Emerging 2D Nanomaterials for Biomedical Applications.

Two-dimensional (2D) nanomaterials are an emerging class of biomaterials with remarkable potential for biomedical applications. The planar topography of these nanomaterials confers unique physical, chemical, electronic and optical properties, making them attractive candidates for therapeutic delivery, biosensing, bioimaging, regenerative medicine, and additive manufacturing strategies. The high surface-to-volume ratio of 2D nanomaterials promotes enhanced interactions with biomolecules and cells. A range of 2D nanomaterials, including transition metal dichalcogenides (TMDs), layered double hydroxides (LDHs), layered silicates (nanoclays), 2D metal carbides and nitrides (MXenes), metal-organic framework (MOFs), covalent organic frameworks (COFs) and polymer nanosheets have been investigated for their potential in biomedical applications. Here, we will critically evaluate recent advances of 2D nanomaterial strategies in biomedical engineering and discuss emerging approaches and current limitations associated with these nanomaterials. Due to their unique physical, chemical, and biological properties, this new class of nanomaterials has the potential to become a platform technology in regenerative medicine and other biomedical applications.

Inorganic Biomaterials Shape the Transcriptome Profile to Induce Endochondral Differentiation.

Minerals play a vital role, working synergistically with enzymes and other cofactors to regulate physiological functions including tissue healing and regeneration. The bioactive characteristics of mineral-based nanomaterials can be harnessed to facilitate in situ tissue regeneration by attracting endogenous progenitor and stem cells and subsequently directing tissue-specific differentiation. Here, cellular responses of human mesenchymal stem/stromal cells to traditional bioactive mineral-based nanomaterials, such as hydroxyapatite, whitlockite, silicon-dioxide, and the emerging synthetic 2D nanosilicates are investigated. Transcriptome sequencing is utilized to probe the cellular response and determine the significantly affected signaling pathways due to exposure to these inorganic nanomaterials. Transcriptome profiles of stem cells treated with nanosilicates reveals a stabilized skeletal progenitor state suggestive of endochondral differentiation. This observation is bolstered by enhanced deposition of matrix mineralization in nanosilicate treated stem cells compared to control or other treatments. Specifically, use of 2D nanosilicates directs osteogenic differentiation of stem cells via activation of bone morphogenetic proteins and hypoxia-inducible factor 1-alpha signaling pathway. This study provides  insight into impact of nanomaterials on cellular gene expression profile and predicts downstream effects of nanomaterial induction of endochondral differentiation.

Dissociation of nanosilicates induces downstream endochondral differentiation gene expression program.

Bioactive materials harness the body's innate regenerative potential by directing endogenous progenitor cells to facilitate tissue repair. Dissolution products of inorganic biomaterials provide unique biomolecular signaling for tissue-specific differentiation. Inorganic ions (minerals) are vital to biological processes and play crucial roles in regulating gene expression patterns and directing cellular fate. However, mechanisms by which ionic dissolution products affect cellular differentiation are not well characterized. We demonstrate the role of the inorganic biomaterial synthetic two-dimensional nanosilicates and its ionic dissolution products on human mesenchymal stem cell differentiation. We use whole-transcriptome sequencing (RNA-sequencing) to characterize the contribution of nanosilicates and its ionic dissolution products on endochondral differentiation. Our study highlights the modulatory role of ions in stem cell transcriptome dynamics by regulating lineage-specific gene expression patterns. This work paves the way for leveraging biochemical characteristics of inorganic biomaterials to direct cellular processes and promote in situ tissue regeneration.

Inorganic Biomaterials for Regenerative Medicine.

Regenerative medicine leverages the innate potential of the human body to efficiently repair and regenerate damaged tissues using engineered biomaterials. By designing responsive biomaterials with the appropriate biophysical and biochemical characteristics, cellular response can be modulated to direct tissue healing. Recently, inorganic biomaterials have been shown to regulate cellular responses including cell-cell and cell-matrix interactions. Moreover, ions released from these mineral-based biomaterials play a vital role in defining cell identity, as well as driving tissue-specific functions. The intrinsic properties of inorganic biomaterials, such as the release of bioactive ions (e.g., Ca, Mg, Sr, Si, B, Fe, Cu, Zn, Cr, Co, Mo, Mn, Au, Ag, V, Eu, and La), can be leveraged to induce phenotypic changes in cells or modulate the immune microenvironment to direct tissue healing and regeneration. Biophysical characteristics of biomaterials, such as topography, charge, size, electrostatic interactions, and stiffness can be modulated by addition of inorganic micro- and nanoparticles to polymeric networks have also been shown to play an important role in their biological response. In this Review, we discuss the recent emergence of inorganic biomaterials to harness the innate regenerative potential of the body. Specifically, we will discuss various biophysical or biochemical effects of inorganic-based materials in directing cellular response for regenerative medicine applications.

2D Nanoclay for Biomedical Applications: Regenerative Medicine, Therapeutic Delivery, and Additive Manufacturing.

Clay nanomaterials are an emerging class of 2D biomaterials of interest due to their atomically thin layered structure, charged characteristics, and well-defined composition. Synthetic nanoclays are plate-like polyions composed of simple or complex salts of silicic acids with a heterogeneous charge distribution and patchy interactions. Due to their biocompatible characteristics, unique shape, high surface-to-volume ratio, and charge, nanoclays are investigated for various biomedical applications. Here, a critical overview of the physical, chemical, and physiological interactions of nanoclay with biological moieties, including cells, proteins, and polymers, is provided. The state-of-the-art biomedical applications of 2D nanoclay in regenerative medicine, therapeutic delivery, and additive manufacturing are reviewed. In addition, recent developments that are shaping this emerging field are discussed and promising new research directions for 2D nanoclay-based biomaterials are identified.