Designing pH-Responsive Biodegradable Polymer Coatings for

Subscriber access provided by UNIV OF BARCELONA

Applications of Polymer, Composite, and Coating Materials

Designing pH-Responsive Biodegradable Polymer Coatings for Controlled Drug Release via Vapor-Based Route Xiao Shi, Yumin Ye, Hui Wang, Fu Liu, and Zhijie Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b14016 • Publication Date (Web): 15 Oct 2018 Downloaded from http://pubs.acs.org on October 15, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Applied Materials & Interfaces

Designing pH-Responsive Biodegradable Polymer Coatings for Controlled Drug Release via Vapor-Based Route Xiao Shi,a Yumin Ye,*,a, b Hui Wang,c Fu Liu,c and Zhijie Wangd

a: Department of Materials Science and Engineering, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China b: State Key Laboratory of Silicon Materials, Zhejiang University, Hangzhou 310027, China c: Key laboratory of Marine Materials and Related Technologies, Ningbo Institute of Materials Technology & Engineering, Chinese Academy of Sciences, Ningbo 315211, China d: Key Laboratory of Semiconductor Materials Science, Beijing Key Laboratory of Low Dimensional Semiconductor Materials and Devices, Institute of Semiconductors, Chinese Academy of Sciences, Beijing 100083, China

*Please

address correspondences to:

Prof. Y. Ye Address: Department of Materials Science and Engineering, Faculty of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China E-mail: [email protected]

Keywords: Controlled drug release, biodegradable, pH-responsive, drug encapsulation, initiated chemical vapor deposition (iCVD) 1 ACS Paragon Plus Environment

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract We present the design of a novel pH-responsive drug release system that is achieved by solventless encapsulation of drugs within a microporous membrane using a thin capping layer of biodegradable polymethacrylic anhydride (PMAH) coating. The coating was synthesized via a mild vapor polymerization process, namely initiated chemical vapor deposition (iCVD), which allowed perfect retention of the anhydride groups during deposition. The synthesized polyanhydride underwent degradation upon exposure to aqueous buffers, resulting in soluble polymethacrylic acid (PMAA). The degradation behavior of PMAH is highly pH-dependent, and the degradation rate under pH 10 is 15 times faster than that under pH 1. The release profile of a model drug rifampicin clearly exhibited two stages: the initial stage that the coatings were being degraded but the drugs were well stored, and the second stage that drugs were gradually exposed to the medium and being released. The drug release also showed strong pH-responsiveness where the duration of the initial stage under pH 1 was more than 7 and 3 times longer than that of pH 10 and 7.4, respectively, and the release rates at pH 7.4 and 10 were significantly faster than that at pH 1. The pH-dependent degradation of encapsulant thus enabled good preservation of drugs under low pH environment, but high drug release efficiency under neutral and alkaline environment, suggesting potential applications in site-specific drug delivery systems.

2 ACS Paragon Plus Environment

Page 2 of 33

Page 3 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1. Introduction Controlled drug release under specific conditions enables active pharmaceutical ingredients (API) to reach target site and significantly enhances their efficacy.1 The controlled release can be achieved by employing an excipient embedding or encapsulating API, which leaches out under external stimulations, such as pH or temperature.2, 3, 4 The choice of excipient and its processing method with API are thus of paramount importance, as a proper excipient helps protect drugs intact till delivery and facilitates their release at desired sites with maximum unloading efficiency, while a proper processing method circumvents the undesired degradation and waste of API.5 Currently, most methods employed for the encapsulation or embedment of drugs are based on liquid phase techniques,6,

7

such as double emulsification,8,

9

emulsion-diffusion,10

layer-by-layer assembly,11 polymer coating,12 etc. Liquid-based methods, however, usually require complex procedures to dissolve and encapsulate drugs, and may introduce plasticizers and surfactants in the system, posing unnecessary health concerns.13 Recently, vapor-based methods have emerged as an alternative route for drug encapsulation.13 Vapor-based polymer deposition techniques, including plasma-enhanced chemical vapor deposition (PECVD)14, 15 and initiated chemical vapor deposition (iCVD),16, 17 avoid the use of any solvent; therefore eliminate the potential contaminants from solutions. Compared to traditional chemical vapor deposition (CVD) methods, which requires high processing temperature, these modified versions of CVD employ a rather mild processing environment that alleviates the risk of drug degradation. The in situ polymerization of these vapor-based methods provides a convenient and solventless way of wrapping drugs with an ultrathin solid polymer layer, thus bypassing the laborious procedures of drug dissolution and encapsulation.



In this work, we designed a novel drug release system that exploits iCVD-synthesized biodegradable polymer coatings to encapsulate rifampicin, a common antibiotic drug, inside microporous polylactide (PLA) membranes. We chose PLA membrane as the drug carrying vehicle because of its good biocompatibility and biodegradability. The iCVD technique uses a resistively heated filament inside a vacuumed chamber to cleave the vaporized initiator, and polymerizes monomers adsorbed on the substrates, resulting in ultrathin conformal coatings.17, 18 Compared to PECVD, the iCVD method is advantageous in producing stoichiometric polymer coatings,19, 20 as it avoids the use of high energy treatments like plasma, which may destruct the chemical composition and functionality of the monomers and disrupt the designed release pathways. High energy plasma may also damage the chemical composition of drugs, inducing loss of its function or even causing toxicity. Several cases have been reported of using iCVD to synthesize responsive hydrogel coatings for controlled drug release.13 McInnes et al reported encapsulation of camptothecin with pH-responsive poly(methacrylic acid-co-ethylene dimethacrylate) using iCVD, which resulted in the release of 30% more drugs in pH 7.4 buffer than under pH 1.8.21 Poly(Nisopropylacrylamide-co-diethylene glycol divinyl ether) coatings synthesized by iCVD have also been employed to impart temperature-responsive drug release, where 16% more drugs were released under 20 ˚C than under 37 ˚C during a time span of 16 h.22 So far, the use of iCVD in drug encapsulation has been restricted to hydrogel encapsulants, where the drugs are released through the meshes of swollen hydrogel network.23, 24 The efficiency, however, has been limited in the reported swelling-induced release, mainly due to the facts that: 1) the heavily crosslinked structure of iCVD-synthesized hydrogel restricted the mesh size of the coating, resulting in slow release of drugs even under swollen state; and 2) the high crosslinking degree also undermined


