Framework Nucleic Acids-Based VEGF Signaling Activating System for Angiogenesis: A Dual Stimulation Strategy.

Angiogenesis is crucial for tissue engineering, wound healing, and regenerative medicine. Nanomaterials constructed based on specific goals can be employed to activate endogenous growth factor-related signaling. In this study, based on the conventional single-stranded DNA self-assembly into tetrahedral framework nucleic acids (tFNAs), the Apt02 nucleic acid aptamer and dimethyloxallyl glycine (DMOG) small molecule are integrated into a complex via a template-based click chemistry reaction and toehold-mediated strand displacement reaction. Thus, being able to simulate the VEGF (vascular endothelial growth factor) function and stabilize HIF (hypoxia-inducible factor), a functional whole is constructed and applied to angiogenesis. Cellular studies demonstrate that the tFNAs-Apt02 complex (TAC) has a conspicuous affinity to human umbilical vein endothelial cells (HUVECs). Further incubation with DMOG yields the tFNAs-Apt02-DMOG complex (TACD), which promotes VEGF secretion, in vitro blood vessel formation, sprouting, and migration of HUVECs. Additionally, TACD enhances angiogenesis by upregulating the VEGF/VEGFR and HIF signaling pathways. Moreover, in a diabetic mouse skin defect repair process, TACD increases blood vessel formation and collagen deposition, therefore accelerating wound healing. The novel strategy simulating VEGF and stabilizing HIF promotes blood-vessel formation in vivo and in vitro and has the potential for broad applications in the vascularization field.

Digital workflow in the design of individualized emergence profiles of implant restorations based on the contralateral tooth.

PURPOSE: To describe a novel digital design technique for creating an individualized emergence profile for implant restoration based on the contralateral tooth. METHODS: Cone beam computed tomography (CBCT) data were used to accurately obtain a three-dimensional (3D) model of the contralateral tooth, which was mirror-flipped to design the emergence profile. The emergence profile was further divided into critical and subcritical areas; the critical area precisely replicated the mirror-flipped 3D model, whereas the subcritical area featured a slight concavity on the buccal side, flatness on the lingual side, and slight convexity on the mesial and distal surfaces. Subsequently, a milling machine was used to fabricate healing abutments with individualized emergence profiles. The design of the definitive restoration completely duplicated the emergence profile of the individualized healing abutment and was fabricated using a milling machine. CONCLUSIONS: This technical procedure presents an alternative novel method for designing the emergence profiles of implant restorations, with the potential to improve esthetics and functions as well as to maintain the long-term stability of peri-implant soft and hard tissues.

A Mitochondrial Nanoguard Modulates Redox Homeostasis and Bioenergy Metabolism in Diabetic Peripheral Neuropathy.

As a major late complication of diabetes, diabetic peripheral neuropathy (DPN) is the primary reason for amputation. Nevertheless, there are no wonder drugs available. Regulating dysfunctional mitochondria is a key therapeutic target for DPN. Resveratrol (RSV) is widely proven to guard mitochondria, yet the unsatisfactory bioavailability restricts its clinical application. Tetrahedral framework nucleic acids (tFNAs) are promising carriers due to their excellent cell entrance efficiency, biological safety, and structure editability. Here, RSV was intercalated into tFNAs to form the tFNAs-RSV complexes. tFNAs-RSV achieved enhanced stability, bioavailability, and biocompatibility compared with tFNAs and RSV alone. With its treatment, reactive oxygen species (ROS) production was minimized and reductases were activated in an in vitro model of DPN. Besides, respiratory function and adenosine triphosphate (ATP) production were enhanced. tFNAs-RSV also exhibited favorable therapeutic effects on sensory dysfunction, neurovascular deterioration, demyelination, and neuroapoptosis in DPN mice. Metabolomics analysis revealed that redox regulation and energy metabolism were two principal mechanisms that were impacted during the process. Comprehensive inspections indicated that tFNAs-RSV inhibited nitrosation and oxidation and activated reductase and respiratory chain. In sum, tFNAs-RSV served as a mitochondrial nanoguard (mito-guard), representing a viable drilling target for clinical drug development of DPN.

