**1. Introduction**

Modern biomaterials must meet several requirements, even involving their biological and structural characteristics. Recently, scientists have taken smart two-dimensional materials (2D materials) into consideration, as the allotropic forms of many such materials have shown peculiar characteristics which may be usable in several applications. The interface between cells and biomaterials should be biocompatible and bioactive: 2D materials are tunable on the nanometric-scale, which can be used to improve the connection between such materials and human tissue. 2D materials have consistently shown unique physical, chemical, electronic, and optical characteristics; recently, MoS2, WSe2 and h-BN have been shown to be useful in the production of many biomedical devices. In this context, graphene was recently investigated for its properties which show grea<sup>t</sup> potential for use in biomedical applications [1,2]. Graphene has physical, antibacterial, and electrical peculiarities that make it ideal for biosensors and medical devices; however, it also has limitations—such as biodegradability in vivo and the cytotoxicity in vitro—that have pushed scientists to search for alternative solutions.

Among the allotropes of phosphorus which are already present in di fferent percentages in our organism, black phosphorus has structural properties which are interesting to investigate in the light of future applications in the medical sciences. As previously reported, other materials are currently under evaluation for use and integration in future medical devices. MoS2, WSe2, and h-BN appear to be biocompatible, similarly to graphene and Black Phosphorene (BP), but with evident di fferences, especially in their electronic performance. H-BN is an insulator, and recent studies on it have mainly focused on its thermal conductivity and ability to transport phonons, for use in the construction of fuel cells that can also be adopted in the biomedical sector. High electrical resistance does not facilitate use in applications for electrochemical sensors or wearable devices, in which the detection of an electrical signal is fundamental [3]. MoS2 and WSe2, as reported by Akinwande et al. [4] and Sahoo et al. [5], have shown peculiar characteristics in the ON-OFF current ratio, which may be useful for the realization of Field E ffect Transistor (FET) sensing, even if the low band-gap (1.2–1.8 eV) limits their use in some fields of biological analysis. 2D nanosheets of black phosphorus are called Black Phosphorene (BP) [6]. The structural anisotropy of BP contributes to optimizing its mechanical, optical, electrical, and thermoelectric conductivity properties for various applications. Briefly, the chemical structure of BP consists of a phosphorus atom covalently linked with three adjacent phosphorus atoms, which generates a crystalline structure characterized by a hexagonal shape [7]. In recent years, several studies have been carried out to evaluate the optoelectronic, photothermic, photodynamic, and electrochemical behavior of BP. It is important to consider that nanomaterials, though biocompatible, may induce inflammatory responses that are not easy to control and heal. This issue should be carefully evaluated before any biomedical application of these nanomaterials. BP is already a bone constituent, albeit in small percentages, constituting −1% of total body weight (about 660 g on average) [8]. In tissue engineering, it is well known that calcium and phosphates play an important role in bone regeneration. Regarding nanomaterials made by 2D layers of such components, the concern is mainly related to the amount of in situ nanoparticles which are released, and their long-time toxicity. Currently, BP seems to be safe due to its chemical and molecular properties that ensure high stability and biocompatibility [9]. These properties may allow BP to be used in various applications, ranging from biosensors (electronic, colorimetric, fluorescent, electrochemical) to medical imaging, from pharmacological applications to serving as a coating on sca ffolds and prosthesis surfaces. This review outlines recent trends and future insights of biomedical applications based on BP, paying specific attention to the following: (i) the physicochemical properties of BP, (ii) the biological properties of BP, (iii) BP synthesis and production, (iv) biomedical applications of BP, and (v) presenting some promising insights on the future applications of BP in biomedicine.

### **2. Physicochemical Properties of BP**
