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Light-sensitive intelligent drug delivery systems of coumarin-modified

mesoporous bioactive glass

H.-M. Lin a,b,*, W.-K. Wang a, P.-A. Hsiung b, S.-G. Shyu c

a Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan 20224, Republic of Chinab Department of Life Science, National Taiwan Ocean University, Keelung, Taiwan 20224, Republic of Chinac Institute of Chemistry, Academia Sinica, Taipei, Taiwan 11529, Republic of China

a r t i c l e i n f o

Article history:

Received 18 September 2009

Received in revised form 20 January 2010

Accepted 5 February 2010

Available online 10 February 2010

Keywords:

Mesoporous bioactive glass

Photo-controlled

Drug delivery system

Light-sensitive intelligent

a b s t r a c t

Functionalized mesoporous bioactive glasses (MBG) with photoactive coumarin demonstrates photo-

responsive dimerization resulting in reversible gate operation. Coumarin-modified MBG was used as a

drug delivery carrier to investigate drug storage/release characteristics using phenanthrene as a model

drug. Irradiation with UV light (>310 nm) induced photo-dimerization of the coumarin-modified MBG,

which led to the pores closing with cyclobutane dimers and trapping of the guest phenanthrene in the

mesopores. However, irradiating the dimerized-coumarin-modified MBG with shorter wavelength UV

light ($250 nm) regenerates the coumarin monomer derivative by the photo-cleavage of cyclobutane

dimers, such that trapped guest molecules are released from the mesopores. The structural, morpholog-

ical, textural and optical properties are well characterized by X-ray diffraction, transmission electron

microscopy, N2 adsorption/desorption, and UVvisible spectroscopy. The results reveal that the MBG

exhibits the typical ordered characteristics of the hexagonal mesostructure. The system demonstrates

great potential in light-sensitive intelligent drug delivery systems and disease therapy fields.

Crown Copyright 2010 Published by Elsevier Ltd. on behalf of Acta Materialia Inc. All rights reserved.

1. Introduction

Since the discovery of bioactive glasses (BG) by Hench et al. [1],

various types of BG, ceramics and glassceramics have been widely

developed and investigated for bone and tooth repair and replace-

ment [24], because such materials can chemically bond to and

integrate with both living soft and hard tissue in the body by the

formation of a biologically active apatite layer at the implanttis-

sue interface, without inducing toxicity, inflammation or immune

response [5,6]. Because of these properties, these biomaterials have

been used in a variety of medical applications, such as implants in

clinical bone repair and regeneration materials, bioactive coatings

of metallic implants in tissue engineering, such as the bioactive

coating of metallic implants, clinical tissue regeneration and tissue

engineering, drug delivery capabilities, biomimetics, treatments

and protein and/or cell activation [115]. When implanted in the

human body, these bioactive materials can develop an amorphous

calcium phosphate layer and then crystallize to hydroxycarbonate

apatite on the surface of the tissue [1].

Recently, a newfamilyof biomaterialshas beendeveloped, called

mesoporous bioactive glasses (MBG), beginning with pioneering

work byYan et al. [16]. Yan and coworkers successfully synthesized

highly well-ordered MBGwith higher specific surface area and pore

volume compared with conventional BG. This new family of MBG

exhibitsenhancedbioactive behaviorwith evenfaster apatite phase

formation thanconventionalBG [1118]. Subsequently, Chang et al.

reported a drug delivery system (DDS) using well-ordered MBG as

the carrier [19].

In recent years, many types of materials, including inorganic sil-

ica, carbon materials and layered double hydroxides [2023] and

polymers [24,25], have been employed as DDS. Inorganic mesopor-

ous silica materials have garnered increased interest, with particu-

lar attention to drug storage and release of the host. Since 2001,

when Vallet-Regi first proposed MCM-41 [20] as a DDS, silica-

based materials such as SBA-15 and MCM-48 have been studied

as drug carriers and controlled release systems. The advantageous

characteristics of mesoporous silica materials for the utilization of

controlled release are due to the unique characteristics and struc-

ture of the surface, including the stability of the stable ordered

pore network, high pore volume and surface area, adjustable pore

size and easily functionalized surface modification of specific loca-

tions for delivery [13,20]. Modified mesoporous silica material is a

well-studied material [26], and the latest research has made much

progress [27].

