2 at 3.0 wt % while 10 wt% nonporous silica nanoparticle solution showed only 7.0 J/m2. Moreover, the CMS nanoparticle solution had 22.0 J/m2 of adhesion energy at 0.3 wt%, which was 11 times higher than that of nonporous nanoparticles at the same concentration. Moreover, those CMS nanoparticles are demonstrated for adhering incised skin tissues of mouse, resulting in rapid healing even at a lower nanoparticle concentration. Finally, CMS nanoparticles had added benefit of quick degradation in biological media due to their porous structure, which may prevent unwanted accumulation in tissues.


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INTRODUCTION Nanoparticles can act as an adhesives for polymeric hydrogels, because polymer chains can be physically and permanently adsorbed on the nanoparticle surface.1 Recently, silica nanoparticles solutions have shown to be successfully glues two hydrogels1 and their adhesion energies were measured.2-3 This seminal work opened the possibility of using those nanoparticles for many biomedical applications, including hemostasis, wound closing, or organ repair,4 since the extracellular matrices of biological tissue have similar properties of crosslinked hydrogels. Since adhesion is essentially an interfacial phenomenon, adhesion strength of nanoparticles can be determined by the specific surface area, surface morphology and their intermolecular interaction with polymers.5-6 Therefore, nanoparticles with rough surfaces could function as a strong adhesive for hydrogel polymer matrix. Such particles include etched silica particles,7 small aggregates of nanoparticles8, or core-shell particles.9-10 In this report, we have prepared colloidal mesoporous silica (CMS) nanoparticles with for uniform and controlled surface roughness by sol-gel reaction in the presence of surfactants or polymers as templates. Then, their adhesion property with polydimethylacrylamide (PDMA) hydrogel were systematically investigated as a function of concentration, pore diameter and particle diameter, which shows substantially higher adhesion energy than nonporous nanoparticles. Since those CMS nanoparticles have been already exploited in biomedical applications11-15 due to their low toxicity and biocompatibility,16-17 we have evaluated them for wound healing in mouse skin and compared the results with conventional suture or treating with nonporous silica nanoparticles. Furthermore, since the CMS nanoparticles are known to degrade in biological fluids,18-23 we measured their degradation rate in a stimulated body fluid and compared with non-porous silica nanoparticles.



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RESULTS AND DISCUSSION Conventional adhesives are usually chemical adjuvants for gluing two materials to ensure good contact,24-25 in which interface can be covalently bonded by chemical reaction as well as physical adsorption or hydrogen bonding.24 Nanoparticles can be introduced for bridging polymers in hydrogels by adsorption as illustrated in Figure 1a. For given materials, total interfacial area between polymers and nanoparticles is a key parameter to determine adhesion strength. Therefore, rough nanoparticles with increased interfacial area could increase the adhesion energy. Since mesoporous nanoparticles are open structures, they have regular and uniform rough surface in which their surface roughness or outer surface area can be controlled by changing their pore diameter or structure. We have prepared mesoporous silica nanoparticles three different pore diameters (e.g., 2.70, 5.25, and 6.45 nm) using either Stöber process or a mini-emulsion method as described in the experimental section.26-29 As illustrated in Figure 1b-d, CMS nanoparticles could have more adsorption sites of PDMA polymer on the surface of crosslinked hydrogels than nonporous smooth silica particles. As a pore diameter of CMS nanoparticles increases for a given particle diameter, the surface becomes rougher so that the number of polymer adsorption site on nanoparticles would increase proportionally. Since it is unlikely for polymer to reach to the deep interior of the CMS nanoparticles due to the high entropic cost of polymer chain, we assumed polymers are adsorbed only near the surfaces and analyzed experimental data based on the specific outer surface area of the particle rather than the specific surface area of entire particles. In the case of larger pores as shown in Figure 2d, configurational entropic cost of polymer chain would be much less 30 which may lead to more adsorption points and better adhesion.


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Figure 1. Graphical illustration of polymer PDMA interacting on the surface of silica nanoparticle; (a) Control and at detached level, (b) Attachment on to the smooth nonporous silica nanoparticle, (c) Attachment on to the rough surface of mesoporous silica nanoparticle with pore diameter 2.70 nm, and (d) Attachment on to the rough surface of mesoporous silica nanoparticle with pore diameter 5.25 nm. It is represented to illustrate the most attachments occur in the case for larger pore diameter.

