Near-Infrared-Detached Adhesion Enabled by Upconverting Nanoparticles.

Achieving efficient and biocompatible detachment between adhered wet materials (i.e., tissues and hydrogels) is a major challenge. Recently, photodetachable topological adhesion has shown great promise as a strategy for conquering this hurdle. However, this photodetachment was triggered by UV light with poor biocompatibility and penetration capacity. This study describes near-infrared (NIR) light-detached topological adhesion based on polyacrylic acid coated upconverting nanoparticles (UCNP@PAA) and a photodetachable adhesive (termed Cell-Fe). Cell-Fe is a coordinated topological adhesive consisting of carboxymethylcellulose and Fe3+ that can be photodecomposed by UV light. To prepare a substrate for NIR-detached topological adhesion, UCNP@PAA and Cell-Fe were mixed and brushed on the surface of the model adherent. The UCNP@PAA can harvest NIR light and convert it into UV light, triggering the decomposition of the Cell-Fe and inducing the detachment. This NIR-detached topological adhesion is also feasible in deep tissue because of the ability of NIR light to penetrate tissue.

Introduction

Adhesion between wet materials (i.e., tissues and hydrogels) has broad applications, including in tissue repair, wound dressing, wearable electronic devices and drug delivery (Yang et al., 2018, Li et al., 2017, Li and Mooney, 2016). For some expensive and biological adherents, non-invasive on-demand detachment is necessary, but it is not easily achieved with traditional adhesives (Yang et al., 2018, Li et al., 2017, Li and Mooney, 2016). Detachable topological adhesion is an attractive solution to this problem (Yu et al., 2011). Topological adhesion, specifically topological entanglement with the two preexisting molecular networks, involves the diffusion of polymer chains into the two preexisting molecular networks, forming a third polymer network in situ due to cross-linking (Steck et al., 2019). As a result, the breaking of the topological adhesion via detachment requires the breaking of the third network formed by the diffused polymer chains (Sun et al., 2013, Xu et al., 2010). Several methods, such as pH (Yang et al., 2018), thermo (Luo et al., 2010), and light (Kamperman and Synytska, 2012), have been developed to detach topological adherents. Light shows promise in detaching topological adherents as it can provide spatiotemporal control (Xu et al., 2018, Guimard et al., 2012). However, photodisrupted topological adhesion has only been achieved by using UV light, which is problematic because its high-energy photons can damage DNA and important chemical bonds (Wang et al., 2017). Moreover, UV photons cannot deeply penetrate tissue, which might limit their applications in thick and macroscopic adherents (Strehmel and Strehmel, 2007). To solve these problems, we turned our attention to near-infrared (NIR) light. NIR light can deeply penetrate guest materials while causing less photodamage to chemical bonds and biological systems (Lederhose et al., 2016). Recently, NIR light-triggered photoreactions based on upconverting nanoparticles have been developed (Wu et al., 2016, Yan et al., 2012, Carling et al., 2009, Chen et al., 2014a, Chen et al., 2014b). Upconverting nanoparticles can convert NIR light into UV and visible light (Chen et al., 2015a, Chen et al., 2015b, Chan et al., 2012, Wu et al., 2016, Huang et al., 2016, Li et al., 2013, Tian et al., 2013, All et al., 2019). Then, the upconverted UV or visible emission can trigger photoreactions of traditional UV- or visible light-responsive compounds. This process is referred to as upconverting nanoparticle-assisted photochemistry (Wu and Butt, 2016, Yang et al., 2012, Yang et al., 2015, Viger et al., 2013, Wu et al., 2011, Ruggiero et al., 2014, Burks et al., 2013). Upconverting nanoparticles have facilitated different photoreactions, including photoisomerization (Wu et al., 2011, Li et al., 2014), photocleavage (Yan et al., 2011, Zhao et al., 2014), photopolymerization (Yang et al., 2012, Stepuk et al., 2012), and photocoupling (Lederhose et al., 2016). These upconverting nanoparticle-assisted photoreactions have been applied to NIR-controlled biointerfaces (Li et al., 2014, Chen et al., 2015a, Chen et al., 2015b), catalysis (Chen et al., 2014a, Chen et al., 2014b), uncaging enzymes (Gao et al., 2015), drug delivery (Yang et al., 2015, He et al., 2015), pH adjustments (Chen et al., 2016), and actuators (Wu and Yao, 2011). Here, we use NIR light to detach a topological adherent based on upconverting nanoparticle-assisted photochemistry (Figure 1). We refer to this new method as photon upconversion topological adhesion detachment (PUTAD). To construct a platform for PUTAD, water-soluble NaYF4:TmYb@NaYF4@PAA upconverting nanoparticles (UCNP@PAA) and photodetachable adhesives (Cell-Fe) were prepared. In this study, topological adhesion was first achieved to a model adherent (polyacrylamide [PAAm] hydrogel) using UCNP@PAA-doped Cell-Fe adhesives via coordination between Fe3+ and carboxymethylcellulose. Upon NIR irradiation, UCNP@PAA can convert NIR light to UV light, which photoreduces Fe3+ to Fe2+ and disrupts the coordination (Figure 1). As a result, the adherent was detached from the hydrogel. Moreover, the as-developed PUTAD demonstrated effective photodetachment in deep tissue. NIR could penetrate 3-mm-thick tissue and trigger detachment between the hydrogel and tissue.