Page 4 of 33

Page 5 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the responsiveness of the coating, and the drug release efficiency was not significantly different between the swollen and shrunk states. We attempt to tackle this problem by designing a drug release system with a pHresponsive biodegradable polymer, polymethacrylic anhydride (PMAH), as the capping layer encapsulating drugs. Unlike hydrogel encapsulants that release drugs through meshes, biodegradable polymer coatings are able to unload encapsulated drugs much more efficiently through coating degradation.25, 26 The complete degradation of encapsulants also eliminates the encapsulant residue in the human body, thus avoiding potential contaminants.27 Biodegradable polymers, however, have not been reported to be synthesized via iCVD method, as most iCVDsynthesized polymers have –C–C– backbones and are not biodegradable. Here we designed PMAH coatings with a crosslinked network that prevents it from immediate dissolution in aqueous solution, but the anhydride groups in the MAH moiety can be hydrolyzed, especially when exposed to an alkaline medium, resulting in water-soluble polymethacrylic acid (PMAA) chains. We note this is the first report on vapor synthesis of polyanhydride with stoichiometric control. Although PMAH has been reported to be synthesized via PECVD, the high energy plasma used during deposition broke down the anhydride linkage of MAH and induced partial hydrolyzation and heavy crosslinking.28 The resultant polymer is not in stoichiometry and the degradation took unusually long time. Attempts have also been made to synthesize PMAH by thermal annealing of iCVD-synthesized PMAA films.29 The chemical composition of the resulting polymer, however, was not controllable. Maleic anhydride has been previously copolymerized with styrene,30 divinylbenzene,31 4-aminostyrene,32 and N,N-dimethylacrylamide and di(ethylene glycol) di(vinyl ether)33 using iCVD, but its homopolymerization has been difficult due to the slow polymerization rate.34



Page 6 of 33

We demonstrate stoichiometric synthesis of PMAH and a series copolymers of poly(methacrylic

anhydride-co-methacrylic

acid)

(P(MAH-co-MAA))

via

iCVD.

The

introduction of MAA in the copolymer expedited the degradation rate, and both PMAH and copolymers degraded drastically faster in alkaline and neutral solutions than that in acidic solutions. We then encapsulated rifampicin inside PLA membranes with a thin capping layer of PMAH coating, and tested its release in different pH buffers. Since the degradation of PLA is significantly slower than polyanhydride, the membrane substrate is stable during the release study.35 The release of rifampicin was not observed during the initial stage upon exposure to all solutions, but increased rapidly once the coatings degraded to a certain stage. The duration of this initial stage is much shorter and the release efficiency was also higher in alkaline and neutral solutions than that in acidic solutions.

2. Experimental Section 2.1 Materials. Precursors of MAH (94%, Aladdin, China), MAA (99%, J&K corporation, China), and tert-butyl peroxide (TBP, 97%, TCI, China) were used without further purification. Trichlorovinylsilane (TCVS, 98%) and rifampicin (97%) were purchased from TCI (China) and Aladdin (China), respectively. Sodium chloride (NaCl, 99.8%), disodium phosphate dihydrate (Na2HPO4, 99%), potassium chloride (KCl, 99.5%), and potassium dihydrogen orthophosphate (KH2PO4, 99%) were purchased from Macklin (China), and used to prepare phosphate buffered saline (PBS) solutions. 2.2 Preparation of PLA Membrane. PLA membranes were prepared using the phase inversion method.36, 37 PLA (2003D, Natural Works, China) and polyvinylpyrrolidone (PVP-k30, Aladdin, China) were dissolved in 1-Methyl-2-pyrrolidinone (NMP, 99%, Aladdin, China) with a stirring speed of 230 rpm for 24 h at 80 ˚C. After eliminating the air bubbles, the mixture was


Page 7 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


spread onto a non-woven fabric, and the thickness of the resultant coating was about 200 μm. The PLA coating was further solidified in water at 25 ˚C, and the resultant membrane was washed and dried for further application. 2.3 Loading of Rifampicin. Rifampicin was dissolved in pH 7.4 PBS buffer with the concentration of 2 mg/ml. PLA membranes were cut into round shapes with a diameter of 2.5 cm, and immersed in the rifampicin solution for 2 h at room temperature to ensure the complete invasion of solution inside the membranes. The membranes were then taken out of the solution and dried under vacuum at 37 ˚C. To estimate the amount of rifampicin loaded in the membrane, the drug-loaded membrane was soaked in PBS solution under constant vibration for 48 h to completely release the loaded rifampicin into solution. The concentration of rifampicin was determined by measuring the optical absorbance of the solution at the wavelength of 473 nm using UV-Visible spectrophotometer (UV-3101PC, Shimadzu).38 The calculated drug loading efficiency on the membrane was about 0.034 mg/cm2. 2.4 iCVD Coating. The iCVD coating was conducted in a custom-made reactor as previously reported.19,

39

Si wafer substrates were immersed in “piranha” solution (sulfuric acid and

hydrogen peroxide, 3:1) at 70 ˚C for 30 min to generate hydroxyl groups on the surface. The wafers were then treated with TCVS vapor in a vacuumed container to obtain surface vinyl groups. PLA membrane substrates with and without loading drugs were used without further treatment. During deposition, precursors of MAH, MAA, and TBP were vaporized at 50 ˚C, 55 ˚C and 30 ˚C, respectively, and fed into the reactor. The flow rate of each precursor was adjusted using needle valves (Swagelok). The filament array mounted on top of the substrates were heated to 200 ˚C, and the substrate temperature was maintained at 30 ˚C using circulating water cooling system equipped at the backside of the sample stage. An interferometry system with a 633 nm