Controlled release from mesopores is an interesting topic. Vari-

ous stimuli-responsive substrate systems responding to tempera-

1742-7061/$ - see front matter Crown Copyright 2010 Published by Elsevier Ltd. on behalf of Acta Materialia Inc. All rights reserved.doi:10.1016/j.actbio.2010.02.014

* Corresponding author. Address: Institute of Bioscience and Biotechnology,

National Taiwan Ocean University, Keelung, Taiwan 20224, Republic of China.

E-mail address: hmlin@mail.ntou.edu.tw (H.-M. Lin).

Acta Biomaterialia 6 (2010) 32563263

Contents lists available at ScienceDirect

Acta Biomaterialia

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / a c t a b i o m a t

http://dx.doi.org/10.1016/j.actbio.2010.02.014mailto:hmlin@mail.ntou.edu.twhttp://www.sciencedirect.com/science/journal/17427061http://www.elsevier.com/locate/actabiomathttp://www.elsevier.com/locate/actabiomathttp://www.sciencedirect.com/science/journal/17427061mailto:hmlin@mail.ntou.edu.twhttp://dx.doi.org/10.1016/j.actbio.2010.02.014

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ture, pH,electrical field, chemicals andUV light havebeen employed

to build novel DDS [2,2831]. DDS that modulate drug release as a

function of the specific stimuli intensity are called intelligent

and can work in open or closed gate [3234]. Light-sensitive inor-

ganic substrate systems that can help achieve improved control of

the loading and release of guest substances have been highlighted

recently [3540]. Light-sensitivity is an attractive phenomenon for

developing advanced DDS capable of precise external modulation

ofthe site.Recently,Ferriset al.[41] andMaletal. [42] demonstrated

the photo-responsive pore size control of mesoporous silica by azo-

benzene and coumarin modification. Azobenzene groups are toxic

according to the Federal Drug Administration, and this limits the

application of such DDS to topical formulations. Thus, coumarin

groups may be better than azobenzene for photo-responsive pore

sizecontrolof biomaterials. Coumarin(Scheme 1) was first reported

and isolatedin the1820s, recognized as thehay-like sweet aromaof

the tonka bean [43]. Ciamician and Silber [44] first discovered the

photo-dimerization reactions of coumarin in 1902, but the photo-

cleavage reaction was not discovered until the 1960s, when Krauch

et al. [45] further studied the photo-dimerization reaction. In

Scheme 1, under UVA irradiation (k = 320400 nm), the [2 + 2]

cycloaddition of a couple of coumarin moieties takes place to form

a cyclobutane ring. After irradiation by UVC light (k = 200

280 nm), the coumarinphoto-dimers can be cleaved and regenerate

the former coumarinmoieties.Several studies relatedto synthesisof

the intermolecular reversible photo-dimerization and photo-cleav-

age of coumarin derivatives have been reported for polymers and

MCM-41 [46,47]. However, there has beenno report onthe drug re-

lease properties of well-ordered coumarin-modified MBG.

In the present paper, the synthesis of a novel coumarin func-

tionalized MBG material is reported. This biomaterial may have po-

tential use in a variety of medical applications, such as implants in

clinical bone repair and regeneration materials, and bioactive coat-

ings of metallic implants in tissue engineering and so on. It shows a

stable mesoporous structure, a large pore volume and pore diame-

ter, and a large specific surface area with a large number of SiOH

groups on the surface, which is suitable for loading drug moleculesand possessing high drug sustained release properties. This mate-

rial with an openclose door system can be used in the photo-

switched controlled release of included compounds. Irradiation

with UV light (>310 nm) induces the photo-dimerization of cou-

marin to close the pore with a cyclobutane dimer (Scheme 1).

Guest molecules such as phenanthrene can neither enter nor es-

cape from the individual pores of the MBG. However, irradiation

with shorter wavelength UV light ($250 nm) cleaves the coumarin

dimer to regenerate the coumarin monomer, the pores are opened,

and the guest molecules can be released. This material with an

openclose double doors system can be used in the photo-

switched controlled release of included compounds.