The CMS nanoparticles with 2.70 nm of pore diameter were synthesized by templating mesostructures of surfactant, hexadecyltrimethylammonium chloride (CTAC) with silica from tetraethylorthosilicate (TEOS) as described in experimental section.26 As shown in TEM image of Figure 2a, average diameter and standard deviation were measured as 30.0 nm and 4.01 nm (see Figure S1a). Their specific pore volume and pore diameter were 0.12 cm3/g and 2.70 nm, respectively, which are obtained from an adsorption branch on the Barrett-JoynerHalenda (BJH) measurement. CMS nanoparticle solution with 2.70 nm of pore diameter is classified as A type and 30-nm-sized A-type CMS nanoparticles are denoted as CMS-A30.



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Figure 2. The TEM images of different types of colloidal mesoporous silica (CMS) nanoparticles; (a) CMS-A30; (b) CMS-A75; (c) CMS-B75; (d) CMS-C50. Scale bar is 20 nm.

Keeping pore diameter at 2.70 nm, we have prepared larger particles by increasing pH with sodium hydroxide (NaOH, 2.0 M) as described.27-28 Resulting CMS nanoparticles were spherical nanoparticles with ordered mesopores as shown in Figure 2b, of which average diameter was 75.0 nm and standard deviation was 6.49 nm (see Figure S1b), and denoted as CMS-A75. Their specific pore volume and pore diameter were measured as 1.34 cm3/g and 2.70 nm, respectively. We have further increased the diameter of the mesopores by applying the nanophase separation of polystyrene and silanes inside mini-emulsions as previously described in previous report by Nandiyanto et al.29 Typically, octane-in-water mini-emulsions were first prepared and then styrene monomer and tetraethylorthosilicate (TEOS) were added. While styrene monomers are polymerized inside mini-emulsions, TEOS are hydrolyzed and condensed into amorphous silica simultaneously, which leads to composite nanoparticles and


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converted into mesoporous particles with relatively large mesopores after high-temperature heat treatment. The average diameter and standard deviation of resulting nanoparticles were 75.0 nm and 9.63 nm, respectively by analyzing TEM image of Figure 2c as shown in Figure S1c. Their specific pore volume and pore diameter were 1.49 cm3/g and 5.25 nm, respectively. These CMS nanoparticles with 5.25 nm of pore diameter were classified as Btype and 75-nm-sized CMS nanoparticle solution was denoted as CMS-B75. Furthermore, when we reduced the volume of octane while adding more styrene monomer, average diameter of CMS nanoparticles was decreased to 50.0 nm (Figure 2d) and standard deviation was reduced slightly (~ 6.16 nm) as shown in Figure S1d. However, their pore diameter and specific pore volume increased up to 6.45 nm and 1.79 cm3/g, respectively. Therefore, we classified this CMS nanoparticle as C type and denoted this nanoparticle solution as CMSC50. In Figure 3a, we plotted the pore size distributions for those four different CMS nanoparticles and listed their values in Table 1.

Figure 3. (a) Pore diameter analysis of each particle measured using the Barrett-JoynerHalenda (BJH) method, (b) The eight samples of PDMA polymer-CMS solution in increased amount of initial PDMA amount (Ci) and increase in concentration of CMS nanoparticle solution has been stirred for three days. The supernatant containing free PDMA polymer (Cp) for TOC analysis was centrifuged at 12,500 rpm for 20 min. The amount of adsorbed PDMA (Ci – Cp) is plotted against silica concentration.



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Table 1. Characteristics and properties of colloidal nonporous silica and colloidal mesoporous silica particles. Particle Specific Specific Specific pore Pore Zeta volume diameter potential Sample diameter surface area outer surface (nm) (cm3/g) (nm) (mV) (m2/g) area (m2/g) ® TM50 30 140 90.91 -43.2 CMS-A30 30 744 219.12 0.12 2.70 -18.5 CMS-A75 75 400 273.76 1.34 2.70 -26.9 CMS-B75 75 505 296.64 1.49 5.25 -32.5 CMS-C50 50 670 513.61* 1.79 6.45 -35.7 Specific outer surface area of CMS-C50 = number of particles × single spherical surface area = ( 3.43 × 1016 )× [Surface area of particle without pore - area of pore × (the number of pores) + hemispherical surface area × (the number of pores)]; the number of pore = [4π×(radius of nanoparticle)2 / π×(radius of pore)2] × 0.9069; assuming 2D hexagonal packing; = 217.99 pores for 50-nm particle with 6.45-nm pore, Specific outer surface area = (3.43×1016) × [4π×(25×10-9)2 – π× (3.225×10-9)2×(217.99) + 2π×(3.225×10-9)2×(217.99)] = 513.61 m2/g *