He-Ne laser (JDS Uniphase) was used to monitor the thickness of film in situ. The detailed deposition conditions for each sample are listed in Table 1. 2.5 Characterizations. Fourier Transform Infrared (FTIR) spectra were obtained using a Nicolet 6700 FTIR spectrometer equipped with a DTGS detector. X-ray photoelectron spectroscopy (XPS) was performed using a Shimadzu Axis Utltradld spectroscope equipped with a Mg-Kα radiation source. The morphology of pristine and PMAH-coated PLA membranes were observed using a scanning electron microscope (SEM, Nova NanoSEM 450, PEI). Water contact angles (WCA) were measured using a contact angle goniometer (Kruss DSA 100), and droplet with the volume of 5 μL was used for each measurement. The contact angle data were averaged out from five measurements on the different spots of each sample. 2.6 Coating Degradation. The degradation behavior of coatings was analyzed by monitoring the remaining amount of MAH unit in PMAH and P(MAH-co-MAA) films deposited on Si wafer soaked in PBS solutions with pH 1, 4, 7.4 and 10 at 37 ˚C. After soaking for certain durations, the films were taken out and their FTIR spectra were obtained. According to the BeerLambert law, the absorbance of the coating at a certain wavelength is proportional to the concentration of the absorbing species and the path length. The remaining amount of MAH unit in the coating was then estimated by quantifying the area of –C-O-C- peak at 1027 cm-1 using Omnic Software, and the coating degradation was characterized by the percentage of remaining amount of MAH unit to the amount in the initial state. 2.7 Drug Release. The drug-encapsulated membranes were soaked in 20 mL PBS solutions with pH=1, 7.4 and 10 at 37 ˚C. The amount of released rifampicin in the solution at a desired time was quantified by measuring the concentration of rifampicin in the solution, which was obtained by measuring the optical absorbance of the solution at the wavelength of 473 nm and


Page 8 of 33

Page 9 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


correlating with the standard concentration-absorbance curve. All data were measured in triplicate, and the drug release percentage was calculated by: 𝐷𝑟𝑢𝑔 𝑟𝑒𝑙𝑒𝑎𝑠𝑒 𝑝𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒 (%) =

𝑎𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑟𝑖𝑓𝑎𝑚𝑝𝑖𝑐𝑖𝑛 𝑟𝑒𝑙𝑒𝑎𝑠𝑒𝑑 𝑎𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑡𝑜𝑡𝑎𝑙 𝑟𝑖𝑓𝑎𝑚𝑝𝑖𝑐𝑖𝑛 𝑙𝑜𝑎𝑑𝑒𝑑

3. Results and Discussion 3.1 Synthesis and Characterizations of PMAH. As illustrated in Figure 1, the encapsulation of rifampicin was carried out by first loading rifampicin inside the PLA membrane, followed by iCVD coating of polymer to occlude the pores. The iCVD coating process was conducted by flowing both vapors of TBP and MAH inside the reactor, where TBP was thermally cleaved into free radicals and initiated polymerization of MAH on the substrates. Each membrane was coated on both sides to cap the pores on both surfaces. The detailed deposition conditions are listed in Table 1. Figure 2a compares the FTIR spectra of MAH monomer and iCVD-synthesized PMAH film. Notably, the absence of the =CH2 wagging at 945 cm-1 and a significant decrease of the – C=C– stretching band at 1636 cm-1 are observed in the spectrum of PMAH compared to that of monomer, which indicate that most of the vinyl bonds in the MAH unit have been polymerized. Very few vinyl bonds remained, possibly due to the steric hindrance during crosslinking, since each MAH unit has two vinyl bonds. The peaks centered at 1802 and 1737 cm-1 are attributed to the carbonyl in-phase and out-of-phase stretching of the anhydride group, respectively, which has been well preserved after iCVD polymerization.33 The observed carbonyl stretching peaks can be associated with a mixture of six-membered rings resulted from the intramolecular crosslinking cyclopolymerization and intermolecular crosslinking polymerization as reported by literature (Figure 1b).28,

40

Compared to the PECVD PMAH,28 the retention of the anhydride

groups is more pronounced in iCVD PMAH and the vinyl bonds are more depleted, indicating 9 ACS Paragon Plus Environment


better stoichiometric control and more thorough polymerization. Figure 2b-d reveals the XPS wide scan spectrum of the synthesized PMAH, along with its C1s and O1s high resolution spectra. As indicated in the inset of Figure 2b, the carbon atoms in the PMAH can be categorized into three environments. Correspondingly, three peaks were decoupled from the C1s high resolution scan spectrum: –C*H3/–C*H2– (284.6 eV), –C*O– (288.9 eV), and –C*–CH3 (285.3 eV). The calculated areas of these three peaks are 50%, 25%, and 25%, respectively, which agrees well with the theoretical composition. The oxygen atoms are categorized into two environments: –CO*− (532.2 eV) and –C–O*–C– (533.5 eV), and the areas of the corresponding peaks are 67% and 33%, respectively. The perfect match between the calculated C and O contents in their respective environments and the theoretical values further confirms the well preserved stoichiometry of MAH during iCVD. 3.2 Synthesis and Characterization of P(MAH-co-MAA). Copolymers of MAH and MAA with different compositions were synthesized employing varied flow ratios between MAH and MAA vapor (Table 1). FTIR spectra of the as-synthesized PMAA, P(MAH-co-MAA), and PMAH films show decrease of the C=O stretching bands at 1802 and 1737 cm-1 associated with the anhydride group as the content of MAH moiety decreased (Figure 3a). On the other hand, peaks centered at 1761 and 1703 cm-1 increased as more MAA was incorporated in the films. These vibration bands are attributed to the C=O stretching in the MAA moiety with and without hydrogen bonding environment, respectively,28,

29

as seen in the enlarged FTIR spectrum of a

P(MAH-co-MAA) copolymer (S4) at the carbonyl stretching region (Figure 3b). The FTIR spectra of the copolymers were further employed to quantify the content of each moiety in the films. The details of the quantification process have previously been reported.19, 41 Briefly, the carbonyl stretching peaks from MAH (1802 and 1737 cm-1) and MAA


