A Near-Infrared Photothermal-Responsive Underwater Adhesive with Tough Adhesion and Antibacterial Properties.

Developing tunable underwater adhesives that possess tough adhesion in service and easy detachment when required remains challenging. Herein, a strategy is proposed to design a near infrared (NIR) photothermal-responsive underwater adhesive by incorporating MXene (Ti3C2Tx)-based nanoparticles within isocyanate-modified polydimethylsiloxane (PDMS) polymer chains. The developed adhesive exhibits long-term and tough adhesion with an underwater adhesion strength reaching 5.478 MPa. Such strong adhesion is mainly attributed to the covalent bonds and hydrogen bonds at the adhesive-substrate interface. By making use of the photothermal-response of MXene-based nanoparticles and the thermal response of PDMS-based chains, the adhesive possesses photothermal-responsive performance, exhibiting sharply diminished adhesion under NIR irradiation. Such NIR-triggered tunable adhesion allows for easy and active detachment of the adhesive when needed. Moreover, the underwater adhesive exhibits photothermal antibacterial property, making it highly desirable for underwater applications. This work enhances the understanding of photothermal-responsive underwater adhesion, enabling the design of tunable underwater adhesives for biomedical and engineering applications.

Three-dimensional analysis of mandibular and mental canals corroborating with teeth and mental foramen by cone beam computed tomography.

BACKGROUND: This study aimed to analyse the 3D patterns of the mandibular and mental canals (MDC and MC) referring to the surrounding prominent surgical landmarks such as teeth and mental foramen by cone beam computed tomography (CBCT). METHODS: CBCT scans of 354 patients aged 18-67 years with mandibular first premolar to second molar were included and reconstructed 3-dimensionally (3D) by mimics. The parameters of MDC and MC were measured referring to teeth and mental foramen. RESULTS: From the first premolars to the second molars, the mandibular canals showed a trend of gradually closer to the cementoenamel junction (CEJ) of the adjacent teeth and farther away from the buccal cortical plate. The distance of the MDC with the root apexes (RA) was relatively constant from the first premolar to the first molar, but became much closer to the second molar. About 10.8% of the second molars had MDC-RA distances of shorter than 2 mm, and 1.34% even had the MDC superior to the RA. Moreover, the Type III of MC presented in 66.0% of the subjects and had a relatively longer length. Besides, the existence of Type I MC may be related to the MDC featuring with close distances to the RA and CEJ of the adjacent teeth. CONCLUSION: Dentists and surgeons should know the patterns of mandibular and mental canals. A better understanding of the MDC and MC and their relationship to local anatomical landmarks may facilitate the planning of surgeries and alert potential nerve injuries in the operative procedures.

Periodontal effect of augmented corticotomy-assisted orthodontics versus conventional orthodontics in treatment of adult patients with bialveolar protrusion.

BACKGROUND: The patients of bialveolar protrusion always demonstrate thin anterior alveoli which may aggravate subsequent gingival recession and bone loss during retraction. This study aimed to investigate the periodontal changes, including alveolar height, thickness, and area, and the width of keratinized gingiva, in mandibular anterior teeth after augmented corticotomy-assisted orthodontics (ACAO) compared with traditional orthodontics. METHODS: Twenty adult patients with skeletal class I bialveolar protrusion were selected from two groups: ACAO group (augmented corticotomy on the labial side of the anterior mandibular teeth, n = 10) and control group (conventional orthodontics, n = 10). In all patients, four first premolars were extracted and the incisors were retracted under the maximum anchorage. The measurements included the labial alveolar bone area, vertical alveolar bone height, alveolar bone thickness surrounding the mandibular anterior teeth, root length, gingival recession and width of keratinized gingiva after alignment (T0) and 3 months after space closure (T1). RESULTS: The labial alveolar height, area, and thicknesses all decreased after space closure in the control group but significantly increased in the ACAO group. The decrease in the lingual alveolar height was statistically less in the ACAO group than that in the control group. Besides, the width of keratinized gingiva increased in the ACAO group but decreased in the control group. There was no significant difference in the changes of root length between groups. The dentoalveolar changes between anterior teeth were consistent but with different scales. The lateral incisors gained the most labial bone height and area. CONCLUSION: Compared to conventional orthodontics, ACAO provided a more favorable effect of improving periodontal status surrounding the mandibular anterior teeth for Class I maxillary protrusion patients.