Since the adhesion of nanoparticles between hydrogels is based on adsorption of polymers onto nanoparticles for a given system, we have investigated adsorption behavior of PDMA polymers onto silica nanoparticles. To this end, we performed the total organic carbon (TOC) analysis as described in a previous report31 which determined the amount of polymer chains interacting on the surface of synthesized mesoporous silica nanoparticles. Mixture of PDMA (Ci) and CMS nanoparticles were prepared and stirred at room temperature for 3 days to ensure that adsorption of polymer was at equilibrium for a given concentration. Then, mesoporous silica nanoparticles were settled down and collected by centrifugation. The supernatant including the free polymer chain (Cp) was recovered and the concentration of free polymers in supernatant was analyzed by TOC analysis. The concentration of polymer on the nanoparticle (Ci - Cp) was calculated and adsorption isotherms for commercially available nonporous silica nanoparticles (LUDOX-TM50®) and four types of different CMS nanoparticles were plotted in Figure 3b. All CMS nanoparticles showed higher polymer adsorption than the nonporous silica nanoparticles at all concentrations. Furthermore, the adsorption clearly showed that CMSC50 with the largest pore diameter can adsorb the largest amount of polymer at a given


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concentration, which is followed by CMS-B75, CMS-A75, CMS-A30, and nonporous silica nanoparticles. These results represent that the PDMA interacts at higher extent with silica nanoparticles with rougher surface (the larger pore diameter) and the larger particle diameter. As plotted in Figure 3a and Table 1, CMS-A30 have higher surface area and smaller specific pore volume than CMS-A75. However, adsorbed polymers are not matched with either parameter. Therefore, as another parameter to determine the number of adsorbed polymers on nanoparticles, we introduce the specific outer surface area which can be mathematically calculated following the density of the particle and the number of the particle occupying certain volume,32 which are discussed in more detail in the Supporting Information with Figure S2. Indeed, ratio of adsorbed polymer on CMS-A30 over A75 is approximately same as their ratio of total outer surface area. On the other hand, when CMS-B75 are compared with CMS-A75 which have similar specific outer surface area as CMS-A75, CMS-B75 shows four times more adsorbed polymers than CMS-A75 as shown in Figure 3b. Since B-type nanoparticles have twice larger mesopores, we speculate that polymer chains can be adsorbed more because polymers do not lose configuration entropy much or can access pore more deeply inside in case of large mesopores in CMS-B75 or CMS-C50. As the characteristics of nanoparticles were in good agreement with TOC analysis, the experiment was extended to measure the adhesion energy between two PDMA hydrogels by lap-shear test on universal testing machine (UTM),1 in which the same amount of silica nanoparticles was applied in between the two PDMA hydrogels (Figure 4a). For consistent measurement, lap-shear rate and forceps holding strength were kept constant for all samples and all the measurements were taken in the same day to minimize the aging effect of assynthesized hydrogels. Figure 4b represents the graph of force holding the two hydrogels against the tensile displacement when 3.0 wt% of CMS-C50 and LUDOX-TM50® used to



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glue the two hydrogels. The maximum displacement at detaching point of the CMS-C50 was 1.8 times larger than that of nonporous silica nanoparticles (LUDOX-TM50®) and the maximum retaining forces were 0.0402 N and 0.0915 N for nonporous silica nanoparticles and CMS-C50, respectively, representing the adhesion force is significantly higher in CMSC50 than nonporous silica nanoparticles.

Figure 4. (a) Universal testing machine (UTM) adhesion analysis of CMS nanoparticles applied between the two polydimethylacrylamide (PDMA) gels. Geometry and dimension of the overlapped region in PDMA gels applied with CMS nanoparticle solutions. Red arrow indicates the tensile force direction. (b) Graph of force holding the two hydrogels against the tensile displacement when 3.0 wt% nonporous silica nanoparticle and CMS nanoparticles with the largest pore diameter. (c) The adhesion energy depending on concentration of silica nanoparticles (wt%). (d) The adhesion energy depending on the total outer surface area (m2), after the maximum peak points showing speculation of polymers from both hydrogels at surface not adsorbing on same nanoparticles but different ones near each surface due to the excess free nanoparticles (inset).


