**3.1 Cardiovascular tissue engineering**

Nowadays, cardiovascular disease has become a major issue affecting the health of countless people. Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide [74]. MI is caused by local obstruction of myocardial blood flow, which leads to permanent damage to the heart pump function and gradually develops into chronic heart failure. Due to the limited regeneration capacity of myocardial tissue, heart transplantation is the only solution for patients with advanced heart failure to restore heart function. However, the shortage of heart donors and the high cost of surgery procedures make it out of reach for many patients (**Figure 11**).

Cardiac tissue engineering is a promising approach to effectively replace or repair damaged myocardium [78]. The approach of cardiac tissue engineering is to create potential 3D scaffolds that mimic ECM to reconstruct injured myocardium.

*Nanocomposite Biomaterials for Tissue Engineering and Regenerative Medicine Applications DOI: http://dx.doi.org/10.5772/intechopen.102417*

#### **Figure 9.**

*Different types of damaged body tissues repaired by applications of nanocomposites biomaterial-based tissue engineering [72].*

Cardiac tissue engineering should meet some essential requirements, such as biodegradability, porosity, and mechanical/conductive properties, to match healthy cardiac tissue. Based on these characteristics, nanocomposite hydrogels containing conductive nanomaterials are considered attractive strategies for cardiacregeneration [79]. There are many reports on the use of electroactive nanocomposite hydrogels for cardiac tissue engineering.

Polypyrrole (Ppy) is widely used in cardiac tissue engineering due to its outstanding electrical conductivity and biocompatibility. Qiu et al. prepared a variety of conductive hydrogel myocardial patches containing Ppy NPs and used them to repair myocardial defects. Some animal experiments results showed that the fractional shortening and ejection fraction are elevated by about 50% and that the infarct size is reduced by 42.6% [77]. Metal-based nanomaterials are also widely used in cardiac tissue engineering, Chen et al. prepared a hyaluronic acid-based injectable hydrogel containing Au NPs to repair myocardial defects by loading human induced pluripotent stem cells [80]. Additionally, Dong et al. introduced Au NPs into silk-based hydrogel (SF/ECM) for cell proliferation and expansion of cardiomyocytes [81]. The uniform distribution of Au NPs in the matrix

#### **Figure 10.**

*Various nanocomposite hydrogels were designed and prepared for different types of tissue engineering [73].*

#### **Figure 11.**

*Schematic illustrating of various nanocomposite conductive hydrogel and their applications in myocardial infarction repair [75–77].*

#### *Nanocomposite Biomaterials for Tissue Engineering and Regenerative Medicine Applications DOI: http://dx.doi.org/10.5772/intechopen.102417*

can provide favorable electrical conductivity and biological effects for cardiac repair. In addition to Au NPs, Liu et al. prepared an injectable PEGylated chitosan hydrogel scaffold for cardiac repair by introducing titanium dioxide (TiO2) nanoparticles [82]. The TiO2 nanocomposite hydrogel significantly enhances the functionalization of the cardiomyocytes, resulting in excellent synchronous contraction by increasing the expression of α-actinin and connexin CX-43. Results of cardiac markers confirmed the formation of interconnected cardiac layers within these nanocomposite hydrogels and the formation of cell-hydrogel matrix interactions. These nanocomposites are well suited for cardiac regeneration and provide a new platform for cardiac tissue engineering.

Mineral-based bioactive nanomaterials, such as SiO2, P2O5, and CaO, can also be used to effectively improve composite hydrogels for cardiac tissue engineering. It has been proven that these materials can stimulate cells to secrete a large number of angiogenic factors, thereby promoting the formation of blood vessels in engineering scaffold [83–85]. To address the lack of functional blood vessels in engineered tissue and low survival rates of injected cells in cardiac tissue engineering, Barabadi et al. [86] introduced bioactive glass nanoparticles into the gelatin-collagen hydrogel to improve the biological properties. In addition, *in vivo* evaluation experiments confirmed that this nanocomposite hydrogel scaffold can effectively promote the formation of capillaries, reduce scar area, and improve cardiac function.

Although electroactive nanocomposite hydrogels can achieve satisfying biocompatibility and durability for the generation of cardiac microtissues *in vitro*, there is still space for improvement in terms of mechanical properties and electrical conductivity [87]. In addition, the goals of high-level cell attachment, viability, endothelialization, and recruitment of cardiac progenitor cells have not yet been fully achieved. Therefore, future research should aim to address these issues.

#### **3.2 Bone tissue engineering**

Among all tissues in the human body, cartilage and bone are some of the most extensively researched tissues in tissue engineering because of their high regeneration potential. Bone graft materials, due to their osteoinductive and osteoconductive properties, have been used to repair fractures and other defects [88]. However, there may be risks of disease metastasis, infection, chronic pain, immunogenicity, and inadequate supply (**Figure 12**).

