Although deoxyribonucleic acid (DNA) is the genetic coding for the very essence of life, these macromolecules or components thereof are not necessarily lost after a cell dies. There appears to be a link between extracellular DNA and biomineralization. Here the authors demonstrate that extracellular DNA functions as an initiator of collagen intrafibrillar mineralization. This is confirmed with in vitro and in vivo biological mineralization models. Because of their polyanionic property, extracellular DNA molecules are capable of stabilizing supersaturated calcium phosphate solution and mineralizing 2D and 3D collagen matrices completely as early as 24 h. The effectiveness of extracellular DNA in biomineralization of collagen is attributed to the relatively stable formation of amorphous liquid droplets triggered by attraction of DNA to the collagen fibrils via hydrogen bonding. These findings suggest that extracellular DNA is biomimetically significant for fabricating inorganic-organic hybrid materials for tissue engineering. DNA-induced collagen intrafibrillar mineralization provides a clue to the pathogenesis of ectopic mineralization in different body tissues. The use of DNase for targeting extracellular DNA at destined tissue sites provides a potential solution for treatment of diseases associated with ectopic mineralization.

The periosteum orchestrates the microenvironment of bone regeneration, including facilitating local neuro-vascularization and regulating immune responses. To mimic the role of natural periosteum for bone repair enhancement, we adopted the principle of biomimetic mineralization to delicately inlay amorphous cerium oxide within eggshell membranes (ESMs) for the first time. Cerium from cerium oxide possesses unique ability to switch its oxidation state from cerium III to cerium IV and vice versa, which provides itself promising potential for biomedical applications. ESMs are mineralized with cerium­(III, IV) oxide and examined for their biocompatibility. Apart from serving as physical barriers, periosteum-like cerium­(III, IV) oxide-mineralized ESMs are biocompatible and can actively regulate immune responses and facilitate local neuro-vascularization along with early-stage bone regeneration in a murine cranial defect model. During the healing process, cerium-inlayed biomimetic periosteum can boost early osteoclastic differentiation of macrophage lineage cells, which may be the dominant mediator of the local repair microenvironment. The present work provides novel insights into expanding the definition and function of a biomimetic periosteum to boost early-stage bone repair and optimize long-term repair with robust neuro-vascularization. This new treatment strategy which employs multifunctional bone-and-periosteum-mimicking systems creates a highly concerted microenvironment to expedite bone regeneration.

Sensory nerves promote osteogenesis through the release of neuropeptides. However, the potential application and mechanism in which sensory nerves promote healing of bone defects in the presence of biomaterials remain elusive. The present study identified that new bone formation was more abundantly produced after implantation of silicified collagen scaffolds into defects created in the distal femur of rats. The wound sites were accompanied by extensive nerve innervation and angiogenesis. Sensory nerve dysfunction by capsaicin injection resulted in significant inhibition of silicon-induced osteogenesis in the aforementioned rodent model. Application of extracellular silicon in vitro induced axon outgrowth and increased expression of semaphorin 3 A (Sema3A) and semaphorin 4D (Sema4D) in the dorsal root ganglion (DRG), as detected by the upregulation of signaling molecules. Culture medium derived from silicon-stimulated DRG cells promoted proliferation and differentiation of bone marrow mesenchymal stem cells and endothelial progenitor cells. These effects were inhibited by the use of Sema3A neutralizing antibodies but not by Sema4D neutralizing antibodies. Knockdown of Sema3A in DRG blocked silicon-induced osteogenesis and angiogenesis almost completely in a femoral defect rat model, whereas overexpression of Sema3A promoted the silicon-induced phenomena. Activation of “mechanistic target of rapamycin” (mTOR) pathway and increase of Sema3A production were identified in the DRG of rats that were implanted with silicified collagen scaffolds. These findings support the role of silicon in inducing Sema3A production by sensory nerves, which, in turn, stimulates osteogenesis and angiogenesis. Taken together, silicon has therapeutic potential in orthopedic rehabilitation.

A poor seal of the titanium implant–soft tissue interface provokes bacterial invasion, aggravates inflammation, and ultimately results in implant failure. To ensure the long‐term success of titanium implants, lactoferrin‐derived amyloid is coated on the titanium surface to increase the expression of cell integrins and hemidesmosomes, with the goal of promoting soft tissue seal and imparting antibacterial activity to the implants. The lactoferrin‐derived amyloid coated titanium structures contain a large number of amino and carboxyl groups on their surfaces, and promote proliferation and adhesion of epithelial cells and fibroblasts via the PI3K/AKT pathway. The amyloid coating also has a strong positive charge and possesses potent antibacterial activities against Staphylococcus aureus and Porphyromonas gingivalis. In a rat immediate implantation model, the amyloid‐coated titanium implants form gingival junctional epithelium at the transmucosal region that resembles the junctional epithelium in natural teeth. This provides a strong soft tissue seal to wall off infection. Taken together, lactoferrin‐derived amyloid is a dual‐function transparent coating that promotes soft tissue seal and possesses antibacterial activity. These unique properties enable the synthesized amyloid to be used as potential biological implant coatings.

Tooth biomineralization is a dynamic and complicated process influenced by local and systemic factors. Abnormal mineralization in teeth occurs when factors related to physiologic mineralization are altered during tooth formation and after tooth maturation, resulting in microscopic and macroscopic manifestations. The present Review provides timely information on the mechanisms and structural alterations of different forms of pathological tooth mineralization. A comprehensive study of these alterations benefits diagnosis and biomimetic treatment of abnormal mineralization in patients.

No abstract

Humans are belittled in their confrontation with the ever expanding galaxies of multidrug‐resistant bacteria. New antibacterial agents are annulled by the emergence of sophisticated bacteria‐resistant strategies that are beyond the imagination of the human mind. In their exploration for new antimicrobial strategies against ESKAPE pathogens, humans have to adopt a surrealistic mindset to unlock their subconscious resourcefulness. In article number https://doi.org/10.1002/advs.201901872, Ji‐Hua Chen, Franklin R. Tay, Li‐Na Niu, and co‐workers review antimicrobial research on ESKAPE pathogens over the past five years and provide prospective clinical applications.

Introduction: Sensory nerves and vessels are critical for skeletal development and regeneration, but crosstalk between neurovascular network and mineralization are not clear. The aim of this study was to explore neurovascular changes and identify bioactive regulators during in situ osteogenesis.Method:In situ osteogenesis model was performed in male rats following Achilles tenotomy. At 3, 6 and 9 weeks after surgery, mineralization, blood vessels, sensory innervation, and bioactive regulators expression were evaluated via micro-computed tomography, immunofluorescent staining, histology and reverse transcriptase-polymerase chain reaction analyses.Result: In the process of in situ osteogenesis, the mineral density increased with time, and the locations of minerals, nerves and blood vessels were highly correlated at each time point. The highest density of sensory nerve was observed in the experimental group at the 3rd week, and then gradually decreased with time, but still higher than that in the sham control group. Among many regulatory factors, semaphorin 3A (Sema3A) was highly expressed in experimental model and its expression was temporally sequential and spatially correlated sensory nerve.Conclusion: The present study showes that during in situ osteogenesis, innervation and angiogenesis are highly correlated, and Sema3A is associated with the position and expression of the sensory nerve.