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Based on the lap-shear test, we next calculated the adhesion energy following the equation; Gadh = 3 (F/w)2 / (2Eh), where F is the maximum force holding the two hydrogel in Newton (N), w and h denoting the width and thickness of the hydrogel in meters (m) respectively, and E denoting elastic modulus of the prepared PDMA hydrogel in pascals (Pa).1 As plotted in Figure 4c, the adhesion energy of all types of CMS nanoparticles were higher than that of nonporous silica over all concentrations. The adhesion energy increased as silica concentration increased, reaching the highest value, for example, at around 3.0 wt% for CMS-C50 nanoparticles, and decreased upon increasing silica concentration. We speculate that the confined adhesion surface available in hydrogels was almost occupied upon applying 3.0 wt% of CMS-C50 so that higher concentrations than 3.0 wt% could be less effective in adhesion between hydrogel. Moreover, lower concentration solutions of CMS-C50 nanoparticles showed similar or even much higher adhesion energy comparing with nonporous nanoparticles, which would be the biggest advantage of using CMS nanoparticles as adhesives. For example, the adhesion energy upon applying 0.3 wt% CMS-C50 was 11 times higher than the case of applying nonporous silica nanoparticle with the same concentration; i.e. 0.3 wt% nonporous silica nanoparticle and CMS-C50 showed the adhesion of 2.0 J/m2 and 22.0 J/m2 respectively. This is consistent with polymer adsorption data in Figure 3b. In order to clarify whether polymer adsorption was enhanced by only surface area or synergistic effect of low loss of conformational entropy of polymer in large pore, we have plotted adhesion energy as a function of total outer surface area as shown in Figure 4d. We can clearly see that adsorption energy increases with total outer surface area but the curves do not overlap because polymer adsorption can be enhanced with pore diameter due to reduced entropic loss of polymer chain conformation. Moreover, surprisingly, we found that the maximum adhesion energy was located in the range between 0.1 and 0.2 m2 of total outer



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surface area, which supports the argument that total outer surface area is important factor determining the optimum concentration of CMS nanoparticle solution for maximizing the adhesion energy. Beyond those maximum peak points, we speculate that polymers from both hydrogels may not be adsorbed on same nanoparticles in interface, but may adsorbed on different ones near each hydrogel surface due to the excess free nanoparticles (inset of Figure 4d). In further discussion on area, when polymer gets adsorbed on the rough surfaces, the mathematical theory has been applied to observe in the integral region as to wave function. In the references as the polymer chain and the surface interacts there is a ‘coil-to-globule transition’.33-36 As for the PDMA case, the globule size, NF-blob, closely approaches 2.0 nm.37 A better adhesion of polymers on the surface could be explained by the NF-blob size fitting to the pore diameter, which coincides as the pore diameter increases. If the pore diameters are much greater than NF-blob size, it has a better chance of fitting inside the pore or diffusing more into deeper inside mesopores. In addition, we have measured time-dependent adhesion strength with 3.0 wt% of CMS-C50 nanoparticle. As shown in the Supporting Information Figure S3, the adhesion energy reaches the half of its maximum within 5 minutes and then become maximum adhesion energy (~35 J/m2) within 15 minutes.


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Figure 5. (a) Schematic illustration of wound healing process on mouse skin by applying CMS nanoparticles; (i) incision opened wound cut, (ii) adhesion of wound by adsorption of extracellular matrix polymer on CMS nanoparticles applied, (iii) CMS nanoparticle degradation partly maintaining the adhesiveness, (iv) finally complete heal of the wound area. (b) In vivo comparison of wound healing on mouse by (5/0, Ethicon) standard suturing (i, iv, vii, x), or applying nonporous LUDOX-TM50® (ii, v, viii, xi), and CMS-C50 (iii, vi, ix, xii). (i-ix) Representative images of wounds of the tested groups. (x-xii) Optical microscopic images of the wounded skin tissue stained with standard haematoxylin and eosin (H&E). Red arrow indicates the healing area. Scale bar is 200 µm. Based on their superior adhesion property with hydrogels, we also tested CMS nanoparticles on wound adhesion of mouse skin since the nature of biological tissue having extracellular matrix is comparable to hydrogel having a polymer and a cross-linker.4 Schematic diagram in Figure 5a illustrates wound healing process on mouse skin by applying CMS nanoparticles. On an open wound site, CMS nanoparticles were brushed and adsorbed onto extracellular