Page 10 of 33

Page 11 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(1761 and 1703 cm-1) were decoupled, and the respective areas were calculated using Omnic software. Since carbonyl peaks with the same vibration mode can be considered to have the same absorption coefficient in homopolymers of PMAH and PMAA and in P(MAH-co-MAA) copolymers, the mole concentration of MAH in copolymer coatings (cMAH) can be expressed as cMAH=cMAH*A(C=O,MAH)/A(C=O,MAH)*, where cMAH* is the mole concentration of MAH in PMAH coating, A(C=O,MAH) is the sum of peak areas of carbonyl stretching from MAH in the copolymer, and A(C=O,MAH)* is the sum of peak areas of carbonyl stretching from MAH in the homopolymer. Similarly, the mole concentration of MAA in copolymer coatings (cMAA) can be expressed as cMAA=cMAA*A(C=O,MAA)/A(C=O,MAA)*, where cMAA* is the mole concentration of MAA in PMAA coating, A(C=O,MAA) is the sum of peak areas of carbonyl stretching from MAA in the copolymer, and A(C=O,MAA)* is the sum of peak areas of carbonyl stretching from MAA in the homopolymer. Assuming the densities of PMAH and PMAA coatings are the same, we can deduce cMAH*/cMAA*=MMAA*/MMAH*, where MMAH* and MMAA* are the molecular weight of MAH and MAA repeating units, respectively. Finally, the ratio of MAH content (nMAH) to MAA content (nMAA) in copolymer coatings can be calculated as: 𝑛𝑀𝐴𝐻 𝑛𝑀𝐴𝐴

=

𝑐𝑀𝐴𝐻 𝑐𝑀𝐴𝐴

=

𝐴(𝐶 = 𝑂,𝑀𝐴𝐻)𝐴(𝐶 = 𝑂,𝑀𝐴𝐴) ∗ 𝑀𝑀𝐴𝐴 ∗ 2𝐴(𝐶 = 𝑂,𝑀𝐴𝐴)𝐴(𝐶 = 𝑂,𝑀𝐴𝐻) ∗ 𝑀𝑀𝐴𝐻 ∗

. A factor of 2 is introduced since

each MAH monomer has two carbonyl groups. The calculated content ratios are listed in Table 1. The incorporation of MAA moiety in the copolymer was also confirmed by analyzing its XPS O1s high resolution spectrum. Compared to the O1s spectrum of PMAH, the O1s spectrum of copolymer S4 shows a relatively larger –O*– peak at 533.4 eV than that of PMAH. This makes sense since the ratio between the number of oxygen atoms at C=O to that at –O– in MAH (2:1) is higher than that in MAA (1:1); therefore the incorporation of MAA increased the relative 11 ACS Paragon Plus Environment


content of –O*–. The increase of MAA moiety in the copolymer offers more carboxylic groups on the film surface, which in turn increases its hydrophilicity. As shown in Figure 4, the PMAH film demonstrates a WCA of 87˚. The incorporation of MAA in the film reduced the WCA. With the MAH/MAA content ratio of 1.56, the WCA reached 70˚. More incorporation of MAA lead to further lower WCA, and copolymer film S6 exhibited WCA of 61˚. 3.3 pH-Dependent Degradation of PMAH and P(MAH-co-MAA). During iCVD polymerization, the two methacrylate bonds either undergo polymerization that creates intermolecular crosslinked network or intramolecular crosslinking cyclopolymerization that creates six-membered rings. The hydrolysis of anhydride groups in the MAH moiety breaks either the crosslinking structure or side chain rings, both resulting in two carboxylic groups and the polymer transforms into homopolymer of PMAA.42 Owing to the excellent solubility of PMAA in aqueous solution, the insoluble PMAH and P(MAH-co-MAA) become soluble upon hydrolysis of the anhydride group, leading to the degradation of the coating (Figure 1). To investigate the degradation behavior of iCVD PMAH and P(MAH-co-MAA) films, we immersed the PMAH and copolymer films (S2 and S4) deposited on Si wafer in aqueous buffer with pH 1, 4, 7.4 and 10, and monitored the remaining amount of MAH units in the films after different durations (Figure 5). The initial thickness of all films were about 1 µm. For PMAH film, the initial degradation was relatively fast, which gradually slowed down towards the end of degradation. The decrease of the degradation rate might be the result of surface grafting of the polymer film onto substrate, which hindered the dissolution of partially transformed PMAH chains at the bottom. For copolymer films, an initial fast degradation stage was also observed under acidic conditions, which slowed down in the middle, followed by


Page 12 of 33

Page 13 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


another fast degradation stage. The initial fast degradation is possibly due to the hydrolysis and dissolution of some short or uncrosslinked polymer chains upon exposure to aqueous medium. As these chains have been depleted, the crosslinked network started to degrade, which was much slower. Upon the hydrolysis of most anhydride groups, the degradation expedited again at the final stage. The discontinuity in these degradation profiles of copolymer suggests the degradation of the films may be the result of both surface and bulk erosions.43 For all films, the degradation rates are significantly faster in alkaline and neutral solutions than in acidic solutions, especially for copolymers with higher MAA content. Since both acids and bases can catalyze the hydrolysis of anhydride groups, the faster dissolution in alkaline solution is probably due to the ionization and faster dissolution of the product PMAA under high pH environment,44 which has a pKa of about 545. The incorporation of MAA in the polymer substantially expedited the degradation rate of coatings, especially in neutral and alkaline solutions. As shown in Figure 5c, the degradation duration of copolymer coating S4 are within 20 and 10 min under pH 7.4 and 10, respectively, while the complete degradation under pH 1 and 4 both took more than 400 min. Such fast degradation rate in alkaline and neutral solutions is resulted from the loosely crosslinked structure of P(MAH-co-MAA) in S4, where MAH served as anchoring points connecting the PMAA chains. As more MAA units were incorporated in the network, the crosslinking density reduced. Therefore, the transformation of P(MAH-co-MAA) into PMAA requires the hydrolysis of only a few anchoring anhydride groups, and the resultant PMAA chains dissolve immediately in solutions with pH above its pKa. In contrast, the transformation of PMAH homopolymer into PMAA chains requires the hydrolysis of much more anhydride groups, thus requiring much longer time.



