Bones and teeth are typical biological minerals in human body, and damage to these hard tissues directly affects our daily life [1], [2]. In recent years, chronic diseases such as osteoporosis and osteoarthritis have large impact on the elderly’s life [3], [4]. From 1990–2019, the number of disabled people due to low bone mineral density increased from 8.6 million to 16.6 million globally. This substantial rise highlights the growing severity of the treatment challenges in hard tissue regeneration worldwide [5], [6]. Orthopedic biomaterials account for 37.5 % of the global biomaterials market, and the market share ranks first in biomaterials [7]. However, increased risks caused by insufficient donor sources, immunogenicity, and secondary trauma have limited their practical application [8]. Guiding repair of bone defects with exogenous implants is urgent. Teeth are composed of enamel, cementum and pulp-dentine complex, their physical properties are largely decided by the enamel [9]. Tooth remineralization usually means the deposition of calcium and phosphorus ions, which rebuilds the tooth [10]. As we eat more sugars these days, enamel demineralization has been an increasingly serious health problem. Nevertheless, designing and constructing microenvironments that accelerate new bone/teeth remineralization and induce bone regeneration to meet the clinical needs of different application scenarios has become an urgent challenge in medicine and health. In recent years, bone tissue engineering has gradually draw researchers’ attention due to its good biocompatibility, excellent bone induction, wide source of raw materials and simple preparation process [11]. Tissue engineering simulates the natural remodeling process and microenvironment of bones and teeth, achieves the orderly mineralization of functional elements in situ under the regulation of organic matter. It has been widely used and has achieved remarkable results [1], [12], [13], [14].
Mineralization is the basis of many biological functions, among which mineralization of hard tissue is the most typical biomineralization process in human body (e.g., bones and teeth) [15]. Bone, one of the most widely studied biominerals, is composed of nano-crystalline calcium phosphate in the form of hydroxyapatite (HAP) embedded in collagen fibers [16]. In view of functions of different parts in natural bone, organic matrix (e.g,. collagen) provide toughness, while inorganic phases (e.g., HAP) provide stiffness. The assembly of organic matrix and inorganic phases equips bone tissue with sufficient hardness and toughness [17].
In the process of biomineralization, organisms can control the site of crystal nucleation, crystal orientation, shape and final formed phase, and the realization of these functions depends on the organic components existing in the mineralization process. Acting as templates, these organic matrix regulate the growth of key microscopic units (i.e., functional motifs) that play a decisive role in a functional mineral, selecting better sites for nucleation and controlling the orientation of crystal growth. These motifs cannot be replaced by other structural units, otherwise the related functions will be lost or severely suppressed. Functional motifs and their arrangement determine the properties of the materials. The transformation from structure to performance relationship can be achieved through the ordered arrangement of functional motifs [18]. That is, organic matrix have the ability to regulate the functional motifs (Ca2+ and PO43-) to form uniformly distributed HAP, and achieve the change of material properties through the micro-regulation of functional motifs, so as for biomimetic mineralization. Inspired by this, numbers of studies have prepared bone repair materials by simply mixing inorganic mineral crystals (e.g., calcium phosphate ceramics and bioactive glass) with organic matter (e.g., gelatin and collagen) to imitate the natural structure of human bones [19], [20], [21]. However, in this biomimetic composite system, ceramic particles are loosely distributed in organic matter. Chen et al. [22] Characterized the morphology of the material obtained by direct mixing, and found that direct mixing made the distribution of HAP in the material uneven, and the formed material had a certain degree of brittleness, which limited its application. Therefore, it is urgent to explore in vitro to achieve the directional growth of nanocrystals (e.g., HAP) and the orderly arrangement between crystals by regulation. The biomimetic mineralization theory was firstly clarified in NATURE by Mann et al. back in 1988 [23]. Taking advantages of benefits of in-situ biomineralization, Munch et al. innovatively combine organic and inorganic phases to synthesize bioinspired ceramic matrix composites by using the mutual recognization mechanism of the two-phase interface to simulate the toughening mechanism of nature in 2009 [24]. In order to solve the defects mentioned above, the in-situ biomimetic mineralization strategy was firstly proposed by Dey et al. Back in 2010 [25]. In-situ mineralization refers to the addition of mineral ions (i.e. Ca2+ and PO43-) in the solution system, or immersing the whole system into solution containing mineral ions instead of directly adding mineral mineral crystals. Under the regulation of organic matrix, mineral ions deposite and grow in different ways, and gradually assemble into mineral crystals. This strategy promotes the in situ sequential assembly of the functional motifs of nHAP induced by the unique structure and functional groups of the organic matrix, which is closer to the mineral formation process of natural bone/teeth, and thus overcomes the deficiencies of brittleness and uneven distribution of minerals caused by the direct addition of mineral crystals [26].
This article summarizes and discusses the latest progress in the in-situ biomimetic mineralization of functional motifs with ordered arrangement regulated by organic matter in recent years. Firstly, the organic matrix functioned as regulator for the mineralized of mineral crystals (e.g., HAP) was discussed from the perspective of the types and progress. Subsequently, from electrostatic interaction to lattic matching and other effects, mechanism and ways of organic matrix regulating functional motifs to carry out sequence mineralized arrangement were discussed emphatically. In addition, the methods and strategies of in-situ mineralization and the application forms in bone and teeth repair were also sorted out (Fig. 1). Finally, challenges faced by strategy of organic matrix regulating functional motifs to achieve arranged mineralization and its further research directions were also elaborated. Crucially, this review emphasizes that the rational nanoscale design of functional motifs within organic matrices is the key to steering biomineralization processes and developing next-generation regenerative materials. On the whole, such a comprehensive summary affords constructive suggestion to the development of in-situ biomimetic mineralization applying in hard tissue regeneration.