**5.1 Tumor or cancer model**

The ability of 3D bioprinting in replicating tumor microenvironment (TME) provides a better model to assess drug response, tumor proliferation, and metastasis. By 3D bioprinting, a tumor model with hypoxic core and necrosis could be recreated similar to the *in vivo* environment [84, 85]. The 3D-printed glioma model comprising of glioma stem cells incorporated in alginate/gelatin/fibrinogen bioink is an example, and it showed higher resistance to temozolomide than in a 2D culture model [86]. Another case in point, fabrication of breast cancer model was achieved via the Organovo 3D NoveGen Bioprinter system where cancer cells are bordered with a stromal milieu of endothelial cells, fibroblast, and adipocytes. The said breast cancer model was viable for up to 14 days and possesses distinct internal compartmentalization. The model has been used to test hormonal drug response

#### **Figure 5.**

*The potential development of organoid models for drug discovery such as for cancer model, skin, cornea, intestines, muscle, cardiac tissue, and liver.*

and chemotherapeutic agents [87]. Most reports conclude that 3D bioprinting gave a higher effect be it tolerance or resistance to the drug tested as compared to the 2D model of the disease, thus proving the value of 3D bioprinting in cancer drug screening.

## **5.2 Skin**

The human skin's inherent multi-layered, multicellular composition is in demand commercially for pharmaceutical and dermatological testing. Dermal skin equivalent has been successfully created using 3D bioprinting through several approaches. One of them is via direct cell printing of fibroblasts and keratinocytes in the collagen-based hydrogel to recreate the skin stratification [88]. The incorporation of melanocytes and fibroblasts in collagen/fibroblast bio-ink was also reported [89]. Maturation and stratification of 3D bioprinted skin construct could be achieved via exposure to the air-liquid interface as shown by Lee et al. with skin construct expressing skin-specific markers [90]. These skin-like constructs are of value in drug toxicity screening as shown by Tseng et al. where five different drugs, i.e. all-trans retinoic acid, dexamethasone, doxorubicin, 5′-fluorouracil, and forskolin, use their 3D bioprinted fibroblasts [91].

#### **5.3 Cornea**

Corneal in vitro/ex vivo model is desperately needed as cornea function as major barrier in penetration of drugs into eye; thus, drug absorption thru cornea need to be optimized for topical ocular drug application. Hence, many studies were done in an animal model which is not cost-effective. The complex arrangement of collagen lamellae could be recapitulated using a 3D bioprinting system. Such a corneal model has been successfully produced utilizing extrusion-based bioprinting (EBB) of collagen/alginate/keratinocyte bio-ink [92]. Similar studies utilizing 3D bioprinting with

**197**

**5.7 Liver**

*3D Printed Bioscaffolds for Developing Tissue-Engineered Constructs*

a promising outcome have also been reported such as the generation of 3D multilamellar silk film incorporated with human corneal stromal stem cells (hCSSCs). The silk film architecture supports the growth and differentiation of hCSSCs in producing matured corneal stroma with the desired optical and mechanical proper-

Drugs are commonly absorbed in the intestine; hence, an in vitro intestinal tissue model is of value in the early phase of drug screening. Such a model was fabricated successfully using the Organovo 3D NovoGen bioprinter system with epithelial cells and myofibroblast that has a polarized columnar epithelium with tight junctions and specialized cells that express cytochromes P450 (CYP450). The above said model is a good model for Crohn's disease and internal bowel disease (IBD) that could be used in early-phase drug screening or toxicology study [94].