Hard tissue stability outside the buccal bone arch contour after guided bone regeneration in the anterior maxilla: A retrospective cohort radiographic study.

OBJECTIVES: To radiographically evaluate the stability of the bone substitute augmented outside the buccal bony arch contour in the maxillary esthetic zone. MATERIALS AND METHODS: Patients who missed a single anterior tooth and received simultaneous GBR in implant surgery were included. The contralateral homonymous area of the implant site was horizontally mirrored as the individual bone arch contour. According to the relative position of the postoperative buccal grafts and bone arch contour at the implant shoulder, 62 patients were allocated into the outside-contour (OC) and inside-contour (IC) groups. Cone-beam computed tomography was performed before surgery, after implant insertion, before re-entry surgery, and at follow-up. The profilometric changes of the buccal bone plate were analyzed via the bone distance to the mirrored bony contour. RESULTS: At the implant shoulder, the bone distance in the OC group was higher than that in the IC group, with statistically significant differences at re-entry surgery and follow-up. However, the bone grafts outside the bone arch contour were reduced into the contour after remodeling and showed more bone resorption than the IC group. At other vertical levels below the implant shoulder, bony grafting of overcontour 1-2 mm range was favorable to regenerate stable bone plates reaching the individual contour at follow-up. CONCLUSIONS: The overaugmented bone outside the buccal bone arch contour tended to remodel into the original contour, which indicates that the anterior bone arch contour is worthy of careful observation for deciding buccolingual implant position and bone augmentation width.

Minimally invasive techniques for lateral maxillary sinus floor elevation: small lateral window and one-stage surgery-a 2-5-year retrospective study.

This study aimed to introduce a minimally invasive technique for maxillary sinus floor elevation using the lateral approach (lSFE) and to determine the factors that influence the stability of the grafted area in the sinus cavity. Thirty patients (30 implants) treated with lSFE using minimally invasive techniques from 2015 to 2019 were included in the study. Five aspects of the implant (central, mesial, distal, buccal, and palatal bone heights [BHs]) were measured using cone-beam computed tomography (CBCT) before implant surgery, immediately after surgery (T0), 6 months after surgery (T1), and at the last follow-up visit (T2). Patients' characteristics were collected. A small bone window (height, (4.40 ± 0.74) mm; length, (6.26 ± 1.03) mm) was prepared. No implant failed during the follow-up period (3.67 ± 1.75) years. Three of the 30 implants exhibited perforations. Changes in BH of the five aspects of implants showed strong correlations with each other and BH decreased dramatically before second-stage surgery. Residual bone height (RBH) did not significantly influence BH changes, whereas smoking status and type of bone graft materials were the potentially influential factors. During the approximate three-year observation period, lSFE with a minimally invasive technique demonstrated high implant survival rate and limited bone reduction in grafted area. In conclusion, lSFE using minimally invasive techniques was a viable treatment option. Patients who were nonsmokers and whose sinus cavity was filled with deproteinized bovine bone mineral (DBBM) had significantly limited bone resorption in grafted area.