2. Materials and methods

2.1. Preparation of MBG

MBG was prepared by a modified procedure using the following

molar composition of the gel in the presence of poly(ethylene gly-

col)-block-poly(propylene glycol)-block-poly(ethylene glycol)

(P123) as a structure directing agent by the solgel process [48]. Ina typical synthesis, 3.00 g P123as surfactant (Aldrich) wasdissolved

in30 mLdistilledH2O and90 mL2 M HCl (37% aqueous,Aldrich)and

stirred at 37 C for$1 h until clear.Then8.5 g tetraethoxysilane (Ac-

ros) (TEOS) and9.64 g CaNO34H2O (98.5%, Showa) were added, and

the solution was stirred for 24 h. Theresultant product was filtered,

washed and dried at 110 C for 12 h. This sample was an as-synthe-

sized MBGsample. CalcinedMBG wasobtained by the calcination of

the as-synthesized MBG at 700 C for 3 h.

2.2. Preparation of 7-[(3-triethoxysilyl)pentyloxy]coumarin

5-Bromo-1-pentene (Acros) (8.23 mL, 66 mmol) was added

dropwiseunderdry nitrogento a stirredmixture of 7-hydroxycoum-

arin (Sigma) (5.0 g, 30 mmol) and anhydrous potassium carbonate(5.8 g, 41 mmol) in dry acetone (150 mL). The resulting mixture

was then boiled under reflux for 5 h, after which it was allowed to

cool. The potassium carbonate was filtered off and washed with

fresh acetone. The solvent was removed in vacuo and the resulting

product was purified by recrystallization from ethanol. The yield

was >90% 7-pentenyloxycoumarin (1) (Scheme 2) according to 1H

and 13C NMR spectra: dH (400 MHz, CDCl3) 1.86 (2H, d, 30-CH2),

2.21(2H, d, 20-CH2), 3.96 (2H, d, 10-CH2), 4.98 (1H, dd, 5

0 = CH2) and

5.04 (1H, dd, 50 = CH2), 5.83 (1H, ddt, 40-H), 6.20 (1H, d, 3-H), 6.73

(1H, d, 8-H), 6.88 (1H, dd, 6-H), 7.33 (1H, d, 5-H) and 7.61 (1H, d,

4-H); dC (400 MHz,CDCl3) 27.9 (C-30), 29.8 (C-20), 67.6 (C-10), 101.2

(C-8), 112.2 (C-4a), 112.72 (C-3), 112.84 (C-6), 115.4 (C-50), 128.6

(C-5), 137.2 (C-40), 143.5 (C-4), 155.7 (C-8a), 161.2 (C-7) and 162.2

(C-2).7-[(3-Triethoxysilyl)pentyloxy]coumarin (2) (Scheme 2) was

prepared as follows. After bubbling of dry nitrogen through the tol-

uene solution (100 mL) of 7-pentenyloxycoumarin (3.68 g,

16 mmol) and triethoxysilane (2.94 g, 17.6 mmol) for 10 min,

0.8 mL of the toluene solution (2 mM) of Pt (dvs) (platinum(0)-

1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex) (Aldrich) was

added, and the resulting solution was stirred for 12 h at room tem-

perature. After removal of the solvent under reduced pressure, the

product obtained was used directly in the modification of MBG.

This product was successfully identified as 7-[(3-triethoxysi-

lyl)pentyloxy]coumarin (2) (Scheme 2) by 1H and 13C NMR spectra:

dH (400 MHz, CDCl3) 1.62 (2H, d, 50-CH2), 1.62 (2H, d, 6

0-CH2), 1.87

(2H, d, 30-CH2), 2.22 (2H, d, 20-CH2), 4.00 (2H, d, 1

0-CH2), 5.84 (1H,

ddt, 40-H), 6.21 (1H, d, 3-H), 6.78 (1H, d, 8-H), 6.83 (1H, dd, 6-H),

7.24 (1H, d, 5-H) and 7.63 (1H, d, 4-H); dC (400 MHz, CDCl3) 14.3

(C-70), 18.6 (C-60), 28.2 (C-30), 29.9 (C-20), 38.3 (C-50), 67.9 (C-10),

101.5 (C-8), 112.6 (C-4a), 113.1 (C-3), 113.4 (C-6), 128.9 (C-5),

137.6 (C-40), 113.7 (C-4), 156.1 (C-8a), 161.6 (C-7) and 162.5 (C-

2). The synthesis of these procedures is shown in Scheme 2.

