**1. Introduction**

Biomineralization is a naturally occurring process in which organisms form minerals and consist in a complex cascade of phenomena generating hybrid nanostructured materials based on organic and inorganic matter [1–3]. These components are hierarchically organized from the nanoscale to the macroscopic scale to create a protective and/or loadbearing structure [4–9]. Resulting structures combine the hardness and pressure resistance, due to the inorganic phase, and elasticity and tensile strength, due to the organic one. Indeed, the inorganic phase helps to protect the living organisms (e.g., mollusk shells or crustacean exoskeleton) and to support organisms (e.g., bones, teeth, and coral skeleton) [10–12]. Due to the strict interaction between biomineralized crystals and organic matter, natural structures are usually very different to the synthetic ones. In detail, the high level of control over the composition, structure, size, and morphology of natural structures allows to create very fascinating properties that often overtake those of the synthetic analogues [13–15]. Organisms use macromolecules (e.g., collagen and chitin) to control the nucleation and growth of biominerals as well as crystalline form and shape of inorganic crystals in a process called molecular recognition [2,16,17].

Biomineralization can be subdivided in two main categories, namely biological induction and biological control. These processes differ for the fine regulation of size, shape

**Citation:** Campodoni, E.; Montanari, M.; Artusi, C.; Bassi, G.; Furlani, F.; Montesi, M.; Panseri, S.; Sandri, M.; Tampieri, A. Calcium-Based Biomineralization: A Smart Approach for the Design of Novel Multifunctional Hybrid Materials. *J. Compos. Sci.* **2021**, *5*, 278. https:// doi.org/10.3390/jcs5100278

Academic Editor: Francesco Tornabene

Received: 23 August 2021 Accepted: 8 October 2021 Published: 15 October 2021

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and arrangement of resulting biominerals [2,8,18]. It is no surprise, then, that scientists are strongly intrigued by these processes that have become a source of inspiration for the development of highly organized materials with customized properties [19–21].

#### *Mimicking Biomineralization in the Lab*

Biominerals compared to natural or synthetic minerals often display excellent mechanical and other properties due to their multi-level order, hierarchically organized from the nanoscale to the microscale. For this reason, in the last decades, researchers have been trying to reproduce the calcium-based biomineralization processes in laboratory, inducing the heterogeneous nucleation of the inorganic phase into organic matrix through fine mechanisms driven by the organic matrix itself. The chemical and physical interaction between phases confers unique features to the resulting hybrid materials, in a similar way compared to what happens in the natural biomineralization process (Figure 1). These peculiar properties cannot be obtained through a simple mixing of the phases [22–24].

**Figure 1.** Schematic illustration of the naturally occurring structure of bone microstructure and the synthetic approach used to reproduce it. More in detail, in the natural occurring structure of bone, collagen fibers are organized in a triple helix, forming tropocollagen fibrils; these fibrils are tightly tied and reinforced by hydroxyapatite crystals; the organization and association of these fibrils confers peculiar structural and mechanical properties to the bone. Within the lab process, a collagen acidic solution containing phosphate ions (e.g., phosphoric acid) is dropwise added and mixed to a basic solution containing calcium ions (e.g., calcium hydroxide), promoting the formation of nano-hydroxyapatite crystals within the collagen fibers. Reproduced from "Biomineralization process generating hybrid nano-and micro-carriers" by E. Campodoni et al., 2018, Core-Shell Nanostructures for Drug Delivery and Theranostics: Challenges, Strategies, and Prospects for Novel Carrier Systems, 19–24, (doi:10.1016/C2016-0-03458-7) (Under a Creative Commons Attribution 4.0 International License).

As a consequence, the biomineralization process study, together with other emerging technologies to synthesize new nanomaterials, has spread into many fields in our life such as mechanical, electrical [25,26], and environmental [27,28], as well as biomedical engineering [29,30].

In this review focused on the biomedical field, we aim to provide an overview of different materials mimicking the natural calcium-based biomineralization process to prove that, finely tuning some process variables, it is possible to design multifunctional materials. These materials can be exploited in several applications in order to obtain customized and precise medical tools [31–34]. We will first provide a brief overview of the biomineralization process: how it happens in nature, and how scientists have translated this natural process

to an in-lab process. Taking into account the wide chosen topic, we decided to focus on calcium-based biomineralization, more specifically on different applications aside from bone regeneration, that were poorly or not considered in other reviews. Specifically, we will discuss biomimetic hybrid material features that can be obtained by modulating different process parameters, focusing on the materials chemical–physical and biological features which are essential to make them suitable for biomedical field. Finally, we will discuss the several applications of these materials besides tissue regeneration, such as their use for the creation of 3D cancer predictive models or drug testing, as well as on their use as innovative physical filters against solar radiations or as nano and micro drug delivery systems.