Figure 1

Schematic Illustration of NIR-Detached Adhesion Enabled by Upconverting Nanoparticles

(A) Schematic of the coordination between carboxymethylcellulose and Fe3+ and NIR-triggered photoreduction assisted by the UCNP@PAA.

(B) Topological adhesion and NIR-disrupted topological adhesion between hydrogels based on UCNP-assisted photoreduction.

Results

NaYF4:TmYb@NaYF4 upconverting nanoparticles with an average diameter of 50 nm were synthesized according to our previous work (Figure 2A) (Chen et al., 2015b). To prepare water-soluble UCNPs, polyacrylic acid (PAA) was used to coat the hydrophobic surface of the UCNPs. In this manner, UCNP@PAA with suitable water solubility were synthesized (Figures 2B and 2C). These UCNP@PAA emitted blue light under 974-nm NIR light excitation (Chen et al., 2015b). The absorption band of Cell-Fe was between those of carboxymethylcellulose and Fe3+ in the UV light region and overlapped with the UV emission of the UCNP@PAA (Figure 2D). To demonstrate the absorption of the upconverted UV light by Cell-Fe, we compared the upconversion luminescence spectra of UCNP@PAA in the presence and absence of Cell-Fe. The intensity of the upconversion luminescence of UCNP@PAA at 360 nm was lower in the presence of Cell-Fe (Figures 2E and S1). A higher concentration of Cell-Fe absorbed more of the upconverted UV light, resulting in a lower emission intensity (Figure 2E). In contrast, the emission at 800 nm, a spectral region where Cell-Fe has no absorption, still remained (Figure S2). The transfer efficiency between UCNP@PAA (2 mg/mL) and Cell-Fe (Cell = 1 wt%, Fe3+ = 0.81 mg) was 51.5% according to the equation (Supplemental information Equation S1). This result suggested the efficient absorption of the upconverted UV light by Cell-Fe. Subsequently, the NIR-triggered reduction of Fe3+ through the assistance of UCNP@PAA was investigated (Figure 2F). Approximately 88% of Fe3+ was reduced to Fe2+ upon NIR irradiation for 100 min (Figure 2G). This spectral change was identical to that observed for Cell-Fe, which was directly photoreduced using UV light (Figure 2G). Thus, Cell-Fe was photocleaved by NIR light radiation. Exposing Cell-Fe to NIR light in the absence of UCNP@PAA did not obviously reduce Fe3+ (Figure S3), proving that the photon upconversion process was required for the photoreduction of Cell-Fe.

Figure 2

NIR-Triggered Photoreduction Assisted by UCNP@PAA

(A–C) TEM images of (A) UCNPs, scale bar: 100 nm; (B) UCNP@PAA, scale bar: 50 nm; and (C) UCNP@PAA, scale bar: 20 nm.

(D) Absorbance of Cell-Fe and fluorescence emission of UCNP@PAA.

(E) Fluorescence emission of UCNP@PAA (ranging from 350 to 390 nm) upon addition of Cell-Fe at different concentrations.

(F) Schematic of NIR-triggered photoreduction assisted by UCNP@PAA.

(G) Changes in the Fe3+/Fe2+ concentrations upon NIR irradiation (1 W) in the presence of UCNP@PAA.

See also Figures S1–S3.