2.3. Preparation of coumarin-modified MBG

Two grams of as-synthesized MBG was suspended in a solution

containing 20 mL of n-hexane and 0.30 g of 7-[(3-triethoxysi-

lyl)pentyloxy]coumarin (2) under stirring at ambient temperature

for 15 min. n-Hexane was evaporated by a rotary evaporator at re-

duced pressure and 100 C for 14 h. Then, 2 g of coumarin-modi-

fied as-synthesized MBG with surfactant was refluxed in 100 mLof ethanol containing 4 mL of conc. HCl at 80 C for 4 h. The solid

O

O

RO

O

O

RO

O

O

RO

O

O

RO

h >310nm

h ~250nm

Scheme 1. The photoreversible dimerization-cleavage reaction of coumarinderivative.

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was decanted and washed with ethanol. This process was carried

out twice in order to ensure the complete removal of surfactant

from the pores of the MBG. The obtained solid was filtered off,

washed with ethanol and water, and finally dried at 80 C for

12 h. This material is referred to as sample A-0.

2.4. Sample loading and release

One gram of coumarin-modified MBG (A-0) was suspended in

20 mL n-hexane solution containing 1.5 g of phenanthrene at

ambient temperature under stirring for 24 h (solution A-1). The

resulting solid (initial A-2) was obtained from solution A-1 by fil-

tering, washing with n-hexane on a filter, and drying at 60 C for

12 h. The solid obtained (initial B-1) was photo-dimerized from an-

other solution of A-1 by UV irradiation with a wavelength longer

than 310 nm for 60 min using a 40-W UV lamp. Then the solids (fi-

nal A-2 and final B-1) were suspended in n-hexane (100 mL) and

stirred at room temperature for 48 h, respectively. Finally, theywere filtered off, washed with n-hexane, dried at room tempera-

ture and pressed into disks. The dimerized materials (B-1) were

subjected to photo-cleavage by irradiation at $250 nm wavelength

for 30 min with a 40-W lamp and treated with n-hexane (100 mL)

at room temperature under stirring. Finally, the disk was decanted,

washed and dried at room temperature (C-1). In the phenanthrene

release experiments, the disk weight was 0.2 g in 20 mLn-hexane

solution. The amounts of phenanthrene released (dissolved in n-

hexane) were analyzed using UVvisible spectrophotometry. Three

parallel samples were tested in drug releasing experiments. The

systematic scheme of these procedures is shown in Scheme 3.

2.5. Product characterization

X-ray diffraction (XRD) patterns were recorded with a Philips

Xpert PRO MPD, MO3X instrument, with Ni filtered Cu Ka radiation

(k = 0.15406 nm). The BrunauerEmmettTeller (BET) specific sur-

face area andpore size were obtainedfromnitrogenadsorption iso-

therms measured at 196 C using an ASAP 2020 instrument

(Micromeritics). Prior to nitrogen adsorption, the samples were de-

gassedat 350 C for 12 h. The poresize distributions were calculated

from the adsorption branches of the nitrogen adsorption isotherms

using the BarrettJoynerHalenda (BJH) method. All samples were

held in a platinumsample holder and were heated under a nitrogen

atmosphere at a rate of 5 C min1. UVvis diffuse reflectance spec-

tra were obtainedwith a Hitachi U-3310 instrument equipped with

an integrating sphere. Solid-state 29Si CP/MAS NMR spectra were

collected on a Bruker model AVANCE300 instrument (7.0 T) at59.62 MHz with a 4-mm zirconia rotor (3.5 kHz rotation speed),

4.3ls pulse width, 5 s pulse delay, and an acquired length of 2048

(transients). Tetrakis-(trimethylsilyl)silane wasusedas the external

chemical shift standard. Solution 1H and 13C NMR spectrum mea-

surements were performed with a Bruker AVA-300 spectrometer.

The content of phenanthrene was analyzed using a UVvis spec-

trometer with a Hitachi U-2900 at 322.5 nm and 337.5 nm. Trans-

mission electron microscopy (TEM) was performed on a JEOL2010

instrument. Scanning electron microscopy (SEM) was performed

on a JEOL-JSM-5400 instrument with an Oxford energy dispersive

spectroscopy (EDS) analysis system. Three samples were tested in

this experiment for different time scales: one for before soaking in

SBF, one for after soaking for 24 h, and one for soaking for 2 weeks.