[Advances in the Application of Hydroxyapatite Composite Materials in Bone Tissue Engineering].

Hydroxyapatite (HAp) is the main inorganic component of the bones and teeth, and it possesses bioactivity and biocompatibility. However, due to its poor mechanical performance, slow degradation speed, and lack of diversity in its function, it is difficult to apply HAp alone as a scaffold material for bone tissue engineering. By combining HAp with other types of materials, composite materials with specific properties can be prepared, and the scopes of HAp applications can be expanded. Firstly, we elaborated on the importance, and strengths and weaknesses of HAp for bone tissue engineering biomaterials and then reviewed the research status of HAp composite materials used in bone regeneration. Secondly, about hot research topics in the field of applying HAp composite materials in bone repair, we summarized the representative findings in the field, and discussions and analysis were made accordingly. Finally, we also examined the future development prospects of HAp composite bone repair materials.

Antibacterial effects of electrospun chitosan/poly(ethylene oxide) nanofibrous membranes loaded with chlorhexidine and silver.

To prevent percutaneous device associated infections (PDAIs), we prepared electrospun chitosan/poly(ethylene oxide) (PEO) nanofibrous membrane containing silver nanoparticles as an implantable delivery vehicle for the dual release of chlorhexidine and silver ions. We observed that the silver nanoparticles were distributed homogeneously throughout the fibers, and a fast release of chlorhexidine in 2days and a sustained release of silver ions for up to 28days. The antibacterial efficacy of the membranes against Staphylococcus aureus showed that the membranes exhibited an obvious inhibition zone upon loading with either chlorhexidine (20µg or more per membrane) or AgNO3 (1 and 5wt% to polymer). Furthermore, long-term antibacterial effect up to 4days was verified using membranes containing 5wt% AgNO3. The results suggest that the membranes have strong potential to act as an active antibacterial dressing for local delivery of antibacterial agents to prevent PDAIs.

Microenvironment-Driven Fenton Nanoreactor Enabled by Metal-Phenolic Encapsulation of Calcium Peroxide for Effective Control of Dental Caries.

Caries are one of the most common oral diseases caused by pathogenic bacterial infections, which are widespread and persistently harmful to human health. Using nanoparticles to invade biofilms and produce reactive oxygen species (ROS) in situ is a promising strategy for killing bacteria and disrupting the structure of biofilms. In this work, a biofilm-targeting Fenton nanoreactor is reported that can generate ROS responsive to the cariogenic microenvironment. The nanoreactor is constructed by metal-phenolic encapsulation of calcium peroxide (CaO2) followed by modification with a biofilm targeting ligand dextran. Within the cariogenic biofilm, the Fenton nanoreactor is activated by an acidic microenvironment to be decomposed into H2O2 and iron ions, triggering a Fenton-like reaction to generate ROS that can eliminate the biofilm by breaking down extracellular polymeric substances (EPS) and killing cariogenic bacteria. Meanwhile, the depletion of excess protons in biofilm leads to a reversal of the cariogenic microenvironment. The Fenton nanoreactor can effectively inhibit the biofilm formation of Streptococcus mutans on ex vivo human teeth and is effective in preventing caries meanwhile maintaining the oral microbial diversity in rat caries infection model. This work provides a novel and efficient modality for acid microenvironment-driven ROS therapy.

Ebselen Optimized the Therapeutic Effects of Silver Nanoparticles for Periodontal Treatment.