Effects of Puerarin-Loaded Tetrahedral Framework Nucleic Acids on Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) is recognized as a common refractory orthopedic disease that causes severe pain and poor quality of life in patients. Puerarin (Pue), a natural isoflavone glycoside, can promote osteogenesis and inhibit apoptosis of bone mesenchymal stem cells (BMSCs), demonstrating its great potential in the treatment of osteonecrosis. However, its low aqueous solubility, fast degradation in vivo, and inadequate bioavailability, limit its clinical application and therapeutic efficacy. Tetrahedral framework nucleic acids (tFNAs) are promising novel DNA nanomaterials in drug delivery. In this study, tFNAs as Pue carriers is used and synthesized a tFNA/Pue complex (TPC) that exhibited better stability, biocompatibility, and tissue utilization than free Pue. A dexamethasone (DEX)-treated BMSC model in vitro and a methylprednisolone (MPS)-induced ONFH model in vivo is also established, to explore the regulatory effects of TPC on osteogenesis and apoptosis of BMSCs. This findings showed that TPC can restore osteogenesis dysfunction and attenuated BMSC apoptosis induced by high-dose glucocorticoids (GCs) through the hedgehog and Akt/Bcl-2 pathways, contributing to the prevention of GC-induced ONFH in rats. Thus, TPC is a promising drug for the treatment of ONFH and other osteogenesis-related diseases.

Nano shield: a new tetrahedral framework nucleic acids-based solution to radiation-induced mucositis.

Radiation-induced oral mucositis (RIOM) is considered to be one of the most important public health problems today, affecting the overall well-being of millions of patients who have received radiotherapy. Nevertheless, the field of preventing and treating RIOM is still widely unexplored. Curcumin (Cur) with its promising anti-inflammatory and antioxidant properties is accompanied with obstacles in application, including poor dissolubility, instability and low bioavailability. In this study, a tetrahedral framework nucleic acid drug delivery system (TFNAS) was synthesized and established using a novel method to carry Cur (Cur-TFNAS) for efficient drug delivery. The results showed that Cur-TFNAS enhanced the antioxidant capacity of human oral mucosal keratin-forming cells (HOKs) compared to free Cur and TFNAS. Meanwhile, Cur-TFNAS reduced DNA damage and shielded the cells from inflammatory factors. A similar result was also well documented in vivo. Herein, we consider that Cur-TFNAS acts as a nano-shield for preventing radiation oral mucositis and shows important clinical value in the future.

Nucleic Acid Nanomaterials-based Therapy for Osteoarthritis: Progress and Prospects.

Osteoarthritis (OA) involves lesions of the entire joint and remains one of the health problems plaguing the world. The pathological mechanism of OA is complex and involves multiple signaling pathways. Over 300 million people worldwide are living with OA, which imposes a huge burden on society. Nucleic acid nanomaterials are of interest to the biomedical field due to their small dimension, ideal biocompatibility, and structure editability. Various nucleic acids have been used as therapeutic drugs to regulate the pathogenesis and development of OA. Among them, some can enter the cell by themselves and others with the aid of vectors. Apart from high therapeutic efficiency, nucleic acid nanomaterials also act as carriers for transporting drugs. This paper reviews recent advances in nucleic acid nanomaterials in OA therapy, suggesting that nucleic acid nanomaterials-based therapy has good prospects for development.

A Lysosome-Activated Tetrahedral Nanobox for Encapsulated siRNA Delivery.

Tetrahedral framework nucleic acids (tFNAs) have attracted extensive attention as drug nanocarriers because of their excellent cellular uptake. However, for oligonucleotide cargos, tFNA mainly acts as a static delivery platform generated via sticky-ended ligation. Here, inspired by the original stable space inside the tetrahedral scaffold, a dynamic lysosome-activated tFNA nanobox is fabricated for completely encapsulating a short interfering RNA (siRNA) of interest. The closed tetrahedral structure endows cargo siRNA with greater resistance against RNase and serum and enables solid integration with the vehicle during delivery. Moreover, the pH-responsive switch of nanobox allows the controlled release of siRNA upon entry into lysosomes at cell culture temperature. Based on protective loading and active unloading, an excellent silencing effect on the target tumor necrosis factor alpha (TNFα) gene is achieved in in vitro and in vivo experiments. Conclusively, the nanobox offers a dynamic pH-sensitive confinement delivery system for siRNA and can be an extendable strategy for other small RNA.

Modulation of the Crosstalk between Schwann Cells and Macrophages for Nerve Regeneration: A Therapeutic Strategy Based on a Multifunctional Tetrahedral Framework Nucleic Acids System.