The SBF test was done by immersing 30 mgMBG in 20 mLSBF solu-

tion, thenplacingit ina 37.5 C incubator androtating it at 160 rpm.

The composition of the SBF solution used here contains 213 mmol

NaCl, 6.3 mmol NaHCO3, 4.5 mmol KCl, 1.5 mmol K2HPO46H2O,

2.3 mmol MgCl26H2O, 3.8 mmol CaCl2, and 0.75 mmol Na2SO4 in

1 L SBF solution.

3. Results and discussion

3.1. Structure, formation, morphology and properties of MBG and

coumarin-modified MBG

Fig. 1 shows the small-angle XRD patterns of MBG and couma-rin-modified MBG in which the characteristic peak (100) associ-

O OO

OOSi

O

H3C

O

H3C

O

H3C

O

O

OHO

Br

SiH

O

H3C

O

H3C

O

H3C

Step1

Step2(2)

1'

2'

3'

4'

5'

1'

2'

3'

4'

1

2

34

4a5

6

78

8a

6'

7'

(1)

Scheme 2. Synthesis of coumarin derivatives: 7-pentenyloxycoumarin (1) and 7-[(3-triethoxysilyl)pentyloxy]coumarin (2).

Scheme 3. Systematic scheme of sample controlled release procedures.

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ated with p6mm hexagonal symmetry, which indicates the exis-

tence of a high degree of hexagonal mesoscopic organization corre-

sponding to a MBG-like structure, can be seen [48]. However, it is

important to note that coumarin-modified MBG still retains a peri-

odic structure after grafting of the coumarin derivatives, as indi-

cated by the presence of the 1 peak of powder XRD, by TEM

images (see Fig. 2) and by isothermal gas adsorption (see Fig. 3).

Fig. 2 displays the TEM images of MBG and coumarin-modified

MBG, respectively. In the TEM images of MBG and coumarin-mod-

ified MBG (Fig. 2), the typical characteristics of highly ordered one-

dimensional channels of hexagonally packed mesostructures are

present. Thus, the coumarin modification did not change the hex-

agonally arranged mesopores. This result is in agreement with

the XRD results.

The nitrogen sorption isotherms of the MBG and coumarin-

modified MBG shown in Fig. 3 are type IV with type H1 hysteresis

loops, which are typical results for mesoporous materials with

one-dimensional cylindrical channels. The MBG has a narrow pore

distribution with average pore size 3.24 nm. This material has a

BET surface area of 319.03 m2 g1, and a pore volume 0.26 cm3 g1.

After modification with coumarin, the BET surface area increased

to 335.67 m2 g1, pore volume and pore size decreased to

0.23 cm3 g1 and 2.74 nm, respectively (Table 1). The results reveal

that the modification with coumarin did not altered the basic pore

structure of mesoporous MBG.

The requisite for bonding to living bone for a biomaterial is the

formation of a HA layer on the surface of the implant in the body.

Therefore, the in vitro bone-forming bioactivity of MBG was tested

Fig. 1. The small-angle XRD pattern of MBG and coumarin-modified MBG.

Fig. 2. TEM images of MBG with difference angles, (a and b) MBG and (c and d) coumarin-modified MBG.

Fig. 3. Nitrogen adsorption-desorption isotherms in MBG and coumarin-modified

MBG.

Table 1

Properties of various MBG sample by BET.

Sample SBET(m2g1) VP(cm

3g1) Pore size

Calcined MBG 319.03 0.26 3.24Coumarin-modified MBG 335.67 0.23 2.74

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in SBF to monitor the formation of hydroxyapatite (HA) on the sur-

face of MBG. The SEM image (Fig. 5a) of MBG before soaking in SBF

shows spherical morphology with a smooth surface. The growth of

spherical-like HA particles (

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$200400 nm in length. Theformationof HA depositionwas further

proved by EDS analysis. The EDS spectra characterize the HA layers

formed on the composite surfaces before and after soaking in SBF

for 2 week. Both Ca and P peaks were detected, as shown in Fig. 4

and in Table 2, and the observed ratio of Si/Ca/P was 97.49/2.51/0

forMBG withoutsoakingin SBFand 24.26/47.33/28.41 forMBG after

soakingin SBFfor 2 weeks.Most importantly,the Ca/Pratiosfor MBG

specimens soaked in SBF after 2 weeks were 1.66.29Si MAS NMR spectra of MBG samples and coumarin-modified