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matrix in which tissues are glued under gentle pressure (Figure 5a i and ii). CMS nanoparticles start being degraded slowly but maintain adhesiveness and finally complete heal of the wound area is achieved as shown in Figure 5a iii and iv. Wound healing effects of CMS nanoparticles were evaluated in normal healthy mice (Figure 5b). The skin wound area was closed either by conventional suturing, or applying nonporous silica nanoparticles (3 wt%), and CMS-C50 (3 wt%). At day 3, wound closure showed no leakages, infection, or inflammatory reactions with nonporous silica nanoparticles and CMSC50 (Figure 5b v, vi), while suturing showed small inflammation (Figure 5b iv). At day 5, wounds showed no leakage, infection, or inflammatory reactions in all cases (Figure 5b vii, viii, ix). Wound sections at day 5 were stained with hematoxylin and eosin to investigate the changes in morphology of skin layers during the healing process (Figure 5b x, xi, xii). CMS50 treatment showed a significant healing response compared to conventional suture and application of non-porous silica nanoparticles. Clearly, the wound closed with applying CMS-C50 nanoparticle solution showed higher arrangement of epidermal layers compared to other conditions. To further investigate the extent of collagen deposition in healed tissue, wound cross-sections at day 5 were stained with Masson’s trichrome (Figure S4). Wounds treated with CMS-50 showed significantly increased density of collagen compared to all other conditions. These results represent that the application of CMS-50 nanoparticles could lead to rapid wound healing. The complete wound healing for relatively short period of time would be advantageous for soft tissues such as liver, spleen, kidney or lungs.38-40 We speculate that the strong adhesion property of mesoporous silica nanoparticles in skin wound be beneficial in hemostasis, the initial phase of wound healing in injured site.41 As wound healing is complex cascades of diverse cellular events of innate immune cells, inflammatory cells, and epithelial cells, more detailed contribution of mesoporous silica nanoparticles in wound healing process needs to be further investigated in the future.


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Furthermore, the biodegradability of the nanoparticles must be considered to prevent unwanted accumulation in tissues after administration into the body. For investigating the degradation of our CMS nanoparticles in body, we have prepared simulated body fluid (SBF) following the previous references related to the silica nanoparticles, 19-23 which is called as corrected simulated body fluid or c-SBF

19-23

and does not contain any enzyme or protein.

The concentration of silicon that leached from the particles in the supernatant was measured via inductive coupled plasma optical emission spectrometry (ICP-OES) analysis (Figure 6).

Figure 6. Degradation study of five different types of silica nanoparticle in simulated body fluid (SBF) (0.1 mg/mL). CMS in SBF could be degraded due to the corrosion reaction with cations such as Ca2+ and Mg2+.19-20 The equilibrium phase seen in the later stage showing a slow degradation rate after faster initial degradation can be explained by the subsequent deposition of calcium and magnesium silicate on the silica surface preventing the continuous corrosion reaction from the cations.21 For all CMS nanoparticles, almost over 70% of silica were degraded within 24 hours, then began to reach plateau afterwards. The complete degradation was not yet achieved after 5 days, which may be due to the saturation limit of silicon species in SBF.19 In any case, the fast degradation rate was observed in order of CMS-A30, followed by CMS-



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C50, CMS-B75, CMS-A75, and nonporous silica nanoparticles, respectively. CMS-C50 particles with the largest pore showed the fastest degradation rate when compared to CMSB75 of CMS-A75. In case of CMS-A30, the degradation was up to 90% within a couple of hours despite the pore diameter is smaller than CMS-C50 and CMS-B75. This might be because higher corrosion reaction induced by cations was resulted in silica nanoparticles with higher specific surface area via facile deposition. This could explain the fastest degradation rate of CMS-A30 compared to other samples despite its smaller pore diameter. Notably, since the CMS nanoparticles are degraded heterogeneously, their mesoporous structures may be maintained partly during the degradation process in simulated body fluids (SBF),20-21 which may keep the biological tissues adhered. Since it is also crucial to maintain adhesiveness during the degradation, adhesiveness was monitored during the degradation stage. We have immersed glued hydrogels in SBF solution. At designated time of 2, 6, and 12 hours, we have observed that the two hydrogels were still held together well without detachment or peeling (Figure S5a). In addition, the morphologies of CMS nanoparticles were also observed during the degradation in 0.1 mg/mL of SBF solution for 2 and 4 hours. As shown in the Figure S5b, the TEM image shows that the degradation begins from the interior so that the exterior shape of CMS nanoparticle does remain spherical. Therefore, as while CMS nanoparticle degrades, the less change of exterior morphology would hold its adhesiveness. Finally, we investigated the cytotoxicity of CMS-C50 nanoparticles that were used as tissue adhesive in animal study. CMS-C50 nanoparticles with different concentrations were incubated with 4T1 cells using cell counting kit 8 (CCK-8) assay. The cell viabilities after 6, 12, and 24 h of incubation with CMS-C50 nanoparticles were similar and no cytotoxicity was observed even up to a concentration of 500 µg/mL (Figure S6), suggesting that CMS-C50 nanoparticles could be used as a tissue adhesive without significant toxicity to the cells.


