**2.8. Application of nanoclay-based composites in bone tissue engineering**

The properties of MMT clay, such as its ability to absorb various types of toxins and the ability to cross the digestive tract (stomach and intestines) [60, 63–66], along with the ability to carry and transfer the drug [67–71], encourage human to use it in tissue engineering applications. It is reported that these nanoparticles are removed from the body because they cannot be absorbed by the intestines and they can also be dissolved by the acids in the stomach or intestine [72]. In addition, clay is used as an edible laxative and an antidiabetes [72]. The above suggests that clay is suitable for tissue engineering applications, and decomposed products can be disposed without any effects on the normal body function. The use of MMT clay for bone tissue engineering applications needs further research. In the few studies that have been done in the past, MMT has been used to prepare nano-composites that examine the effect of adding clay on the mechanical and biological properties of polymers [73, 74]. Researchers have used 5-aminovaleric acid-modified MMT clay to prepare polymer composites for bone tissue engineering studies [75].

**2.9. Montmorillonite (MMT) as a carrier for drug delivery**

**Geometry Nanoclay Chemical formula Purity** 

y(Al2-yMgy

(OH)<sup>4</sup> × 2H2

(OH)<sup>4</sup> × 2H2

(Al,Fe,Mg)<sup>4</sup>

)(Si<sup>4</sup>

O10(F<sup>y</sup> OH1-y)

)O10(OH)<sup>2</sup> × nH2

,Xn,m(H<sup>2</sup>

O20(OH)<sup>4</sup>

Si4

Si2 O5

Si2 O5

**Figure 4.** SEM and TEM images [57].

Tubular Halloysite MP1 Al2

Platelet Nanomer PGV M+

ND, not tested.

Halloysite Al2

ME-100 Na2xMg3.0-xSi<sup>4</sup>

Bentone MA Na0.4Mg2.7Li0.3Si<sup>4</sup>

**Table 1.** Physiochemical properties of clay nanoparticles [57].

Cloisite Na+ (Na,Ca)0.33(Al,Mg)<sup>2</sup>

Delelite LVF (Si,Al)<sup>8</sup>

Clay as a carrier for drug delivery is an amazing interdisciplinary field that brings together biology, materials science, and nanotechnology. Composites based on clay minerals have

**(%)**

O 90 −41 65

O 90 −32.1 64

O10(OH)<sup>2</sup> 98 −36.6 600

O10(OH)<sup>2</sup> 98 −48.6 800

<sup>2</sup> 100 −52.3 9

**Zeta potential (Mv)**

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O 100 −51.9 ND

O) 100 −45.1 600

**Specific surface area (m<sup>2</sup> /g)**

**Figure 4.** SEM and TEM images [57].

such as clay nanoparticles, can have positive effects on tissue development. According to the obtained results, it can be concluded that the mineral clay nanoparticles have a favorable effect on total serum protein and its cleft [51]. Nanoparticles have been reported to exhibit several new characteristics of transfer and absorption and also have more effective absorption. The researchers suggested that the superior performance of clay nanoparticles may be

The extending continuous use of products containing nanoparticle for a wide range of applications has raised public health and safety concerns. Although products containing clay nanoparticles cannot be toxic, human contact during its preparation, production, or disposal process can have undesirable effects on health, which makes it necessary to evaluate the biocompatibility of clay nanoparticles. A group of researchers examined the effects of platelet toxicity (Bentone MA, ME-100, Cloisite Na+, Nanomer PGV, and Delite LVF) on human lung [57]. They used automated cells for the first time in real-time impedance imaging compositions and also showed the effect of toxicity on the difference in the dose level and the timedependent of both types of clay nanoparticles [57]. Clay nanoparticles are used in a wide range of modern products such as electronic, food, clothing, tire, medicine, sunscreen, cosmetics, sports equipment, polymer composites, bone implantation, controlled drug delivery systems, protective coatings (such as anti-corrosion, antibacterial, or antimolding), and for the synthesis of materials [58]. Clay nanoparticles, for example, plastic nanocomposites, are being developed to create unique devices for the next generation of biological applications,

due to smaller size and larger surfaces that improve intestinal absorption [56].

including antimicrobial agents, drug delivery, and cancer treatment [59–62].

