Efficacy of sintered Zinc-doped fluorapatite scaffold as an antimicrobial regenerative bone filler for dental applications.

OBJECTIVES: The objective of this study was to assess whether zinc-doped fluorapatite (ZnFA) could serve as an effective antimicrobial dental bone filler for bone regeneration compared to autografts. METHODS: FA and 2 % zinc-doped FA (2ZnFA) were synthesized and characterized in-house. Compressed and sintered FA and 2ZnFA disks were incubated with bacteria to assess antimicrobial properties. Adipose-derived stem cells were cultured on these discs to evaluate the surfaces' ability to support cell growth and promote osteogenic differentiation. Surfaces exhibiting the highest expressions of the bone markers osteopontin and osteocalcin were selected for an in vivo study in a rat mandibular defect model. Twenty rats were divided into 5 groups, equally, and a 5 mm surgical defect of the jaw was left untreated or filled with 2ZnFA, FA, autograft, or demineralized bone matrix (DBM). At 12 weeks, the defects and surrounding tissues were harvested and subjected to microCT and histological evaluations. RESULTS: Standard techniques such as FTIR, ICP-MS, fluoride probe, and XRD revealed the sintered FA and ZnFA's chemical compositions and structures. Bacterial studies revealed no significant differences in surface bacterial adhesion properties between FA and 2ZnFA, but significantly fewer bacterial loads than control titanium discs (p < 0.05). Cell culture data confirmed that both surfaces could support cell growth and promote the osteogenic differentiation of stem cells. MicroCT analysis confirmed statistical similarities in bone regeneration within FA, 2ZnFA, and autograft groups. CONCLUSION: The data suggests that both FA and 2ZnFA could serve as alternatives to autograft materials, which are the current gold standard. Moreover, these bone fillers outperformed DBM, an allograft material commonly used as a dental bone void filler. CLINICAL SIGNIFICANCE: The use of FA or 2ZnFA for treating mandibular defects led to bone regeneration statistically similar to autograft repair and significantly outperformed the widely used dental bone filler, DBM. Additional translational research may confirm FA-based materials as superior substitutes for existing synthetic bone fillers, ultimately enhancing patient outcomes.

Freeze casting of hydroxyapatite-titania composites for bone substitutes.

Hydroxyapatite (HA) is commonly used as a bone substitute material, but it lacks mechanical strength when compared to native bone tissues. To improve the efficacy of HA as a bone substitute by improving the mechanical strength and cell growth attributes, porous composite scaffolds of HA and titania (HA-TiO2 ) were fabricated through a freeze-casting process. Three different compositions by weight percent, 25-75 HA-TiO2 , 50-50 HA-TiO2 , and 75-25 HA-TiO2 , were custom-made for testing. After sintering at 1250°C, these composite scaffolds exhibited improved mechanical properties compared to porous HA scaffolds. Substrate mixing was observed, which helped reduce crystal size and introduced new phases such as ß-TCP and CaTiO3 , which also led to improved mechanical properties. The composition of 50-50 HA-TiO2 had the highest ultimate compressive strength of 3.12 ± 0.36 MPa and elastic modulus 63.29 ± 28.75 MPa. Human osteoblast cell proliferation assay also increased on all three different compositions when compared to porous HA at 14 days. These results highlight the potential of freeze casting composites for the fabrication of bone substitutes, which provide enhanced mechanical strength and biocompatibility while maintaining porosity.

Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity.

Mitochondria are integral to cellular energy metabolism and ATP production and are involved in regulating many cellular processes. Mitochondria produce reactive oxygen species (ROS), which not only can damage cellular components but also participate in signal transduction. The kinase ATM, which is mutated in the neurodegenerative, autosomal recessive disease ataxia-telangiectasia (A-T), is a key player in the nuclear DNA damage response. However, ATM also performs a redox-sensing function mediated through formation of ROS-dependent disulfide-linked dimers. We found that mitochondria-derived hydrogen peroxide promoted ATM dimerization. In HeLa cells, ATM dimers were localized to the nucleus and inhibited by the redox regulatory protein thioredoxin 1 (TRX1), suggesting the existence of a ROS-mediated, stress-signaling relay from mitochondria to the nucleus. ATM dimer formation did not affect its association with chromatin in the absence or presence of nuclear DNA damage, consistent with the separation of its redox and DNA damage signaling functions. Comparative analysis of U2OS cells expressing either wild-type ATM or the redox sensing-deficient C2991L mutant revealed that one function of ATM redox sensing is to promote glucose flux through the pentose phosphate pathway (PPP) by increasing the abundance and activity of glucose-6-phosphate dehydrogenase (G6PD), thereby increasing cellular antioxidant capacity. The PPP produces the coenzyme NADPH needed for a robust antioxidant response, including the regeneration of TRX1, indicating the existence of a regulatory feedback loop involving ATM and TRX1. We propose that loss of the mitochondrial ROS-sensing function of ATM may cause cellular ROS accumulation and oxidative stress in A-T.