After that, an aqueous solution of carboxymethylcellulose chains was brushed on the surfaces of two pieces of polyacrylamide (PAAm) hydrogel, and the pieces were left to stand for some time to allow the carboxymethylcellulose chains to diffuse into the hydrogels. Subsequently, an aqueous solution of Fe3+ with citric acid at a controlled pH (pH = 3) and UCNP@PAA was added to one piece of hydrogel, and the other piece of hydrogel was immediately pressed on top of the coated piece. The Fe3+ ions diffused into the hydrogel and formed coordination complexes with the carboxyl groups, which cross-linked into a carboxymethylcellulose network, resulting in topological entanglement with the two preexisting PAAm networks of the hydrogels. The strength of the topological adhesion was dynamically detected. After 60 min, the adhesion strength reached ∼50 J m−2 (Figures 3A and S4). Having determined the topological adhesion, NIR-triggered photodetachment was investigated (Figures 3B and S5). Before NIR irradiation, SEM images of the interface of the two hydrogels were acquired. A dense interfacial zone ∼0.5 μm thick formed between the two hydrogels (Figure 3C, left). Upon NIR irradiation, UCNP@PAA converted the NIR light to UV light, which photoreduced Fe3+ to Fe2+. After that, the Fe3+-cross-linked carboxymethylcellulose network dissociated, regenerating the polymer chains, and an obvious crack was observed (Figure 3C, right). The adhesion strength also decreased from ∼60 to ∼9 J m−2 upon NIR irradiation (Figure 3D). As a control, the adhesion strength did not show an obvious change without NIR irradiation (Figure 3D). To investigate the possible thermal effect on the detaching process, we used an IR camera to detect the temperature change during the detachment and ∼6°C increase was observed (Figure S8). To check whether this photothermal effect contributed to the detachment, a control group in the absence of UCNP@PAA upon NIR excitation was added. The adhesion strength did not show obvious changes (Figure 3D). These results confirmed that the detachment was triggered by photon upconversion process rather than by photothermal effect. To make the detachment more obvious, a weight was attached to the glued hydrogel. The glued hydrogel was detached and the weight dropped upon NIR irradiation (Figure S6A and Video S1). While, no any change was observed without NIR irradiation (Figure S6B and Video S2). The photodetachment was closely related to the concentration of UCNP@PAA. Higher concentrations of UCNP@PAA triggered more obvious photodetachment of the hydrogels. When the concentration of UCNP@PAA in the adhesive formula was 3 mg/mL, NIR irradiation triggered a loss of ∼80% of the adhesion strength (from ∼42 to ∼8 J m−2, Figure 3E). The photodetachment of the hydrogels was also investigated upon NIR irradiation at different intensities. More obvious photodetachment was observed with higher-intensity NIR radiation. NIR irradiation at 1 W only triggered a 40% decrease in the adhesion strength (∼53 to ∼31 J m−2, Figure 3F). In contrast, a loss of ∼80% adhesion strength was observed upon NIR irradiation at 4 W (∼53 to ∼8.5 J m−2, Figure 3F). These results demonstrated that an NIR source could be used to detach topological adherents in a well-controlled manner.

Figure 3

NIR-Detached Hydrogel Adesion Assisted by UCNP@PAA

(A) Strength of the topological adhesion between hydrogels at different times.

(B) Schematic of NIR-triggered detachment of topologically adhered hydrogels.

(C) SEM images of topological adhesion between hydrogels before (left) and after NIR irradiation (right); scale bar: 5 μm.

(D) Strength of the topological adhesion between hydrogels before and after NIR irradiation (NIR intensity = 4 W). Control 1: before irradiation with UCNP@PAA, Control 2: after irradiation without UCNP@PAA.

(E) Strength of the topological adhesion between hydrogels before and after NIR irradiation at different concentrations of UCNP@PAA (NIR intensity = 4 W, irradiation time = 5 min).

(F) Strength of the topological adhesion between hydrogels upon NIR irradiation at different intensities.

*p < 0.05, **p < 0.01, ***p < 0.001, ns = no statistical difference. See also Figures S4–S6 and S8.