To further analyze the degradation process of PMAH, we obtained the FTIR spectra of PMAH films after immersing in pH 1 PBS solution for different duration of time. As shown in Figure 5d, the spectrum of the initial film only exhibited carbonyl stretching bands associated with anhydride groups. Upon immersion in PBS solution for 60 min, the remaining film shows substantially reduced carbonyl stretching peaks of MAH at 1802 and 1737 cm-1 and the appearance of peaks at 1761 and 1703 cm-1 stemmed from carbonyl stretching associated with MAA, indicating partial transformation of MAH units to MAA.46 The carbonyl stretching peaks stemmed from MAH continued to decrease as the hydrolysis continued. The carbonyl stretching peaks stemmed from MAA, however, did not increase along with the hydrolysis, which was due to the dissolution of resultant PMAA chains. Finally, the coating was completely degraded upon immersion for 1920 min. The evolution of FTIR spectra confirms the degradation of PMAH was originated from the hydrolysis of anhydride groups, which generated soluble PMAA chains. 3.4 Encapsulation and pH-Responsive Release of Drugs. By analyzing the different degradation behavior of PMAH and P(MAH-co-MAA), we find the degradation rate of PMAH suits better with the duration time of orally administered drugs in the human body.27, 47, 48 We then used it as a model coating to examine its performance on drug release. Figure 6 shows the SEM images of PLA membranes before and after loading with rifampicin, and after encapsulation with PMAH coating. The pristine membrane shows surface pores with the size of several tens of nanometers (Figure 6a), which develop into micrometer-sized pores inside the membrane. The rifampicin was loaded both inside the membrane and on the surface, as seen in Figure 6b. Upon coating with 1 µm PMAH, the membrane surface became fairly smooth, which was due to the planarization effect of iCVD coating (Figure 6c).49 Owing to the conformal coating characteristic of the iCVD technique, the deposited PMAH penetrated through the pores


Page 14 of 33

Page 15 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


on both sides of the membrane, and created a uniform coating wrapping around the deposited rifampicin crystal. The pH-dependent degradation behavior of the PMAH coating resulted in pH-responsive release of loaded drugs. As shown in Figure 7, the release of rifampicin can be divided into two stages under all pH environments. At the initial stage, the PMAH coating underwent degradation, but the drugs were well stored underneath the coating. The duration of this stage varied substantially between different pH environments, which were about 30 min and 2 h under pH 10 and 7.4, respectively, but more than 8 h under pH 1. This disparity can be explained by the aforementioned higher degradation rate of PMAH under alkaline and neutral environment than under acidic environment. As the degradation proceeded, the drug molecules started to leach out. The release efficiency also depended on the pH of the medium. Fastest release of rifampicin was observed under pH of 10, where the release of most drugs took about 2 h. The release under pH of 1, however, was much slower and took more than 6 h for the complete unload. We further observed the PMAH coating morphology on PLA membrane at different degradation time using SEM (Figure S6). No cracks or pores was observed in the coating at any stage of degradation from the cross-sectional view. The thicknesses of the remained coatings on the membrane at each stage was then correlated to the calculated percentage of remaining MAH on Si wafer (Figure S6f). The plotted curve reveals a linear dependence, indicating that the degradation profile between the coatings on Si wafer and PLA membrane are similar. By correlating the drug release profile with the degradation profile of PMAH coating, we find that the release of drugs possibly initiated when the remaining amount of MAH was reduced to about 20%. At this stage of the degradation process, most of the anhydride groups have been hydrolyzed and the compact PMAH coating converted into a loose thin PMAA hydrogel



network, which can be confirmed by the evolution of FTIR spectra during degradation (Figure 5d). The rifampicin molecules can thus be leached out through the hydrogel meshes. As the degradation continued, coatings occluding the pores gradually diminished, exposing the drugs to the medium, resulting in fast and thorough release. Compared with previously reported iCVD coatings for drug release based on leaching through hydrogel meshes, we find the drug release profile in this work have the following merits: First of all, the drug release rate in this work is much higher and the release is much more thorough, owing to the direct exposure of drug molecules to the aqueous medium once the degradation was completed. Second, the drug release profile can be clearly divided into two stages, and the release did not occur until the degradation of the coating reached a certain stage. This helps prevent the release of drugs at undesired sites and improve the drug efficacy. Most importantly, the pH-dependent release behavior is considerably more pronounced, since the initial degradation stage is much longer in the acidic environment and the release rate is also slower than that in the alkaline and neutral environment. The observed pH-dependent release behavior could be beneficial for the design of novel drug delivery systems that is able to store the drugs under low pH environment, e.g. stomach, and release efficiently under neutral and alkaline environment, e.g. intestines.

4. Conclusions Biodegradable coatings of PMAH and P(MAH-co-MAA) were synthesized using iCVD method for the first time. The mild polymerization process during iCVD allowed perfect preservation of the stoichiometry of both PMAH and its copolymer, in contrast to the PECVD synthesized counterpart. The resultant coatings exhibited pH-dependent degradation performance, which was


Page 16 of 33

Page 17 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


due to the faster ionization and dissolution of the PMAA product in alkaline solutions. The degradation rate was also adjustable by incorporating different content of MAA in the system. Employing the iCVD method, we were able to encapsulate drugs with PMAH coating in PLA membranes, which served as a biodegradable drug carrying vehicle. The drug was well stored inside the membrane until the majority of the coating was degraded. The release rate was much faster in alkaline and neutral solutions than in acidic solution, which was in accordance with the degradation profile of the coating. The facile drug encapsulation and the pH-responsive drug release therefore suggest potential applications of the designed PMAH and its copolymer coatings in high-efficacy site-specific drug therapy. Furthermore, a wider spectrum of polymer composition could be achieved by incorporating crosslinkers, such as ethylene glycol diacrylate, and other soluble components into the system, which would offer more opportunities in designing proper biodegradable polymers with desired degradation rate for different biomedical applications.