Development of drugs that are delivered through intramuscular injection or for muscle injuries and muscular dystrophy require an in vitro muscle model for screening and testing. Alginate and Pluronic mixed with murine C2C12 cells have been successfully printed using the EBB method to create a 3D muscle construct that is used to screen several drugs and observe the cell viability, myogenic differen-

Cardiovascular disease (CVD) is the leading cause of death in the world. Cardiotoxicity is the primary cause of CVD drug retraction from the market and is often done in 2D cell cultures. Therefore, the development of cardiovascular disease modeling and drug screening platform is a necessity. Most work focuses on recreating the left ventricular myocardium where cardiac pathologies occur. A spontaneously and synchronously contracting tissue was successfully developed with aligning endothelial cells that are used for cardiotoxicity screening [97]. In another study, Lind et al. fabricated self-assembled rat-derived cardiac cells by direct printing of six functional bio-inks that are highly conductance, piezoresistive, and biocompatible material. This model exhibits inotropic responses similar to isolated post-natal whole rat heart to several CVD drugs, i.e., L-type calcium

channel blocker, verapamil, and β adrenergic agonist isoproterenol [98].

3D bioprinting approaches have been utilized in creating a liver disease model and liver tissue. Hepatotoxicity study of any drug introduced in the market is essential in any preclinical drug development. The establishment of in vitro liver models includes the incorporation of primary hepatocytes, hepatic cell lines, and stem cell-derived hepatic cells [99–101]. Kang et al. created a five-layer 3D hepatic structure using alginate and mouse induced hepatocyte-like cells that express albumin, ASGR1, and HNF4a [102]. Biomimetic liver tissue builds by Ma et al. showed better liver-specific function and drug metabolism potential compared to 2D monolayer culture [103]. The application of 3D bioprinting technology in the development of in vitro tissue or organoid models for drug discovery has fruitfully shown a better model in mitigating the risk associated with drug development. A 3D environment provides a

tiation, and tissue contractile force against the drug [95, 96].

*DOI: http://dx.doi.org/10.5772/intechopen.92418*

ties close to the native cornea [93].

**5.4 Intestines**

**5.5 Muscle**

**5.6 Cardiac tissue**

#### *3D Printed Bioscaffolds for Developing Tissue-Engineered Constructs DOI: http://dx.doi.org/10.5772/intechopen.92418*

a promising outcome have also been reported such as the generation of 3D multilamellar silk film incorporated with human corneal stromal stem cells (hCSSCs). The silk film architecture supports the growth and differentiation of hCSSCs in producing matured corneal stroma with the desired optical and mechanical properties close to the native cornea [93].

## **5.4 Intestines**

Drugs are commonly absorbed in the intestine; hence, an in vitro intestinal tissue model is of value in the early phase of drug screening. Such a model was fabricated successfully using the Organovo 3D NovoGen bioprinter system with epithelial cells and myofibroblast that has a polarized columnar epithelium with tight junctions and specialized cells that express cytochromes P450 (CYP450). The above said model is a good model for Crohn's disease and internal bowel disease (IBD) that could be used in early-phase drug screening or toxicology study [94].

#### **5.5 Muscle**

Development of drugs that are delivered through intramuscular injection or for muscle injuries and muscular dystrophy require an in vitro muscle model for screening and testing. Alginate and Pluronic mixed with murine C2C12 cells have been successfully printed using the EBB method to create a 3D muscle construct that is used to screen several drugs and observe the cell viability, myogenic differentiation, and tissue contractile force against the drug [95, 96].

## **5.6 Cardiac tissue**

Cardiovascular disease (CVD) is the leading cause of death in the world. Cardiotoxicity is the primary cause of CVD drug retraction from the market and is often done in 2D cell cultures. Therefore, the development of cardiovascular disease modeling and drug screening platform is a necessity. Most work focuses on recreating the left ventricular myocardium where cardiac pathologies occur. A spontaneously and synchronously contracting tissue was successfully developed with aligning endothelial cells that are used for cardiotoxicity screening [97]. In another study, Lind et al. fabricated self-assembled rat-derived cardiac cells by direct printing of six functional bio-inks that are highly conductance, piezoresistive, and biocompatible material. This model exhibits inotropic responses similar to isolated post-natal whole rat heart to several CVD drugs, i.e., L-type calcium channel blocker, verapamil, and β adrenergic agonist isoproterenol [98].