Topological adhesion disruption is of great importance in bio-medical fields. Thus, the as-developed PUTAD strategy was explored for disrupting the adhesion between tissue (3 mm) and a hydrogel. Before that, the biocompatibility of the PUTAD strategy was investigated. MTT assays showed that cell growth was not obviously inhibited when the concentration of the PUTAD formula (30% UCNP@PAA, 10% Cell, 40% Fe3+, and 20% citric acid) reached 1,000 μg/mL (Figure S7). The biocompatibility of upconverted UV light was also evaluated by MTT assay. There is no obvious difference between the cellular viability with and without UCNP@PAA upon excitation of NIR light (Figure S9). These results demonstrated that the PUTAD strategy has good biocompatibility and can be used in biological systems. After that, topological adhesion between tissue and a hydrogel was achieved using a UCNP@PAA Cell-Fe composite. Subsequently, NIR radiation penetrated the tissue to photodetach the adherents (Figure 4A). The topological adhesion strength between the hydrogel and tissue decreased from ∼22 to ∼3 J m−2 upon NIR irradiation (Figure 4B). As a comparison, UV irradiation alone triggered a decrease in adhesion strength from ∼22 to ∼15 J m−2 (Figure 4B). In a control experiment, the adhesion strength did not obviously change upon NIR irradiation in the absence of UCNP@PAA (Figure 4B). To further demonstrate the general applicability of the as-developed PUTAD method, UCNP@PAA was combined with different topological adhesives including sodium alginate (SA)/Fe3+ and hyaluronic acid (HA)/Fe3+ (termed SA-Fe and HA-Fe, respectively) for hydrogel and tissue adhesion. Both of the topological adhesives (SA-Fe and HA-Fe) showed good biocompatibility (Figure S7). For all samples, the adhesive strengths did not show obvious changes without irradiation (Figures 4C and 4D). However, losses of ∼63% and 86% of the adhesive strength was observed for the UCNP@PAA+SA-Fe and UCNP@PAA+HA-Fe samples, respectively (18 to 7 J m−2 and 20 to 6 J m−2) (Figures 4C and 4D). UV-treated UCNP@PAA+SA-Fe and UCNP@PAA+HA-Fe only demonstrated losses of ∼36% and ∼30% of the adhesive strength, respectively (Figures 4C and 4D). These results demonstrated that, compared with UV light, NIR light more efficiently triggered detachment of the tissue and hydrogel after penetrating the tissue. To further demonstrate the safety and applicability of the as-developed PUTAD method, hydrogel hematoxylin-eosin (H&E) staining between tissue and hydrogel was performed. We conducted the detachment using NIR light between the hydrogel and skin of mice. The HE results showed that NIR-triggered detachment did not alter the skin tissue obviously (Figure S10). These results, combined with the results of cellular experiment, confirmed the biosafety of our PUTAD strategy. This elegant photodetachment of topologically adhered surfaces in deep tissue makes the system broadly applicable in future bio-medical applications.

Figure 4

NIR-Detached Adesion Assisted by UCNP@PAA in the Deep Tissue

(A) Schematic of NIR-triggered disruption of topological adhesion between a hydrogel and tissue.

(B–D) Strength of the topological adhesion between a hydrogel and tissue upon UV irradiation (5 min), NIR light irradiation (5 min), and without irradiation. UCNP@PAA: 3 mg/mL, Fe3+: 0.25 mol/L, molar ratio of Fe3+/citric acid = 2: 1, (B) Cell: 1 wt%; (C) SA: 1 wt%; (C) HA: 0.5 wt%.

*p < 0.05, **p < 0.005, ***p < 0.001, ns = no statistical difference. See also Figures S7, S9, and S10.

Discussion

In summary, we developed a PUTAD method assisted by upconverting nanoparticles for achieving NIR-regulated detachment. Owing to the strong penetrating ability of NIR radiation, PUTAD can be applied in deep tissue, which makes it suitable for applications in bio-medical fields. Notably, although NIR-triggered photothermal effect in our study did not cause the side effect for the detachment, attention should still be paid for its future application. The NIR-triggered photothermal effect might be greatly suppressed and even eliminated using more efficient UCNPs or cooling setup. Actually, NIR light can trigger different photoreactions via upconverting nanoparticle-assisted process, such as photocleavage or photoisomerization. Thus, in the future, combining UCNPs and these photosensitive reactions might develop lots of potential NIR-regulated detachment between the wetting soft materials, tissue, or other bio-medical adherents. Thus, our method provides not only a platform for detaching topological coordination adhesion but also a general strategy for developing NIR-detachable adhesives.

Limitation of the Study

We have developed a PUTAD method assisted by upconverting nanoparticles for achieving NIR-regulated detachment. However, the adhesion was slow as the photodetachable adhesive Cell-Fe needed time to penetrate in hydrogel substrate and the interlinks could not form quickly. Instability of ionic cross-linking results in weak adhesion strengthen. To conquer this problem, the stable cross-linking covalent bond, which could be photocleaved, might be employed for the adhesion and photodetachment in the future.

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.