Acknowledgements We are grateful for the funding support from the National Key Research and Development Program of China (Grant No. 2017YFA0206600), the National Natural Science Foundation of China (51873093), Technology Foundation for Selected Overseas Chinese Scholars by Ministry of Personnel of China, and Ningbo “3315” Innovation Initiative. This work was also sponsored by K. C. Wong Magna Fund in Ningbo University.

Supporting Information Additional experimental data of the relation between the flow ratio of precursors and the 17 ACS Paragon Plus Environment


resultant composition of P(MAH-co-MAA) copolymers, the original FTIR data of films at different degradation stages, the AFM images of PMAH at different degradation stages, the drug release profile of drug-loaded membrane without encapsulation and encapsulated with copolymer, and the SEM of PMAH coatings on PLA membrane after different immersion time during degradation are provided in the Supporting Information. The Supporting Information is available free of charge on the ACS Publications website.

Notes The authors declare no competing financial interest.


Page 18 of 33

Page 19 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


References 1.

Tibbitt, M. W.; Dahlman, J. E.; Langer, R. Emerging Frontiers in Drug Delivery. J. Am.

Chem. Soc. 2016, 138, 704-717. 2.

Du, Y.; Chen, W.; Zheng, M.; Meng, F.; Zhong, Z. pH-Sensitive Degradable Chimaeric

Polymersomes for the Intracellular Release of Doxorubicin Hydrochloride. Biomaterials 2012, 33, 7291-7299. 3.

Wu, Y.; Chen, W.; Meng, F.; Wang, Z.; Cheng, R.; Deng, C.; Liu, H.; Zhong, Z. Core-

Crosslinked pH-Sensitive Degradable Micelles: A Promising Approach to Resolve the Extracellular Stability Versus Intracellular Drug Release Dilemma. J. Controlled Release 2012, 164, 338-345. 4.

Esser-Kahn, A. P.; Odom, S. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Triggered

Release from Polymer Capsules. Macromolecules 2011, 44, 5539-5553. 5.

Badruddoza, A. Z.; Godfrin, P. D.; Myerson, A. S.; Trout, B. L.; Doyle, P. S. Core-Shell

Composite Hydrogels for Controlled Nanocrystal Formation and Release of Hydrophobic Active Pharmaceutical Ingredients. Adv. Healthcare Mater. 2016, 5, 1960-1968. 6.

Mora-Huertas, C. E.; Fessi, H.; Elaissari, A. Polymer-Based Nanocapsules for Drug

Delivery. Int. J. Pharm. 2010, 385, 113-142. 7.

Sosnik, A.; das Neves, J.; Sarmento, B. Mucoadhesive Polymers in the Design of Nano-

Drug Delivery Systems for Administration by Non-Parenteral Routes: A Review. Prog. Polym. Sci. 2014, 39, 2030-2075. 8.

Grigoriev, D. O.; Miller, R. Mono- and Multilayer Covered Drops as Carriers. Curr.

Opin. Colloid Interface Sci. 2009, 14, 48-59. 9.

Khoee, S.; Yaghoobian, M. An Investigation into the Role of Surfactants in Controlling



Particle Size of Polymeric Nanocapsules Containing Penicillin-G in Double Emulsion. Eur. J. Med. Chem. 2009, 44, 2392-2399. 10.

Pisani, E.; Fattal, E.; Paris, J.; Ringard, C.; Rosilio, V.; Tsapis, N. Surfactant Dependent

Morphology of Polymeric Capsules of Perfluorooctyl Bromide: Influence of Polymer Adsorption at the Dichloromethane-Water Interface. J. Colloid Interface Sci. 2008, 326, 66-71. 11.

Preetz, C.; Rube, A.; Reiche, I.; Hause, G.; Mader, K. Preparation and Characterization

of Biocompatible Oil-Loaded Polyelectrolyte Nanocapsules. Nanomed. Nanotechnol. Biol. Med. 2008, 4, 106-114. 12.

Baranello, M. P.; Bauer, L.; Benoit, D. S. Poly(styrene-alt-maleic anhydride)-Based

Diblock Copolymer Micelles Exhibit Versatile Hydrophobic Drug Loading, Drug-Dependent Release, and Internalization by Multidrug Resistant Ovarian Cancer Cells. Biomacromolecules 2014, 15, 2629-2641. 13.

Perrotta, A.; Werzer, O.; Coclite, A. M. Strategies for Drug Encapsulation and Controlled

Delivery Based on Vapor-Phase Deposited Thin Films. Adv. Eng. Mater. 2018, 20, 1700639. 14.

Mertz, G.; Fouquet, T.; Ahrach, H. I. E.; Becker, C.; Phan, T. N. T.; Ziarelli, F.; Gigmes,

D.; Ruch, D. Water Sensitive Coatings Deposited by Aerosol Assisted Atmospheric Plasma Process: Tailoring the Hydrolysis Rate by the Precursor Chemistry. Plasma Processes Polym. 2015, 12, 1293-1301. 15.

Labay, C.; Buxadera-Palomero, J.; Avilés, M.; Canal, C.; Ginebra, M. P. Modulation of

Release Kinetics by Plasma Polymerization of Ampicillin-Loaded β-TCP Ceramics. J. Phys. D: Appl. Phys. 2016, 49, 304004. 16.

Coclite, A. M.; Howden, R. M.; Borrelli, D. C.; Petruczok, C. D.; Yang, R.; Yague, J. L.;

Ugur, A.; Chen, N.; Lee, S.; Jo, W. J.; Liu, A.; Wang, X.; Gleason, K. K. 25th Anniversary


Page 20 of 33

Page 21 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Article: CVD Polymers: A New Paradigm for Surface Modification and Device Fabrication. Adv. Mater. 2013, 25, 5392-5423. 17.

Wang, M.; Wang, X.; Moni, P.; Liu, A.; Kim, D. H.; Jo, W. J.; Sojoudi, H.; Gleason, K.