Objective: Silver nanoparticles (AgNPs) possess excellent antibacterial effects on periodontal pathogens, but their clinical application is limited mainly due to their cytotoxicity through inducing oxidative stress in human cells. Ebselen disrupts the reactive oxygen species (ROS) scavenging in bacteria and relieves oxidative stress in mammalian cells. This study aimed to assess the antibacterial and anti-inflammatory effects of AgNPs and ebselen as well as the protective effect of ebselen, to further provide the theoretical basis for their future application in periodontal treatment. Methods: The antibacterial and anti-biofilm effects of the synthesized AgNPs combined with ebselen were assessed on Porphyromonas gingivalis (P. gingivalis), Streptococcus gordonii (S. gordonii), and Fusobacterium nucleatum (F. nucleatum) in planktonic condition and as biofilms. In addition, the intracellular bactericidal efficiency of AgNPs and ebselen was evaluated in P. gingivalis-infected human gingival fibroblasts (HGFs). The cytotoxicity, intracellular ROS levels, and potential antioxidative enzymes were detected in HGFs treated with AgNPs and ebselen. Further, the anti-inflammatory effects were evaluated by in vitro and in vivo experiments. Results: The combination of AgNPs and ebselen showed excellent antibacterial effects against planktonic P. gingivalis and F. nucleatum and synergistic antibiofilm effects on all mono- and multi-species biofilms. In addition, ebselen significantly enhanced the intracellular bactericidal efficiency of AgNPs. Furthermore, ebselen combined with up to 20 µg/mL AgNPs showed no obvious cytotoxicity to HGFs. Evidently, ebselen alleviated the AgNPs-induced ROS by increasing the levels of glutathione and superoxide dismutase 2. Moreover, AgNPs and ebselen together declined the release of P. gingivalis-stimulated inflammatory cytokines both in vitro and in vivo, and reduced alveolar bone resorption effectively. Conclusion: AgNPs combined with ebselen would be an effective adjuvant for periodontal treatment owing to their synergistic antibacterial and anti-inflammatory effects.

An underwater stable and durable gelatin composite hydrogel coating for biomedical applications.

Developing underwater stable and durable hydrogel coatings with drag-reducing, drug release, and antibacterial properties is essential for lots of biomedical applications. However, most hydrogel coatings cannot meet the requirement of underwater stability and versatility, which severely limits their widespread use. In this work, an underwater stable, durable and substrate-independent gelatin composite hydrogel (GMP) coating is developed through covalent crosslinks, where a silane coupling agent with an unsaturated double bond is grafted onto a substrate of co-deposited polydopamine and polyethylenimine. GMP coating can be easily coated onto various medical device surfaces, such as artificial joints, catheters, tracheal tubes and titanium alloys, showing excellent structural stability and mechanical tunability under extreme conditions of ultrasonic treatment for 1 h (400 W of ultrasonic power) or underwater shearing for 14 days (400 rpm). Besides, friction experiment reveals that GMP coating exhibits good lubrication properties (coefficient of friction < 0.003). The drug-loading and bacterial inhibition ring tests show that the GMP coating has a tunable drug release ability with the final releasing ratios of 70-95% by changing the content of poly (ethylene glycol) diacrylate. This work offers a scalable approach of fabricating bio-functional and stable hydrogel coatings, which can be potentially used in biomedical applications.

Surface-Confined Piezocatalysis Inspired by ROS Generation of Mitochondria Respiratory Chain for Ultrasound-Driven Noninvasive Elimination of Implant Infection.

Implant-associated infections (IAI) are great challenges to medical healthcare and human wellness, yet current clinical treatments are limited to the use of antibiotics and physical removal of infected tissue or the implant. Inspired by the protein/membrane complex structure and its generation of reactive oxygen species in the mitochondria respiration process of immune cells during bacteria invasion, we herein propose a metal/piezoelectric nanostructure embedded on the polymer implant surface to achieve efficient piezocatalysis for combating IAI. The piezoelectricity-enabled local electron discharge and the induced oxidative stress generated at the implant-bacteria interface can efficiently inhibit the activity of the attachedStaphylococcus aureusby cell membrane disruption and sugar energy exhaustion, possess high biocompatibility, and eliminate the subcutaneous infection by simply applying the ultrasound stimulation. For further demonstration, the treatment of root canal reinfection with simplified procedures has been achieved by using piezoelectric gutta-percha implanted in ex vivo human teeth. This surface-confined piezocatalysis antibacterial strategy, which takes advantage of the limited infection interspace, easiness of polymer processing, and noninvasiveness of sonodynamic therapy, has potential applications in IAI treatment.

