**1. Introduction**

Regardless of the therapeutic area of new emerging therapies and novel agents entering the market, nephrotoxicity is a major challenge, as the kidney is the second target of drugs and chemicals after the liver. More than 25% of the adverse effects in today's pharmacotherapy are caused by nephrotoxic effects [1]. Of these, 20% are reported during postmarket surveillance [2], as early stages of drug development fail to deliver relevant output with this respect [3]. Consequently, the poor correlation between the preclinical and clinical outcomes has led to the failure of most drugs before reaching the patient [4]. Preclinically approved drugs have been withdrawn a few times due to the side effects observed in the clinical trials [5,6]. Therefore, the pharmaceutical industry is under high pressure to speed up the drug-development process and to design new cures that are very effective in humans with reasonable costs [7].

The traditional in vivo tests on animal models are costly and often fail to accurately predict the efficiency and toxicity in humans due to the species' different metabolic responses to specific agents and the variations in some genes' expressions, such as cytochrome

**Citation:** Galateanu, B.; Hudita, A.; Biru, E.I.; Iovu, H.; Zaharia, C.; Simsensohn, E.; Costache, M.; Petca, R.-C.; Jinga, V. Applications of Polymers for Organ-on-Chip Technology in Urology. *Polymers* **2022**, *14*, 1668. https://doi.org/10.3390/ polym14091668

Academic Editor: Ángel Serrano-Aroca

Received: 26 February 2022 Accepted: 18 April 2022 Published: 20 April 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

P450 genes [8]. Consequently, the poor similarity between the physiological environment in animals and human bodies, which may alter the results of drug efficiency in various diseases, is a major barrier for future use of in vivo tests on animals [9]. With respect to cancer research, animal models in particular lack predictability [10] since they do not recreate the exact human tumor microenvironment (TME) and may exhibit different cell biology and cancer behavior when tumorous cells interact locally with stromal cells. In addition, the ethics concerns of sacrificing animals are a significant barrier in testing many discovered drugs on animals [11,12]. In 2021, the European Parliament agreed with a large majority to ban experiments on animals, which have killed about 12 million animals in 2017, revealing the importance of finding alternatives for biological assays developed with other procedures than sacrificing animals [13].

Despite tremendous research efforts and advanced medical treatments, cancer continues to be one of the most frequent causes of death in the world. In 2020, 18.1 million new cases and 9.5 million cancer-associated deaths were reported worldwide [14]. According to American Institute for Cancer Research, more than 50% of cancer cases were reported in men. Prostate, bladder, and kidney cancers account for an estimated 23% of all cancers diagnosed in men in the last two years. Furthermore, recent World Health Organization (WHO) statistics are estimating a ~55% increase of overall cancer cases from 2020 to 2040 [15]. Alarmingly, the mortality rate is expected to increase by ~65% by 2040, highlighting the urge to find and acquire more efficient anticancer remedies.

The main difficulties in cancer research are forming an effective in vitro TME able to accurately recapitulate the local tissue in which the tumor is forming [16]. Conventional preclinical in vitro models for anticancer drug screening are generally classified in 2D cell cultures and 3D cell architectures and have been extensively exploited as simple and cost-efficient methods to simulate cancer propagation and drug response [17]. The 3D cancer models deliver a helpful substitute to animals, but they still do not consider the dynamic environment of the human tissues or organs. However, they do not reproduce the complex assemblage of the human 3D cells from living organs to properly elucidate the cancer cell migration and invasion, also taking into consideration the mechanical forces (such as hydrostatic pressure, fluid shear stress, breathing motions in lung) naturally occurring in human bodies. Nonetheless, neither of these systems is transporting a blood or nutrient-rich medium through an endothelium-lined vasculature, limiting the real prediction of tissue–tissue interactions and circulating immune cells during therapeutic drug dosage [18,19].

Standard cell-culture techniques fail to provide insights into complex multifaced interactions that take place in a multiorgan system. The need to transport fluids containing pharmaceutical compounds through models of different pathological conditions while accurately simulating physiological processes is challenging the scientific media to engineer new technology able to replace animal testing.

Microfluidics is the science and technology of systems that allow the processing and manipulation of microscale fluids (10−<sup>9</sup> to 10−<sup>18</sup> L) using channels with sizes of tens to hundreds of micrometers [20]. By combining microelectronics with structural analysis and molecular biology, microfluidics leads to a deeper understanding of the mechanism by which the cellular, biochemical, and physiochemical environment indicate tumor sensitivity and resistance to therapy [21].

Recently, new devices known as organ-on-chips (OOCs), which are able to recapitulate the multicellular assemblage, tissue–tissue interactions, and to replicate human pathologies and the appropriate physical TME, have emerged as a practical cost-efficient solution for tumor-growth investigation and anticancer-drug screening by combining the microfluidic technology with 3D cell-culture procedure to simulate the entanglement of the cells as in their native environment [19,22,23]. OOCs are compact and easy-to-use microphysiological functional units that recapitulate the native function and the mechanical strain that the cells experience in the human bodies, allowing the development of a wide range of applications such as disease modeling or even the development of diagnostic devices. However, impor-

tant features of the membranes involved in the fabrication of OOC compartments to allow cells' structural support and nutrient transportation are often poorly investigated. Nowadays, both synthetic and natural polymers are explored for the manufacturing process of advanced OOC microdevices, being able to replicate various organ bionic pathophysiological models. Poly(dimethylsiloxane) is one of the most employed synthetic polymers used for lung, liver, heart, and multi-organ-on-chip (MOOC) membranes in microfluidic devices due to its extraordinary high transparency and flexibility. However, it is not a degradable material able to contribute to the formation of the natural extracellular matrix (ECM). Alternative biopolymers with higher biocompatibility, such as collagen-based materials containing cell-growth factors and hormones, have been used for OOC fabrication to simulate the physiological behavior of living organs. Despite significant advances, many polymeric materials still do not meet the mechanical properties of the in vivo organs and do not exhibit optimal cytocompatibility suitable for accurate pharmaceutical screening or dynamic simulation of cancer cell behavior.

This review brings to attention the specifications and fabrication methods for OOCs and the importance of polymeric porous materials used in OOCs in relation to cell behavior. In this context, the current work aims to review the scientific literature in the field of microfluidic devices and materials designed for urology applications in terms of OOC fabrication (principles of manufacture and materials used), development of kidney-on-chip models for drugs toxicity screening, and kidney tumors modeling, bladder-on-chip models for urinary tract infections and bladder cancer modeling, and prostate-on-chip models for prostate cancer modeling.