**2.8. Application of nanoclay-based composites in bone tissue engineering**

SEM and TEM images are shown in **Figure 4**. In **Table 1**, a summary of the physiochemical properties of clay nanoparticles such as purity, specific surface area, zeta potential, and so on

The properties of MMT clay, such as its ability to absorb various types of toxins and the ability to cross the digestive tract (stomach and intestines) [60, 63–66], along with the ability to carry and transfer the drug [67–71], encourage human to use it in tissue engineering applications. It is reported that these nanoparticles are removed from the body because they cannot be absorbed by the intestines and they can also be dissolved by the acids in the stomach or intestine [72]. In addition, clay is used as an edible laxative and an antidiabetes [72]. The above suggests that clay is suitable for tissue engineering applications, and decomposed products can be disposed without any effects on the normal body function. The use of MMT clay for bone tissue engineering applications needs further research. In the few studies that have been done in the past, MMT has been used to prepare nano-composites that examine the effect of adding clay on the mechanical and biological properties of polymers [73, 74]. Researchers have used 5-aminovaleric acid-modified MMT clay to prepare polymer composites for bone

has been shown, which essentially affects the absorption and toxicity of nanoparticles.

**2.7. Characterization of clay nanoparticles**

tissue engineering studies [75].

**2.6. Evaluation of the clay nanoparticles toxicity in epithelial cells**

172 Current Topics in the Utilization of Clay in Industrial and Medical Applications


ND, not tested.

**Table 1.** Physiochemical properties of clay nanoparticles [57].

#### **2.9. Montmorillonite (MMT) as a carrier for drug delivery**

Clay as a carrier for drug delivery is an amazing interdisciplinary field that brings together biology, materials science, and nanotechnology. Composites based on clay minerals have effect on a variety of fields, especially in pharmaceutical science. The tremendous variety of these natural materials has made the widespread collection of clays and polymers available to researchers [76–84]. The controlled drug delivery system is a method for the development of nanostructures and materials that can encapsulate high concentrations of materials, pass through a cell membrane, and release the drug in the target region for a given period. Clay minerals have exceptional (unique) characteristics such as low toxicity, better biocompatibility, and are guaranteed for a controlled drug release, and thus they are used in biological applications in pharmaceuticals, cosmetics, and even medical purposes [85, 86]. MMT is a natural mineral clay with a layered structure and prominent features such as a high internal surface area and cation exchange capacity (CEC), a high absorption capacity, and low toxicity [64, 87]. MMT with a net charge of the network can well be swollen in the presence of water and hydrophilic solvents, because positive-charged bioactive compounds can be inserted in interlayer (inside layer) spaces by electrostatic interaction. Many attempts have been made to develop MMT as a carrier for drug delivery, for example, to improve the water solubility of insoluble drugs and control the release of bioactive molecules [61, 83, 84, 88–93]. Biochemical properties, which make clay valuable for pharmaceutical applications, include high absorption capacity, high internal surface, high exchange ability, interlayer spatial reactions with drug molecules, chemical moisture, and low toxicity [61, 72, 83, 84, 94–96]. Clay is widely used as an active agent and an additive in pharmaceutical formulations [97–99]. In pharmaceuticals, MMT has found extensive applications as a suspension and a stabilizer, as well as an absorbent and clear factor. Also, MMT has been used as a drug carrier or an additive in pharmaceutical formulations [71, 72, 99–104]. The MMT's ion exchange capacity provides the possibility of replacing Na + with other organic and inorganic cations to increase performance. It also causes the use of MMT and other clay species as a tissue regeneration agent [71, 76–84, 96, 105] (**Table 2**).

chitosan-montmorillonite (HTCC/MMT) nanocomposites for the application as protein carriers [103]. In 2010, Shhameli et al. showed a new green color combination for MMT/chitosan nanoparticles (CS) and its antibacterial actions [108]. Lee and Fu found that the properties of the released drug can be controlled by the charge of N-isopropylacrylamide/MMT nanocomposites [109]. In general, the ability to exchange ions, interoperability, and biocompatibility of MMT has made it an ideal candidate for drug delivery. In addition to pharmaceutical use, MMT and its nanocomposites are bioactive agents that have a wide range of applications. MMT can play an important and powerful role in intestinal detoxification, since it can absorb food, microbial, and metabolic toxins and, surprisingly, can increase the hydrogen ions in acidosis. Also, MMT can be used for edible purpose for digestive system detoxification, constipation reduction, internal parasite eradication, strengthening of the immune system, liver detoxification, reduction of stomach pain, and poisoning by bacteria. Revitalizing drugs and tissue engineering programs include bone remodeling as growth agents and wound dressing.