Bone tissues, connective tissues, that are composed primarily of cells and extracellular matrix. These tissues are hard tissues that can withstand repeated mechanical stimulation without harm or loss of human functions. Bone tissue is closely related to the movement of the human body. Once damaged, it will cause great inconvenience to the patient's life. Based on this, the key goal of bone tissue engineering is to develop a tough and natural 3D microenvironment with the physiological environment required to form the target tissue [6, 90]. In recent years, more and more nanocomposite hydrogels have been developed for bone tissue engineering, especially bone and cartilage tissue engineering.

Inspired by the nature of bones, there is a need for three-dimensional hierarchical structures and nanocomposites that can contain multiple levels of tissues, that is, from the macroscopic tissue arrangement to the molecular arrangement of proteins [91]. These nanostructured materials can provide enhanced mechanical properties and allow the proper transduction of mechanical stimuli to the cellular level. Bioabsorbable β-TCP can improve the clinical application of pure HAp to achieve

#### **Figure 12.**

better bone regeneration. The main attraction of these materials is that they can bind well with host tissues to form a robust interface. However, these materials are limited to non-load-bearing applications due to their poor mechanical properties.

The mineral composition of bone is similar to HAp, but it contains other ions in composition, which can better prepare biological materials. Yazaki et al. developed the incorporation of carbonate or fluoride into the DNA-fibronectin-apatite composite layer for tissue engineering to adjust the solubility of the layer [92]. The incorporation of carbonate increases the effect of gene transfer on the efficiency layer, while fluoride reduces the efficiency and delays the time of gene transfer in a dose-dependent manner. In addition, manganese (Mn), detected as a minor component of teeth and bones, modulates bone remodeling.

The scaffold is designed to mimic the 3D support structure of the ECM in the surrounding bone tissue and offers the following advantages**—**(i) porous interconnected structure, that afford the transport of quality, nutrition, and regulatory factors to allow cell survival, proliferation and differentiation, (ii) sufficient mechanical properties for the support of cells, (iii) controllable degradation and minimal inflammation or toxicity to the body [93]. Besides, the scaffold has the desirable properties of transferring cells to the defect site, limiting cell loss, and even recruiting the body's own cells, rather than simply injecting cells into the defect site [94].

The challenge is to ensure good compatibility of the scaffold while maintaining the porous structure and mechanical properties. It is important to achieve a uniform distribution of NPs within the scaffold. Methods for maximizing the distribution of NPs include precipitating nanoparticles *in situ* in a polymer matrix or using dispersants. For example, the *in situ* synthesis method is used to prepare nanocomposite scaffolds of SF and CaPs. Phosphate ions are added to the calcium chloride solution in which SF is dissolved, and then the diammonium hydrogen phosphate solution is added by salt immersion/freeze drying technology [95]. The scaffold exhibits highly interconnected macropores with a size of approximately 500 μm and a micropore size range of 10–100 μm under SEM.

#### **3.3 Skin tissue engineering**

The skin is the first line of defense against infection and its injuries (such as burns) may cause serious health problems. Skin tissue engineering is a promising method of skin regeneration. In addition to the proper mechanical properties, the scaffold material for skin tissue engineering should also possess antibacterial and anti-infective properties, and can play a role in drug delivery to promote wound repair. To achieve

*Nanocomposite Biomaterials for Tissue Engineering and Regenerative Medicine Applications DOI: http://dx.doi.org/10.5772/intechopen.102417*

**Figure 13.** *Skin healing process and mechanism using the nanocomposite wound dressing [97].*

this goal, nanocomposite hydrogels are widely used in skin tissue engineering. Studies have shown that zinc oxide (ZnO) NPs exhibit strong antibacterial activity and have no side effects on normal tissue. Rakhshaei et al. introduced ZnO nanoparticles into chitosan/gelatin hydrogel (CS-gel/ZnO) to endow the hydrogel with additional antibacterial and drug delivery properties [96]. The ZnO NPs on the surface of the scaffold extremely enhance the flexibility of the scaffold. These nanocomposite hydrogels can effectively destroy the cell walls of gram-negative bacteria to achieve antibacterial properties, which is due to ROS and Zn2+ in the nanocomposite hydrogel can attack the negatively charged bacterial cell wall, causing bacterial death (**Figure 13**).