K. CVD Polymers for Devices and Device Fabrication. Adv. Mater. 2017, 29, 1604606. 18.

Yagüe, J. L.; Coclite, A. M.; Petruczok, C.; Gleason, K. K. Chemical Vapor Deposition

for Solvent-Free Polymerization at Surfaces. Macromol. Chem. Phys. 2013, 214, 302-312. 19.

Sun, M.; Wu, Q.; Xu, J.; He, F.; Brown, A. P.; Ye, Y. Vapor-Based Grafting of

Crosslinked Poly(N-Vinyl Pyrrolidone) Coatings with Tuned Hydrophilicity and Anti-Biofouling Properties. J. Mater. Chem. B 2016, 4, 2669-2678. 20.

Ye, Y.; Song, Q.; Mao, Y. Solventless Hybrid Grafting of Antimicrobial Polymers for

Self-Sterilizing Surfaces. J. Mater. Chem. 2011, 21, 13188. 21.

McInnes, S. J.; Szili, E. J.; Al-Bataineh, S. A.; Xu, J.; Alf, M. E.; Gleason, K. K.; Short,

R. D.; Voelcker, N. H. Combination of iCVD and Porous Silicon for the Development of a Controlled Drug Delivery System. ACS Appl. Mater. Interfaces 2012, 4, 3566-3574. 22.

McInnes, S. J.; Szili, E. J.; Al-Bataineh, S. A.; Vasani, R. B.; Xu, J.; Alf, M. E.; Gleason,

K. K.; Short, R. D.; Voelcker, N. H. Fabrication and Characterization of a Porous Silicon Drug Delivery System with an Initiated Chemical Vapor Deposition Temperature-Responsive Coating. Langmuir 2016, 32, 301-308. 23.

Christian, P.; Tumphart, S.; Ehmann, H. M. A.; Riegler, H.; Coclite, A. M.; Werzer, O.

Controlling Indomethacin Release through Vapor-Phase Deposited Hydrogel Films by Adjusting the Cross-Linker Density. Sci. Rep. 2018, 8, 7134. 24.

Armagan, E.; Qureshi, P.; Ince, G. O. Functional Nanotubes for Triggered Release of

Molecules. Nanosci. Nanotechnol. Lett. 2015, 7, 79-83.



25.

Kamaly, N.; Yameen, B.; Wu, J.; Farokhzad O. C. Degradable Controlled-Release

Polymers and Polymeric Nanoparticles: Mechanisms of Controlling Drug Release. Chem. Rev. 2016, 116, 2602-2663. 26.

Ganas, C.; Weiss, A.; Nazarenus, M.; Rosler, S.; Kissel, T.; Rivera Gil, P.; Parak, W. J.

Biodegradable Capsules as Non-Viral Vectors for in Vitro Delivery of PEI/siRNA Polyplexes for Efficient Gene Silencing. J. Controlled Release 2014, 196, 132-138. 27.

Koyamatsu, Y.; Hirano, T.; Kakizawa, Y.; Okano, F.; Takarada, T.; Maeda, M. pH-

Responsive Release of Proteins from Biocompatible and Biodegradable Reverse Polymer Micelles. J. Controlled Release 2014, 173, 89-95. 28.

Mertz, G.; Fouquet, T.; Becker, C.; Ziarelli, F.; Ruch, D. A Methacrylic Anhydride

Difunctional Precursor to Produce a Hydrolysis-Sensitive Coating by Aerosol-Assisted Atmospheric Plasma Process. Plasma Processes Polym. 2014, 11, 728-733. 29.

Seidel, S.; Chu Cheong, C.; Kwong, P.; Gupta, M. All-Dry Fabrication of

Poly(Methacrylic Acid)-Based Membranes with Controlled Dissolution Behavior. Macromol. Mater. Eng. 2015, 300, 1079-1084. 30.

Tenhaeff, W. E.; Gleason, K. K. Initiated Chemical Vapor Deposition of Perfectly

Alternating Poly(styrene-alt-maleic anhydride). Surf. Coat. Technol. 2007, 201, 9417-9421. 31.

Chen, N.; Wang, X.; Gleason, K. K. Conformal Single-Layer Encapsulation of PEDOT at

Low Substrate Temperature. Appl. Surf. Sci. 2014, 323, 2-6. 32.

Xu, J.; Asatekin, A.; Gleason, K. K. The Design and Synthesis of Hard and Impermeable,

yet Flexible, Conformal Organic Coatings. Adv. Mater. 2012, 24, 3692-3696. 33.

Tenhaeff, W. E.; Gleason, K. K. Surface-Tethered pH-Responsive Hydrogel Thin Films

as Size-Selective Layers on Nanoporous Asymmetric Membranes. Chem. Mater. 2009, 21, 4323-


Page 22 of 33

Page 23 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


4331. 34.

Tenhaeff, W. E.; Gleason, K. K. Initiated Chemical Vapor Deposition of Alternating

Copolymers of Styrene and Maleic Anhydride. Langmuir 2007, 23, 6624-6630. 35.

Nampoothiri, K. M.; Nair, N. R.; John, R. P. An Overview of the Recent Developments

in Polylactide (PLA) Research. Bioresour. Technol. 2010, 101, 8493-8501. 36.

Wang, H.; Shi, X.; Gao, A.; Lin, H.; Chen, Y.; Ye, Y.; He, J.; Liu, F.; Deng, G. Heparin

Free Coating on PLA Membranes for Enhanced Hemocompatibility via iCVD. Appl. Surf. Sci. 2018, 433, 869-878. 37.

Gao, A.; Liu, F.; Shi, H.; Xue, L. Controllable Transition from Finger-Like Pores to

Inter-Connected Pores of PLLA Membranes. J. Membr. Sci. 2015, 478, 96-104. 38.

Zeng, J.; Xu, X.; Chen, X.; Liang, Q.; Bian, X.; Yang, L.; Jing, X.. Biodegradable

Electrospun Fibers for Drug Delivery. J. Controlled Release 2003, 92, 227-31. 39.