Peripheral nerve injury (PNI) is currently recognized as one of the most significant public health issues and affects the general well-being of millions of individuals worldwide. Despite advances in nerve tissue engineering, nerve repair still cannot guarantee complete functional recovery. In the present study, an innovative approach is adopted to establish a multifunctional tetrahedral framework nucleic acids (tFNAs) system, denoted as MiDs, which can integrate the powerful programmability, permeability, and structural stability of tFNAs, with the nerve regeneration potential of microRNA-22 to enhance the communication between Schwann cells (SCs) and macrophages for more effective functional rehabilitation of peripheral nerves. Relevant results demonstrate that MiDs can amplify the ability of SCs to recruit macrophages and facilitate their polarization into the pro-healing M2 phenotype to reconstruct the post-injury microenvironment. Furthermore, MiDs can initiate the adaptive intracellular reprogramming of SCs within a short period to further promote axon regeneration and remyelination. MiDs represent a new possibility for enhancing nerve repair and may have critical clinical applications in the future.

Tetrahedral Framework Nucleic Acids Reverse New-Onset Type 1 Diabetes.

Type 1 diabetes (T1D) is caused by breakdowns of central and peripheral immune tolerance and destructions of insulin-producing ß-cells. Conventional insulin injection cannot cure the disease. Regulatory immune cells, including regulatory T-cells (Tregs) and regulatory B-cells (Bregs), play critical roles in immune tolerance. Inducing regulatory immune cells to halt the progress of T1D and restore immune tolerance is the promising approach in T1D immunotherapy. Here, tetrahedral framework nucleic acids (tFNAs) were utilized to treat T1D in non-obese diabetic (NOD) mice. 250 nM tFNA treatment was adopted in the experiment to reverse hyperglycemia and protect insulin-secreting ß-cells in diabetic NOD mice. In addition, 250 nM tFNA treatment could induce Tregs and Bregs and suppress helper T (Th)-cells in the pancreas. In the pancreas, cytokines, as a significant signal during CD4+ T-cell differentiation, directly direct the differentiation programs. Apart from cytokines directing the differentiation of T-cells, the signal transducer and activator of transcription (STAT) signal is strongly associated with T-cell differentiation and T1D progression. We demonstrated tFNA treatment inducing regulatory immune cells probably by increasing TGF-ß levels and the STAT signal. To sum up, 250 nM tFNA treatment could protect the diabetic NOD mice from hyperglycemia and preserve the functions of ß-cells by restoring peripheral immune tolerance. The possible mechanism of inducing immune tolerance was related to the STAT signal and cytokine changes in the pancreas. Moreover, immunoregulation capabilities of tFNAs were demonstrated in the experiment, which set the foundation of tFNAs participating in further antigen-specific immunotherapies.

Tetrahedral framework nucleic acids facilitate neurorestoration of facial nerves by activating the NGF/PI3K/AKT pathway.

The facial nerve is a crucial nerve in the maxillofacial region and is vulnerable to damage. As a consequence of the complications during nerve restoration, existing remedies have certain limitations, thus the treatment of facial nerve injury is always a perplexing task for people. Regulation of Schwann cells is always the breakpoint of neurorestoration since Schwann cells count a great deal in injured nerve repair. In this study, we presented proof that tetrahedral framework nucleic acids (tFNAs), a kind of nucleic acid nanomaterial, were capable of regulating the neurorestorative pathway NGF/PI3 K/AKT, resulting in the activation of a series of cell behaviors related to injured nerve restoration such as proliferation and migration. In vivo experiments also proved that tFNAs enhanced the expressions of axon and myelin marker proteins, impelled histological recovery, promoted the efficient restoration of nerve conduction and muscle movement. Additionally, tFNAs possessed excellent biocompatibility and superior endocytosis ability. Thus, there is good potential for tFNAs to be applied in the therapy of facial nerve injury or even peripheral nerve injury.