MBG are shown in Fig. 6. In Fig. 6, the 29Si MAS NMR spectra of both

calcined MBG exhibited and coumarin-modified MBG show three

characteristic resonances at 92.09, 101.05 and 109.13 ppm,

indicating (HO)2Si(OSi)2 (Q2), (HO)Si(OSi)3 (Q

3) and Si(OSi)4 (Q4)

species. In Fig. 6b, coumarin-modified MBG shows two weak addi-

tional resonances $55 and 63.5 ppm, which were assigned to Si

atoms covalently bound to organic groups R-Si(OSi)2(OH) (T2) and

R-Si(OSi)3 (T3), respectively. These results are similar to those in a

previous report [49,50].

3.2. Photo-dimerization and photo-cleavage behavior of coumarin-

modified MBG

The reversibility of the photo-dimerization and photo-cleavage

were observed with the absorbance shown in Fig. 7. The irradiation

with >310 nm wavelength of UV light leads to a decrease in the

absorption at 324 nm with increasing time of irradiation, which

indicates the disappearance of the double bond of coumarin to

form a cyclobutane ring by the dimerization of coumarin mono-

mers. The change in absorbance is due to the photo-dimerization

reaction. In contrast, Fig. 7b shows subsequent irradiation with

UV light at a shorter wavelength of$250 nm, where the absorption

band centered at 324 nm increased with increasing time of irradi-

ation, indicating cleavage of the cyclobutane ring and a return to

the initial state monomers due to photo-cleavage of the coumarin

dimmers. Photo-cleavage at 250 nm proceeded more rapidly than

photo-dimerization at 350 nm, and this result indicates a similar

trend to the case of polymers [51,52]. Thus, reversible photo-reac-

Fig. 6. 29Si NMR spectra of MBG (a) MBG (b) coumarin-modified MBG.

Fig. 7a. UV absorption spectral change of coumarin-modified MBG by irradiation

above 310 nm. Decrease in absorbent at 325 nm due to dimerization of coumarinendgroup in coumarin-modified MBG.

Fig. 7b. UV absorption spectral change of coumarin-modified MBG by irradiation

with 250 nm. Increase in absorbent at 325 nm due to dimerization of coumarinendgroup in coumarin-modified MBG.

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Appendix A. Figures with essential colour discrimination

Certain figures in this article, particularly Figures 1, 3, 4, 7, and

8, are difficult to interpret in black and white. The full colour

images can be found in the on-line version, at doi: 10.1016/

j.actbio.2010.02.014).

References

[1] Hench LL, Splinter RJ, Allen WC, Greenlee TK. Bonding mechanisms at the

interface of ceramic prosthetic materials. J Biomed Mater Res 1971;2:117.

[2] Colilla M, Izquierdo-Barba I, Vallet-Regi M. Novel biomaterials for drug

delivery. Expert Opin Ther Pat 2008;18:63956.

[3] Yamagishi K, Onuma K, Suzuki T, Okada F, Tagami J, Otsuki M, et al. A synthetic

enamel for rapid tooth repair. Nature 2005;433:819.

[4] Kenny SM, Buggy M. Bone cements and fillers: a review. J Mater Sci-Mater M

2003;14:92338.

[5] Vallet-Regi M, Ramila A, Padilla S, Munoz B. Bioactive glasses as accelerators of

apatite bioactivity. J Biomed Mater Res A 2003;66A:5805.

[6] Jokinen M, Rahiala H, RosenholmJB, Peltola T, Kangasniemi I. Relation between

aggregation and heterogeneity of obtained structure in solgel derived CaO

P2O5SiO2. J SolGel Sci Technol 1998;12:15967.

[7] Gomez-Vega JM, Hozumi A, Saiz E, Tomsia AP, Sugimura H, Takai O.