Feng, J.; Sun, M.; Ye, Y. Ultradurable Underwater Superoleophobic Surfaces Obtained

by Vapor-Synthesized Layered Polymer Nanocoatings for Highly Efficient Oil–Water Separation. J. Mater. Chem.A 2017, 5, 14990-14995. 40.

Kitaura, T.; Moroi, N.; Kitayama, T. Anionic Cyclopolymerization of Methacrylic

Anhydride with the Aid of Bulky Aluminum Lewis Acid. Polymer 2013, 54, 1987-1992. 41.

Ye, Y.; Song, Q.; Mao, Y. Single-Step Fabrication of Non-Leaching Antibacterial

Surfaces Using Vapor Crosslinking. J. Mater. Chem. 2011, 21, 257-262. 42.

Chan, C.-K.; Chu, I. M. In Vitro Degradation of Poly(sebacic anhydride-co-ethylene

glycol). Mater. Chem. Phys. 2004, 88, 59-66. 43.

Gopferich, A.; Tessmar, J. Polyanhydride Degradation and Erosion. Adv. Drug Del. Rev.

2002, 54, 911-931.



44.

Hirota, W. H.; Rodrigues, R. B.; Sayer, C.; Giudici, R. Hydrolysis of Acetic Anhydride:

Non-Adiabatic Calorimetric Determination of Kinetics and Heat Exchange. Chem. Eng. Sci. 2010, 65, 3849-3858. 45.

Kim, B.; Lim, S. H.; Ryoo, W. Preparation and Characterization of pH-Sensitive Anionic

Hydrogel Microparticles for Oral Protein-Delivery Applications. J. Biomater. Sci., Polym. Ed. 2009, 20, 427-436. 46.

Dong, A. J.; Zhang, J. W.; Jiang, K.; Deng, L. D. Characterization and in Vitro

Degradation of Poly(octadecanoic anhydride). J. Mater. Sci.-Mater. Med. 2008, 19, 39-46. 47.

Gao, W.; Chan, J. M.; Farokhzad, O. C. pH-Responsive Nanoparticles for Drug Delivery.

Mol. Pharm. 2010, 7, 1913-1920. 48.

McDowell, A.; McLeod, B. J. Physiology and Pharmacology of the Brushtail Possum

Gastrointestinal Tract: Relationship to the Human Gastrointestinal Tract. Adv. Drug Del. Rev. 2007, 59, 1121-1132. 49.

Coclite, A. M.; Gleason, K. K. Global and Local Planarization of Surface Roughness by

Chemical Vapor Deposition of Organosilicon Polymer for Barrier Applications. J. Appl. Phys. 2012, 111, 073516.


Page 24 of 33

Page 25 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 1. a) Schematic illustration of the drug loading, iCVD coating, drug encapsulation, and drug release processes; b) Chemical reactions occurred during the iCVD polymerization of MAH and the subsequent degradation of synthesized PMAH.



Figure 2. a) FTIR spectra of MAH monomer and iCVD-synthesized PMAH film; b) XPS wide scan, c) XPS C1s high-resolution spectrum, and d) XPS O1s high-resolution spectrum of the synthesized PMAH film. The FTIR spectra confirm good preservation of anhydride groups, while the XPS spectra prove good stoichiometric control of the film.


Page 26 of 33

Page 27 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 3. a) FTIR spectra of PMAH (S1), P(MAH-co-MAA) (S2, S4, S6), and PMAA (S8) films; b) Enlarged FTIR spectrum of copolymer S4 at the carbonyl stretching region; c) Chemical structure of P(MAH-co-MAA); and d) XPS C1s high resolution spectrum of copolymer S4. The FTIR spectra indicate good composition control over MAH/MAA ratio during deposition.



Figure 4. Water contact angles for PMAH (S1) and P(MAH-co-MAA) copolymers (S2, S4, and S6) films. Each contact angle was averaged out from five measurements on different spots on the film surface.


Page 28 of 33

Page 29 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 5. Degradation profiles of a) PMAH (S1) and copolymers of b) S2 and c) S4 after different immersion time in PBS buffer with pH 1, 4, 7.4, and 10; and d) Evolution of FTIR spectra of PMAH film deposited on Si wafer after immersion in pH 1 PBS solution for different durations. To better demonstrate the initial stage of degradation, the degradation time in X axis was not plotted to scale. All films exhibited pH-dependent degradation behavior, while the films with higher MAA moiety content show even more significant variations under different pH.



Figure 6. SEM images of a) the original PLA membrane, b) PLA membrane after loading rifampicin, and c) PLA membrane after encapsulation of drugs with iCVD-synthesized PMAH coating. The SEM images at the first row (a-1, b-1, and c-1) were obtained from top view, and the rest were obtained from cross-sectional view. Images a-3, b-3, and c-3 are enlarged views of a-2, b-2, and c-2, respectively. The inset of c-2 shows the thickness of the PMAH coating is approximately 1 µm. SEM images show conformal coating both on the surface and inside membrane pores via iCVD.


Page 30 of 33

Page 31 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 7. Release profiles of rifampicin upon exposure to PBS buffer with pH 1, 7.4 and 10. The drugs were well stored at the initial stage and released at the second stage. The release at both the initial stage and the release stage exhibited strong pH-dependency.



Page 32 of 33

Table 1. Deposition conditions of PMAH (S1), P(MAH-co-MAA) (S2-S7), and PMAA (S8).

MAH

MAA

TBP

Pressure （mTorr ）

S1

0.8

0

0.6

400

--

--

S2

0.8

0.2

0.6

400

4

1.56

S3

0.8

0.4

0.6

400

2

0.81

S4

0.8

0.8

0.6

400

1

0.41

S5

0.8

1.06

0.6

400

0.8

0.32

S6

0.8

1.6

0.6

400

0.5

0.21

S7

0.8

4

0.6

400

0.2

0.08

S8

0

4

0.6

400

--

--

Sample

Flow rate（sccm）

Feed ratio (MAH/MAA)

nMAH/nMAA


Page 33 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TOC graphic


Designing pH-Responsive Biodegradable Polymer Coatings for

Recommend Documents