In addition to ZnO nanoparticles, graphene-based nanomaterials are also used as fillers to prepare nanocomposite hydrogels for skin tissue engineering. Narayanan et al. mixed rGO nanosheets with PAAm to form nanocomposite hydrogels which have antibacterial activity and can promote the formation of biofilms [98]. Besides, it is confirmed that the ginsenoside molecules in the nanocomposite scaffold can be released slowly to achieve antioxidant effects. Xu et al. introduced ginsenoside Rg3 (GS-Rg3) into an electrospun fiber of polyglutamic acid, this nanocomposite hydrogel exhibits fast tissue repair and inhibits the excessive scar formation [99]. The results show that this nanocomposite hydrogel can be used as a wound dressing in skin tissue engineering.

#### **3.4 Other tissue engineering applications**

In addition to the aforementioned fields, nanocomposite scaffolds also have a wide range of applications in other areas, such as muscle tissue and nerve tissue.

#### *3.4.1 Skeletal muscle tissue engineering*

Skeletal muscle is one of the most abundant tissues in the body, possessing a complex structure. In addition to supporting, connecting, nourishing, and protecting muscle tissue, skeletal muscle also has the function of regulating the activity of muscle fiber groups. Extensive skeletal muscle defects caused by trauma or tumor ablation can cause movement disorders and organ dysfunction, which can lead to pain in patients [100]. Restoration of the original function of skeletal muscle is limited and fibrosis and scarring may occur for serious injuries of a mass loss of more than 20% [101].

The purpose of skeletal muscle tissue engineering is to replicate the natural structure and function of muscle *in vitro* and to transplant this tissue to the damaged area, since the behavior of myogenic cells is regulated by the flexibility and strength of the scaffold, such scaffold systems in skeletal muscle tissue engineering should have mechanical elasticity. Nanocomposite hydrogels with conductive components have proven to be good candidates as 3D biomaterials for skeletal muscle tissue engineering. In the field of skeletal muscle regeneration, graphene and carbon nanotubes are the two most widely used carbon nanomaterials in skeletal muscle regeneration. To further optimize the mechanical properties of the scaffold, Patel et al. combined graphene with chitosan and gellan gum to develop a graphene-polysaccharide nanocomposite hydrogel scaffold [102]. This nanocomposite hydrogel can positively affect myoblasts, and as an ideal multifunctional biomaterial, it has the mechanical properties of natural skeletal muscle tissue and the ideal conductivity for transmitting electrical signals to cells.

Metal oxides can also be used in skeletal muscle tissue engineering as nanoreinforcing materials. For example, Tognato et al. introduced iron oxide (Fe2O3) nanoparticles into gelatin methacrylic acid (GelMA) [103]. In an external magnetic field, the magnetic Fe2O3 nanoparticles can be aligned, which then caused the seed cells to line up in the same direction. In particular, in the absence of differentiation media, the skeletal myoblasts in the nanocomposite hydrogel can differentiate into myotubes. One of the challenges of current research *in vitro* skeletal muscle regeneration is the lack of functional vascular structure, which also exists in most areas of tissue engineering today. Therefore, the direction of skeletal muscle tissue engineering in the future is to overcome the challenge above to promote the formation of muscle-like intravascular structures.

### *3.4.2 Nervous tissue engineering*

The function of the nervous system is to receive information from cells in different parts of the body, process the received information, and send signals to other cells and organs to elicit appropriate responses [104]. Nervous system damage caused by ischemia, chemical, mechanical or thermal factors is very common in our current society. Surgical strategies, such as nerve repair and autologous nerve transplantation, are widely used in nervous system injuries to achieve optimal recovery. However, the prognosis is not ideal. Recent studies have shown that only 40–50% of patients recover their motor function after receiving autologous nerve transplantation [105]. Therefore, tissue engineering technology is considered an ideal method to repair nerve damage.

The goal of nervous tissue engineering is to manufacture nerve graft substitutes for the treatment of nerve damage and achieve long-term functional recovery. Among them, graphene-based nanocomposite hydrogels can be used as a viable option to promote nerve regeneration. Huang et al. prepared a nanocomposite hydrogel based on graphene and polyurethane [106]. This polyurethane hydrogel can improve the growth of neural stem cells and the differentiation of neurons. Qiao and his colleagues introduced GO into poly(acrylic acid) (PAA) and formed an electrically responsive nanocomposite hydrogel through *in situ* polymerization [107]. In particular, scientists also proved that carbon nanotube (CNT)-based polyethylene glycol (PEG) nanocomposite hydrogels can increase total neurite growth and average neurite length through electrical stimulation.

However, the influence of these nanocomposite hydrogels on the activity of neural stem cells needs to be further studied.

*Nanocomposite Biomaterials for Tissue Engineering and Regenerative Medicine Applications DOI: http://dx.doi.org/10.5772/intechopen.102417*