Bioactive glass-mesoporous silica coatings on Ti6Al4V through enameling

and triblock-copolymer-templated solgel processing. J Biomed Mater Res

2001;56:3829.

[8] Domingues ZR, Cortes ME, Gomes TA, Diniz HF, Freitas CS, Gomes JB, et al.Biomaterials 2004;25:32733.

[9] Karageorgiou V, Kaplan D. Porosity of 3D biomaterial scaffolds and

osteogenesis. Biomaterials 2005;26:547491.

[10] Ginebra MP, Traykova T, Planell JA. Calcium phosphate cements as bone drug

delivery systems: a review. J Control Release 2006;113:10210.

[11] Avnir D, Coradin T, LevO, Livage J. Recentbio-applications of solgel materials.

J Mater Chem 2006;16:101330.

[12] Habraken WJEM, Wolke JGC, Jansen JA. Ceramic composites as matrices and

scaffolds for drug delivery in tissue engineering. Adv Drug Deliver Rev

2007;59:23448.

[13] Wang SB. Ordered mesoporous materials for drug delivery. Micropor Mesopor

Mat 2009;117:19.

[14] Arcos D, Greenspan DC, Vallet-Regi M. A new quantitative method to evaluate

the in vitro bioactivity of melt and solgel-derived silicate glasses. J BiomedMater Res A 2003;65A:34451.

[15] Hench LL. The story of Bioglass (R). J Mater Sci-Mater M 2006;17:96778.

[16] Yan X, Yu C, Zhou X, Tang J, Zhao D. Highly ordered mesoporous bioactive

glasses with superior in vitro bone-forming bioactivities. Angew Chem Int Ed2004;43:59804.

[17] Yan XX, Deng HX, Huang XH, Lu GQ, Qiao SZ, Zhao DY, et al. Mesoporous

bioactive glasses. I. Synthesis and structural characterization. J Non-Cryst

Solids 2005;351:320917.

[18] Yan X,Huang X,Yu C,DengH, WangY, Zhang Z,et al. The in-vitrobioactivity of

mesoporous bioactive glasses. Biomaterials 2006;27:3396403.

[19] Xia W, Chang J. Well-ordered mesoporous bioactive glasses (MBG): a

promising bioactive drug delivery system. J Control Release 2006;110:

52230.

[20] Vallet-Regi M, Ramila A, del Real RP, Perez-Pariente J. A newpropertyof MCM-

41: drug delivery system. Chem Mater 2001;13:30811.

[21] Zhi PX, Qing HZ, Gao QL. Ai BY. Chem Eng Sci 2006;61:102740.

[22] Vallet-Regi M. Ordered mesoporous materials in the context of drug delivery

systems and bone tissue engineering. Chem Eur J 2006;12:593443.

[23] Oh JK, Drumright R, Siegwart DJ, Matyjaszewski K. The development of

microgels/nanogels for drug delivery applications. Prog Polym Sci 2008;33:

44877.

[24] Stevanovic M, Uskokovic D. Poly(lactide-co-glycolide)-based micro and

nanoparticles for the controlled drug delivery of vitamins. Curr Nanosci2009;5:114.

[25] Sokolsky-Papkov M, Agashi K, Olaye A, Shakesheff K, Domb AJ. Polymer

carriers for drug delivery in tissue engineering. Adv Drug Deliver Rev

2007;59:187206.

[26] Ariga K, Vinu A, Hill JP, Mori T. Coordination chemistry and

supramolecular chemistry in mesoporous nanospace. Coordin Chem Rev

2007;251:256291.

[27] Ariga K, Hill JP, Lee MV, Vinu A, Charvet R, Acharya S. Challenges and

breakthroughs in recent research on self-assembly. Sci Technol Adv Mat

2008;9:014109.

[28] Yoshida R, Sakai K, Okano T, Sakurai Y. Surface-modulated skin layers of

thermal responsive hydrogels as onoff switches: II. Drug permeation. J

Biomater Sci Polymer Ed 1992;3:24352.

[29] Wu XS, Hoffman AS, Yager P. Synthesis and characterization of thermally

reversible macroporous poly(N-isopropylacrylamide) hydrogels. J Polym Sci A1992;30:21219.