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MMT is widely used in the treatment of bone pain and damaged muscle, chronic headache, open wounds, special skin conditions (acne, eczema, red seeds on the skin, etc.), diarrhea, hemorrhoids, stomach ulcers, intestinal problems, anemia, rapid recovery of injuries (bruises, stretching, burns, etc.), severe bacterial infections, skin rejuvenation, and various health issues. Therefore, it can be beneficial to health because all its activities are physical and there is no chemical reaction on the body. After taking, no or small amount of MMT is absorbed in the digestive system and the rest is excreted (repulsed) by feces. According to the ISI database, interest in drug delivery by clay

According to the tests conducted, the basis of controlled drug delivery is the use of laminar (layer) interference. Interference may occur by mixing sub-solids (ion converters) with ionic

The network structure of this is shown in **Figure 5** [106].

**Figure 5.** MMT network structure [106].

shows a significant increase in scientific publications (**Figure 6**) [106].

**2.10. Mechanisms of drug-clay interactions**

The authors have shown that increasing the concentration of silicate nanoparticles increases the mechanical strength of polymer nanoparticles [107]. Wang et al. prepared 2008 complex


**Table 2.** List of drugs used in clay as carrier [106].

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**Figure 5.** MMT network structure [106].

effect on a variety of fields, especially in pharmaceutical science. The tremendous variety of these natural materials has made the widespread collection of clays and polymers available to researchers [76–84]. The controlled drug delivery system is a method for the development of nanostructures and materials that can encapsulate high concentrations of materials, pass through a cell membrane, and release the drug in the target region for a given period. Clay minerals have exceptional (unique) characteristics such as low toxicity, better biocompatibility, and are guaranteed for a controlled drug release, and thus they are used in biological applications in pharmaceuticals, cosmetics, and even medical purposes [85, 86]. MMT is a natural mineral clay with a layered structure and prominent features such as a high internal surface area and cation exchange capacity (CEC), a high absorption capacity, and low toxicity [64, 87]. MMT with a net charge of the network can well be swollen in the presence of water and hydrophilic solvents, because positive-charged bioactive compounds can be inserted in interlayer (inside layer) spaces by electrostatic interaction. Many attempts have been made to develop MMT as a carrier for drug delivery, for example, to improve the water solubility of insoluble drugs and control the release of bioactive molecules [61, 83, 84, 88–93]. Biochemical properties, which make clay valuable for pharmaceutical applications, include high absorption capacity, high internal surface, high exchange ability, interlayer spatial reactions with drug molecules, chemical moisture, and low toxicity [61, 72, 83, 84, 94–96]. Clay is widely used as an active agent and an additive in pharmaceutical formulations [97–99]. In pharmaceuticals, MMT has found extensive applications as a suspension and a stabilizer, as well as an absorbent and clear factor. Also, MMT has been used as a drug carrier or an additive in pharmaceutical formulations [71, 72, 99–104]. The MMT's ion exchange capacity provides the possibility of replacing Na + with other organic and inorganic cations to increase performance. It also causes the use of MMT and other clay species as a tissue regeneration agent [71,

174 Current Topics in the Utilization of Clay in Industrial and Medical Applications

The authors have shown that increasing the concentration of silicate nanoparticles increases the mechanical strength of polymer nanoparticles [107]. Wang et al. prepared 2008 complex

5-Flurouracil (anticancer) Ibuprofen (nonsteroidal anti-inflammatory)

Ibuprofen (anti-inflammatory) Buspirone hydrochloride (antianxiety)

Vitamin B1 Ranitidine hydrochloride (antacid)

Captopril (hypertension) Timolol maleate (β-adrenergic blocking agent)

Quinine (antimalarial drug) Procainamide hydrochloride (antiarrhythmia drug) Tamoxifen (anticancer drug) Epidermal growth factor (tissue engineering)

Amino acids BSA (model protein) Plasmid DNA (gene delivery) Donepezil (Alzheimer) Paclitaxel (anticancer drug) Docetaxel (anticancer drug) Lidocaine (local anesthetic drug) 5-Fluorouracil (anticancer drug) Glutathione (antioxidant) Doxorubicin (anticancer drug)

**Table 2.** List of drugs used in clay as carrier [106].

76–84, 96, 105] (**Table 2**).