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CONCLUSION The concept of utilizing colloidal mesoporous silica (CMS) nanoparticle as strong adhesives for hydrogels and biological tissues has been explored with varying the average particle diameter and its pore diameter. First, the stable colloidal mesoporous silica nanoparticles were successfully prepared in solution. As for the adhesion strength and the interaction of PDMA hydrogels on the surface of the CMS nanoparticles, the TOC analysis showed a good agreement with the adhesion data. As the CMS nanoparticles were compared to commercially available nonporous silica nanoparticles, the intrinsic feature of CMS nanoparticles is the presence of pore inside, but their total outer surface area was key parameter in determining the adhesion energy. The single strand polymer chain has vesture amount of space to interact on the large total surface of CMS nanoparticles resulting from increase in diameter and the presence of larger pore diameter. Using CMS nanoparticles, in vivo wound closure and healing test on mouse skin was conducted, which showed better wound healing compared with conventional suturing. In addition, the degradation study of the CMS nanoparticles in SBF showed that porous silica may degrade in physiological condition, which might be beneficial aspect of using those as bio-adhesives. Furthermore, more detailed and better understanding of biological wound healing from the adhesion by CMS nanoparticles could enhance the future regenerative tissue engineering.



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EXPERIMENTAL SECTION Materials.

LUDOX-TM50®,

hexadecyltrimethylammonium

chloride

99%

(CTAC),

hexadecyltrimethylammonium bromide 99% (CTAB), triethanolamine 99% (TEOA), tetraethyl orthosilicate 98% (TEOS), L-lysine 98%, styrene 99%, 2,2’-azobis(2methylpropionamide) dihydrochloride 97% (AIBA), hydrochloric acid 37% (HCl), ethanol 99%, sodium hydroxide 98% (NaOH), N,N-dimethylacrylamide 99% (DMA), potassium persulfate 98% (KPS), N,N,N’,N’-tetramethylethylenediamine 99.5% (TEMED), N,N’methylenebis(acrylamide) 99% (MBA), sodium chloride 99% (NaCl), sodium bicarbonate 99% (NaHCO3), potassium chloride 99% (KCl), potassium phosphate dibasic trihydrate 99% (K2HPO4·3H2O), magnesium chloride hexahydrate 99% (MgCl2·6H2O), calcium chloride 96% (CaCl2), sodium sulfate 99% (Na2SO4), and tris(hydroxymethyl)aminomethane 99.8% were purchased from Sigma-Aldrich and used without further purification. The solvent reaction was Millipore purified deionized water.

Colloidal Mesoporous Silica (CMS) Nanoparticles. Three pore types of the mesoporous silica nanoparticle are synthesized using a well-known sol-gel process with templates. CMS nanoparticles with small mesopores (5nm) (type B and C) was synthesized using mini-emulsion with polymers and silica precursor.29 Templates for mesopores are removed by either calcination at high temperature or an acid extraction.

To synthesize small A-type CMS nanoparticles [PNB 110005], typically, a stock solution was firstly prepared as follows: 64.0 mL water, 10.5 mL ethanol, and 10.4 mL of 25.0 wt% CTAC solution were mixed and stirred for 10 min. at room temperature. To the above solution, 4.125


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mL TEOA was subsequently added and further stirred until all TEOA was dissolved, resulting in pH values of 11.5. Then the 20.0 mL of the stock solution was heated in an oil bath at 60 °C in which TEOS (1.454 mL) as silica precursor is added dropwise (within 2-3 min.) under stirring. The whole solution started to become turbid in 10 min. The solution was cooled to room temperature after 2 hours. Once the reaction was stopped, the samples were collected by centrifugation at 28,000 rpm for 35 min. The white solid product was immediately taken up in distilled water, sonicated, and repeatedly washed three times with ethanol. Surfactant templates are burned out at 400 °C for 3 hours inside furnace, in which temperature is raised at a constant rate of 1.5 °C/min.