Immunomodulatory Properties: The Accelerant of Hydroxyapatite-Based Materials for Bone Regeneration.

The immunoinflammatory response is the prerequisite step for wound healing and tissue regeneration, and the immunomodulatory effects of biomaterials have attracted increasing attention. Hydroxyapatite [Ca10(PO4)6(OH)2] (HAp), a common calcium phosphate ceramic, due to its structural and functional similarity to the inorganic constituent of natural bones, has been developed for different application purposes such as bone substitutes, tissue engineering scaffolds, and implant coatings. Recently, the interaction between HAp-based materials and the immune system (various immune cells), and the immunomodulatory effects of HAp-based materials on bone tissue regeneration have been explored extensively. Macrophages-mediated regenerative effect by HAp stimulation occupies the mainstream status of immunomodulatory strategies. The immunomodulation of HAp can be manipulated by tuning the physical, chemical, and biological cues such as surface functionalization (physical or chemical modifications), structural and textural characteristics (size, shape, and surface topography), and the incorporation of bioactive substances (cytokines, rare-earth elements, and bioactive ions). Therefore, HAp ceramic materials can contribute to bone regeneration by creating a favorable osteoimmune microenvironment, which would provide a more comprehensive theoretical basis for their further clinical applications. Considering the rapidly developed HAp-based materials as well as their excellent biological performances in the field of regenerative medicine, this review discusses the recent advances concerning the immunomodulatory methods for HAp-based biomaterials and their roles in bone tissue regeneration. Impact statement This review summarized the immunomodulatory methods for hydroxyapatite-based biomaterials in bone tissue regeneration, and further discussed the affecting factors of immunomodulation as well as the challenges for the immunomodulatory strategies. The comprehensive understanding of immunomodulatory strategies for tissue regeneration would provide more guidance for the development of novel hydroxyapatite composite biomaterials.

Advances on biodegradable zinc-silver-based alloys for biomedical applications.

The biodegradable metals have great potential for the biomedical applications, which could be gradually degraded, absorbed, or excreted in the human body, avoiding the removal though secondary surgery. Zinc-based alloys are novel series of degradable metals for medical applications, and they are gaining lots of attention in the research field of absorbable metals. Zinc-silver (Zn-Ag) alloys show superior mechanical strength, good biodegradability, biocompatibility, and antibacterial properties, which render them to be potential candidates for biomedical applications. In this paper, we reviewed the development of Zn-Ag alloys in terms of mechanical properties, degradabilities, biocompatibilities, antibacterial properties, and potential applications in dentistry.

Immunomodulatory functions of oral mesenchymal stem cells: Novel force for tissue regeneration and disease therapy.

Mesenchymal stem cells (MSCs)-based therapeutic strategies have achieved remarkable efficacies. Oral tissue-derived MSCs, with powerful self-renewal and multilineage differentiation abilities, possess the features of abundant sources and easy accessibility and hold great potential in tissue regeneration and disease therapies. Oral MSCs mainly consist of periodontal ligament stem cells, gingival mesenchymal stem cells, dental pulp stem cells, stem cells from human exfoliated deciduous teeth, stem cells from the apical papilla, dental follicle stem cells, and alveolar bone-derived mesenchymal stem. Early immunoinflammatory response stage is the prerequisite phase of healing process. Besides the potent capacities of differentiation and regeneration, oral MSCs are capable of interacting with various immune cells and function as immunomodulatory regulators. Consequently, the immunomodulatory effects of oral MSCs during damage repair seem to be crucial for exploring novel immunomodulatory strategies to achieve disease recovery and tissue regeneration. Herein, we reviewed various oral MSCs with their immunomodulatory properties and the potential mechanism, as well as their effects on immunomodulation-mediated disease therapies and tissue regeneration.