**Drug**

chitosan-montmorillonite (HTCC/MMT) nanocomposites for the application as protein carriers [103]. In 2010, Shhameli et al. showed a new green color combination for MMT/chitosan nanoparticles (CS) and its antibacterial actions [108]. Lee and Fu found that the properties of the released drug can be controlled by the charge of N-isopropylacrylamide/MMT nanocomposites [109]. In general, the ability to exchange ions, interoperability, and biocompatibility of MMT has made it an ideal candidate for drug delivery. In addition to pharmaceutical use, MMT and its nanocomposites are bioactive agents that have a wide range of applications. MMT can play an important and powerful role in intestinal detoxification, since it can absorb food, microbial, and metabolic toxins and, surprisingly, can increase the hydrogen ions in acidosis. Also, MMT can be used for edible purpose for digestive system detoxification, constipation reduction, internal parasite eradication, strengthening of the immune system, liver detoxification, reduction of stomach pain, and poisoning by bacteria. Revitalizing drugs and tissue engineering programs include bone remodeling as growth agents and wound dressing. The network structure of this is shown in **Figure 5** [106].

MMT is widely used in the treatment of bone pain and damaged muscle, chronic headache, open wounds, special skin conditions (acne, eczema, red seeds on the skin, etc.), diarrhea, hemorrhoids, stomach ulcers, intestinal problems, anemia, rapid recovery of injuries (bruises, stretching, burns, etc.), severe bacterial infections, skin rejuvenation, and various health issues. Therefore, it can be beneficial to health because all its activities are physical and there is no chemical reaction on the body. After taking, no or small amount of MMT is absorbed in the digestive system and the rest is excreted (repulsed) by feces. According to the ISI database, interest in drug delivery by clay shows a significant increase in scientific publications (**Figure 6**) [106].

#### **2.10. Mechanisms of drug-clay interactions**

According to the tests conducted, the basis of controlled drug delivery is the use of laminar (layer) interference. Interference may occur by mixing sub-solids (ion converters) with ionic

of organic compounds [109–111]. Silicate-based composites exhibit a good inhibitory (barrier) effect due to complicated intrusive pathways that small molecules need to undergo (pass) in

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Lin et al. showed the 5-FU interference on the MMT inner layers [61]. 5-FU-MMT was determined and the successful interference of the drug in MMT was confirmed by opening the inner layer and changing the XRD pattern to the lower 2θ angle, and the results are presented in **Figure 9**. Finally, it can be concluded that the total amount of 5-FU absorbed in MMT is

Park et al. reported the placement of donepezil molecules on clay (Laponite, LA, saponite, SA and MMT) and provided descriptive information, which confirmed the well-located donepezil molecules in the inner layers of clay (**Figure 10**) [91]. The absorption amount and the donepezil molecular structure depend on the cationic exchange ability of clay, which has designed drug release patterns. The rate of release can be increased easily by using a large cationic polymer. The Eudragit® E-100 hybrid, coated with such a polymer, shows the release of drug at higher speeds over a short period. Therefore, nanoclay materials are proposed as

order to clarify the material (**Figure 8**) [112].

approximately 87.5 mg/g MMT.

**2.11. The latest MMT pattern used in drug delivery systems**

an advanced carrier for drug delivery with a controllable release feature.

**Figure 8.** Mechanism of drug release from nanocomposites [106].

**Figure 6.** The number of studies on the use of clay nanoparticles as carrier for drug delivery [106].

**Figure 7.** Mechanism of release of MMT and absorption in the body [106].

material in solution. In biological fluids, "anti-ions" can move the drug into the substrate and transfer it to the body, so the converter can be removed or decomposed at the end (**Figure 7**) [106]. Smectites, especially MMT and saponite, have been further studied due to their ionic exchange capacity compared to other silicates (talc, kaolin, and fibrous mineral clay). A specific mechanism depends on factors such as functional groups and chemical physical properties of organic compounds [109–111]. Silicate-based composites exhibit a good inhibitory (barrier) effect due to complicated intrusive pathways that small molecules need to undergo (pass) in order to clarify the material (**Figure 8**) [112].