For larger CMS nanoparticles of type A, a different method was applied. The method is adapted from the Yang et al, modified without co-template PFOA.27 In a typical synthesis, 0.2 g of CTAB was dissolved in 192.0 g of deionized water. While stirring 0.7 mL of 2.0 M of NaOH was added and the temperature of the reaction was maintained at 80 °C. To this solution, 1.34 mL of TEOS was added and the mixture was continuously stirred for an additional 12 hours. The resulting white powder was collected by centrifugation at 8,000 rpm for 25 min and repeatedly washed three times. The template removal was again conducted by calcination method mentioned above. The synthesized particle was also analyzed with TEM.

To vary the pore diameter of the mesoporous nanoparticle (type B and type C), the miniemulsion method by Nandiyanto et al has been adapted with slight modification.29 First, an aqueous solution was prepared by dissolving 0.1 g of CTAB in 30.0 mL at 60 °C in threenecked flask reactor. The mixture was stirred about 30 minutes until all the material was dissolved. Then in subsequent order octane, styrene monomer, L-lysine, TEOS and AIBA were added. The whole mixture was allowed to react for 3 hours under nitrogen at constant



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temperature of 60 °C. The reaction was stopped and the suspension was gradually cooled to room temperature. Then the cooled suspension was decanted for overnight and purified by centrifugation with ethanol several times. Finally, the template was removed by heat treatment of the particles at 500 °C under atmospheric condition for 5 hours. In this synthesis, the overall mass ratio of H2O:octane:TEOS:L-lysine:CTAB was 310:100:10:0.22:1; the amount of styrene monomer was 0.39 mg/mL and the amount of AIBA was 0.84 mg/mL relative to whole volume of the mixture. The amount of octane within the same system from synthesis of type B CMS nanoparticles, was decreased and the amount of styrene monomer was increased to produce type C CMS nanoparticles, which had smaller average diameter and larger pore diameter.

Characterization. The morphologies of the nanoparticles were observed under transmission electron microscopy (TEM JEM-2100F, JEOL LTD, USA). The specific pore volume and pore diameter distributions were analyzed from an adsorption branch on a BELSORP-max (MicrotracBEL Corp., Japan) by using the Barrett-Joyner-Halenda (BJH) method. The specific surface area was measured using the Brunauer-Emmett-Teller (BET) method on a BELSORP-max (MircrotracBEL Corp., Japan). The zeta potential of each particle was measured on a Zetasizer Nano ZS90 (Malvern Instruments Ltd., UK).

Adsorption Measurements. The total organic carbon (TOC) analysis on a TOC-V CSH (Shimadzu Corp., Japan) was used to determine and calculate the amount of polymer chains interacting on the surface of synthesized mesoporous silica nanoparticle following experimental procedure in previous report.31 In briefly, eight different series of PDMA-CMS nanoparticles mixtures were prepared in pH 8.0 by increasing the amounts of polymer (Ci). During the addition, concentration of mesoporous silica nanoparticle was increased from 1.0


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mg/mL to 25.0 mg/mL. The samples were stirred at room temperature for 3 days to insure enough interaction and mesoporous silica nanoparticle was settled down and collected by centrifugation at 12500 rpm for 20 minutes in 1.5 mL centrifuge tubes at room temperature. The supernatant, which contains the free polymer chain (Cp), was recovered and submitted for TOC. Thus, the adsorbed concentration of polymer on the mesoporous silica nanoparticle would be equal to Ci - Cp.

Adhesion Test. Universal testing machine (UTM) on Cometech QC-508E equipped with 50N load cell at a speed of 150 mm/min was used to conduct lap-shear test. In order to keep the experiment condition comparable to the earlier experiment conducted with nonporous silica nanoparticles (LUDOX-TM50®) from the previous report,1 the same PDMA hydrogel was synthesized accordingly and followed. For typical experiment, the pre-synthesized PDMA hydrogel (S0.1) with elastic modulus of 10 kPa was cut to dimension of 30 mm × 5.0 mm × 1.5 mm (L × w × h; denoting length × width × thickness). On to one side of the hydrogel, the 10.0 µL solution of CMS nanoparticles prepared earlier and dispersed in water was spread for gluing the two hydrogels. The overlap region was 10 mm × 5.0 mm in length and width respectively, thus volume of droplet is 0.20 µL/mm2. The adhesion energy, when the dispatching is occurred by interfacial peeling between the hydrogels, was measuring from the maximum holding force is evaluated using the equation; Gadh = 3 (F/w)2 / (2Eh); where F is the maximum force holding the two hydrogel in Newton (N), w and h denoting the width and thickness of the hydrogel in meters (m) respectively, and E denoting elastic modulus of the prepared PDMA hydrogel in pascals (Pa). Therefore the unit of Gadh is Joules per meter square (J/m2).1