Gingipain-Responsive Thermosensitive Hydrogel Loaded with SDF-1 Facilitates In Situ Periodontal Tissue Regeneration.

Existing local drug delivery systems for periodontitis suffer from poor antibacterial effect and unsatisfied periodontal regeneration. In this study, a smart gingipain-responsive hydrogel (PEGPD@SDF-1) was synthesized as an environmentally sensitive carrier for on-demand drug delivery. The PEGPD@SDF-1 hydrogel was synthesized from polyethylene glycol diacrylate (PEG-DA) based scaffolds, dithiothreitol (DTT), and a novel designed functional peptide module (FPM) via Michael-type addition reaction, and the hydrogel was further loaded with stromal cell derived factor-1 (SDF-1). The FPM exhibiting a structure of anchor peptide-short antimicrobial peptide (SAMP)-anchor peptide could be cleaved by gingipain specifically, and the SAMP was released out of the hydrogel for antibacterial effect in response to gingipain. The hydrogel properties were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), swelling ratio analysis, degradation evaluation, and release curve description of the SAMP and SDF-1. Results in vitro indicated the PEGPD@SDF-1 hydrogel exhibited preferable biocompatibility and could promote the proliferation, migration, and osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Antibacterial testing demonstrated that the PEGPD@SDF-1 hydrogel released the SAMP stressfully in response to gingipain stimulation, thereby strongly inhibiting the growth of Porphyromonas gingivalis. Furthermore, the study in vivo indicated that the PEGPD@SDF-1 hydrogel inhibited P. gingivalis reproduction, created a low-inflammatory environment, facilitated the recruitment of CD90+/CD34- stromal cells, and induced osteogenesis. Taken together, these results suggest that the gingipain-responsive PEGPD@SDF-1 hydrogel could facilitate in situ periodontal tissue regeneration and is a promising candidate for the on-demand local drug delivery system for periodontitis.

6-Bromoindirubin-3'-oxime Promotes Osteogenic Differentiation of Periodontal Ligament Stem Cells and Facilitates Bone Regeneration in a Mouse Periodontitis Model.

Effective bone tissue engineering is important to overcome the unmet clinical challenges of periodontal tissue regeneration. Successful bone tissue engineering comprises three key factors: stem cells, growth factors, and scaffolds. 6-Bromoindirubin-3'-oxime (BIO) is an inhibitor of glycogen synthase kinase-3 (GSK-3) that can activate the Wnt signaling pathway by enhancing ß-catenin activity. In this study, the effects of BIO on the proliferation, migration, and osteogenic differentiation of periodontal ligament stem cells (PDLSCs) were investigated. Poly(lactic-co-glycolic acid) (PLGA) and hyaluronic acid (HA) emerged as promising biomaterials; thus, we developed a novel HA hydrogel embedded with BIO-encapsulated PLGA microspheres and injected the formulation into the gingival sulcus of mice with experimental periodontitis. The release speed of this system was fast in the first week and followed a sustained release phase until week 4. In vivo experiments showed that this PLGA-BIO-HA hydrogel system can inhibit periodontal inflammation, promote bone regeneration, and induce the expression of bone-forming markers alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and osteocalcin (OCN) in a mouse periodontitis model. Therefore, this PLGA-BIO-HA hydrogel system provides a promising therapeutic strategy for periodontal bone regeneration.

A tunable and injectable local drug delivery system for personalized periodontal application.