[30] Negishi M, Hiroki A, Miyajima M, Yoshida M, Asano M, Katakai R. In vitro

release control of ketoprofen from pH-sensitive gels consisting of

poly(acryloyl-L-proline methyl ester) and saturated fatty acid sodium salts.

Radiat Phys Chem 1999;55:16772.

[31] Zhang RS, Tang MG, Bowyer A, Eisenthal R, Hubble J. A novel pH- and ionic-

strength-sensitive carboxy methyl dextran hydrogel. Biomaterials

2005;26:467783.

[32] Kost J, Langer R. Responsive polymeric delivery systems. Adv Drug Deliver Rev

2001;46:12548.

[33] Sershen S, West J. Implantable, polymeric systems for modulated drug

delivery. Adv Drug Deliver Rev 2002;54:122535.

[34] Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Adv Drug

Deliver Rev 2001;53:32139.

[35] Haraguchi K. Nanocomposite hydrogels. Curr Opin Solid St M

2007;11:4754.

[36] Sortino S. Nanostructured molecular films and nanoparticles with

photoactivable functionalities. Photochem Photobiol Sci 2008;7:91124.

[37] Johansson E, Choi E, Angelos S, Liong M, Zink JI. Light-activated functional

mesostructured silica. J SolGel Sci Technol 2008;46:31322.

[38] Aznar E, Marcos MD, Martinez-Manez R, Sancenon F, Soto J, Amoros P, et al.

PH- and photo-switched release of guest molecules from mesoporous silica

supports. J Am Chem Soc 2009;131:683343.

[39] Aznar E, Casasus R, Garcia-Acosta B, Marcos MD, Martinez-Manez R.

Photochemical and chemical two-channel control of functional nanogated

hybrid architectures. Adv Mater 2007;19:222831.

[40] Vivero-Escoto JL, Slowing II, Wu CW, Lin VSY. Photoinduced intracellular

controlled release drug delivery in human cells by gold-capped mesoporous

silica nanosphere. J Am Chem Soc 2009;131:34623.

[41] Ferris DP, Zhao YL, Khashab NM, Khatib HA, Stoddart JF, Zink JI. Light-operated

mechanized nanoparticles. J Am Chem Soc 2009;131:16868.

[42] Mal NK, Fujiwara M, Tanaka Y. Photocontrolled reversible release of guest

molecules from coumarin-modified mesoporous silica. Nature

2003;421:3503.

[43] Murray RDH, Mendez J, Brown SA. The natural coumarins: occurrence,

chemistry and biochemistry. New York: John Wiley; 1982.

[44] Ciamician G, Silber P. Chemical light effects [V announcement]. Ber DtschChem Ges 1902;35:4128.

[45] Krauch C, Farid S, Schenck G. Photo-C4-cyclodimerisation von cumarin. Chem

Ber 1966;99:625.

[46] He J, Tong X, Zhao Y. Photoresponsive nanogels based on photocontrollable

cross-links. Macromolecules 2009;42:484552.

[47] Mal NK, Fujiwara M, Tanaka Y, Taguchi T, Matsukata M. Photo-switched

storage and release of guest molecules in the pore void of coumarin-modified

MCM-41. Chem Mater 2003;15:338594.

[48] Wei J, Chen F, Shin JW, Hong H, Dai C, Su J, et al. Preparation and

characterization of bioactive mesoporous wollastonitepolycaprolactone

composite scaffold. Biomaterials 2009;30:10808.

[49] Zeng W, Qian XF, Yin J, Zhu ZK. The drug delivery systemof MCM-41 materials

via co-condensation synthesis. Mater Chem Phys 2006;97:43741.

[50] Qu FY, Zhu GS, Lin HM, Sun JY, Zhang DL, Li SG, et al. Drug self-templated

synthesis of ibuprofen/mesoporous silica for sustained release. Eur J Inorg

Chem 2006:39437.

[51] Fu Q, Cheng LL, Zhang Y, Shi WF. Preparation and reversible photo-

crosslinking/photo-cleavage behavior of 4-methylcoumarin functionalized

hyperbranched polyester. Polymer 2008;49:49818.[52] Trenor SR, Shultz AR, Love BJ, Long TE. Coumarins in polymers: From light

harvesting to photo-cross-linkable tissue scaffolds. Chem Rev

2004;104:305977.

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