In Vivo Mouse Study. In order to observe the potential usage in real application, the CMS



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silica nanoparticle was applied on mouse (BALB/C) wound skin for in vivo study similar to the one mentioned by Meddahi-Pellé et al.4 First the mouse was treated to anesthesia for 5 minutes. A thin skin wound of 1.5 cm in length and 3.0 mm in depth was made by cutaneous incision. In first case the wound of a mouse was treated with clinical thread (5/0, Ethicon) standard suture technique, second wound was treated with 3.0 wt% 10.0 µL of nonporous silica nanoparticles and the third wound was treated with 3.0wt% of 10.0 µL CMS-C50. The wound area was held steady for 30 minutes while the mouse was anesthesia. Once the wound has been closed the mouse was returned to its normal life. At day 3 and 5, the wound area was di-sectioned to 1.0 cm × 1.0 cm. The cut area was first embedded in epoxy resin, then cross-sectional slices was stained with hematoxylin and eosin (H&E) and Masson’s Trichrome. The cross-sectional of wound skin that was observed under the optical microscope.

Degradation Study of Colloidal Mesoporous Silica Nanoparticle in Physiological Condition. The degradation study of different CMS nanoparticles were conducted in simulated body fluid (SBF) over designated time period similar to those reported earlier.19-23 First the SBF was prepared according to the previous reports.20 To prepare 1.0 L of SBF; NaCl (7.996 g), NaHCO3 (0.35 g), KCl (0.224 g), K2HPO4·3H2O (0.228 g), and MgCl2·6H2O (0.305 g) were dissolved in 750 mL of deionized water. Then HCl (3.34 mL, 12 M) was added to the solution; and in sequential manner CaCl2 (0.278 g) Na2SO4 (0.0701 g), and tris(hydroxymethyl)aminomethane (6.057 g) were added in order. Finally, the solution was diluted to 1.0 L and pH was adjusted to 7.4 with HCl. The prepared SBF was filtered with 0.25 µm steritop filter before use. For the degradation study, each CMS nanoparticles were dispersed in SBF at concentration of 0.1 mg/mL. The solutions were shaken at 150 rpm at 37 °C. In designated time interval (0h, 2 h, 4h, day 1, and day 5), the samples were collected


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and centrifuged at 11,000 rpm for 10 min. The supernatant was collected and analyzed via inductively coupled plasma optical emission spectroscopy (ICP-OES) on 5100 ICP-OES (Agilent, USA) to measure the amount of silicon that leached from the particles.19

ASSOCIATED CONTENTS Supporting Information Histograms of the CMS nanoparticle characterization, calculation of specific total outer surface area of the CMS nanoparticle, time-dependent adhesion energy profile of the CMS nanoparticle, Optical microscopic images of the wounded skin tissue stained with Masson’s trichrome, cytotoxicity/biocompatibility of the CMS nanoparticle with 4T1 cells, and further SBF study is included in the supporting information. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Authors *Email: [email protected] *Email: [email protected] Author Contributions #

J.-H. K. and H. K. authors contributed equally.

ACKNOWLEDGMENTS We would like to thank Prof. Leibler for his helpful discussion in initial stage and Dr. Sung H. Lim for his critical reading. This work was supported by a grant from the Research Program (2014M3A9B8023471 and 2010-0029409) of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, Korea.



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ABBREVIATIONS CMS; colloidal mesoporous silica, BJH; Barrett-Joyner-Halenda, BET; Brunauer-EmmettTeller, DI; deionized water, TEM; transmission electron microscopy, TOC; total organic carbon, SBF; simulated body fluid, ICP-OES; inductively coupled plasma optical emission spectrometry


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TOC graphic

Colloidal Mesoporous Silica Nanoparticles as Strong Adhesives for Hydrogels and Biological Tissues Joo-Hyung Kim,†,# Hodae Kim,†,# Youngjin Choi,† Doo Sung Lee,† Jaeyun Kim,†,§, ‡ * and GiRa Yi†,* †

School of Chemical Engineering, §Department of Health Sciences and Technology, Samsung

Advanced Institute for Health Science & Technology (SAIHST) and ‡Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, Republic of Korea *Email: [email protected] (G.-R.Y.), [email protected] (J.K.)


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Colloidal Mesoporous Silica Nanoparticles as ... - ACS Publications

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