In periodontal treatment, patient differences in disease phenotype and treatment responses are well documented. Therefore, therapy duration and dosage should be tailored to the requirements of individual patients. To facilitate such personalized medication, a tunable and controllable system is needed to deliver drugs directly into the diseased periodontal pockets. The current study established a system to achieve different drug release rates and periods by incorporating bioactive agents into poly(lactic-co-glycolic acid) (PLGA) microspheres dispersed into a novel thermo-reversible polyisocyanopeptide (PIC) hydrogel. Specifically, two drugs, i.e. doxycycline and lipoxin, were separately loaded into acid-terminated and ester-capped PLGA by electrospraying. Different formulations were developed by loading the two kinds of PLGA microspheres with different mass ratios in the PIC gels. The results demonstrated that the PIC-PLGA vehicle exhibited appropriate injectability, long-term structural stability, and no obvious in vivo inflammatory response for the desired clinical application. Furthermore, the release profiles of drugs could be manipulated by adjusting the loaded mass ratio of acid- and ester- terminated PLGA microspheres in the PIC gels. The more ester-capped PLGA was used, the slower the release rate and the longer the release period, and vice versa. Additionally, the released drugs still preserved their bio-efficacy. This PIC-PLGA system can be further developed and tested in translational studies to demonstrate the final clinical benefit.

Antimicrobial and anti-inflammatory thermo-reversible hydrogel for periodontal delivery.

In periodontal treatment, topical adjunctive therapy with antimicrobials or anti-inflammatory agents is frequently applied. However, currently available drug carrier biomaterials often exhibit poor perfusion into small crevices, such as the deep and irregular periodontal pockets, due to relatively high viscosity. Moreover, high polymer concentrations of the polymer can potentially be cytotoxic upon confined local administration. This study aimed to formulate an antimicrobial and anti-inflammatory treatment option, by incorporating doxycycline (DOX) and/or lipoxin A4 (LXA4) into 0.5 wt% thermo-reversible polyisocyanopeptide (PIC). PIC can form hydrogels upon low polymer concentration, and we hypothesized that the thermo-reversible nature of the material would allow for application into the periodontal pocket. The formulations were characterized in vitro and finally tested in dogs with naturally occurring periodontitis, which were not euthanized afterward. Results showed that PIC/DOX/LXA4 hydrogel could be easily prepared and injected into periodontal pockets. The PIC hydrogel facilitated the release of DOX or LXA4 for around 4 days in vitro. When applied in dogs, the hydrogel exerted no local or systemic adverse effects. Gels loaded with LXA4 and/or DOX reduced the subgingival bacterial load and pro-inflammatory interleukin-8 level. In addition, PIC-DOX and PIC-DOX+LXA4 improved gingival clinical attachment by 0.6 mm compared with conventional periodontal treatment alone (i.e. mechanical debridement). In conclusion, the thermo-reversible PIC hydrogel is a safe and effective vehicle for periodontal drug delivery.

Encapsulation and release of doxycycline from electrospray-generated PLGA microspheres: Effect of polymer end groups.

The aim of this study was to investigate the influence of end group of poly(lactic-co-glycolic acid) (PLGA) on the drug loading and release behavior of electrospray-generated PLGA microspheres. To this end, doxycycline hyclate (DOX) was selected as a model drug, and PLGA (molecular weight: 17 and 44 kDa) with either an acid or ester end group were electrosprayed with DOX. The processing parameters were optimized to obtain microspheres comparable in size. Drug loading efficiency and release profile were determined by the high-performance liquid chromatography-ultraviolet detection (HPLC-UV) method. PLGA polymers or drug-loaded microspheres were characterized before and after exposure to phosphate buffer saline at 37 °C regarding the wettability of polymers, pH changes of the buffer, molecular weight of PLGA and morphology of the microspheres. The acid end group of PLGA microspheres brought about lower encapsulation efficiency and faster DOX release rate in our study, indicating that different hydrophilicity of polymer and degradation speed were the main reasons causing a difference in encapsulation efficiency and release profile. In addition, DOX released from the PLGA microspheres was active by showing antibacterial effects against Porphyromonas gingivalis as measured using a zone of inhibition test, and varying the end groups showed no impact on the antibacterial efficacy. This study demonstrated that the end group of PLGA can be used as a new tool to regulate drug encapsulation efficiency and release rate to meet different clinical drug delivery requirements.

Topical Host-Modulating Therapy for Periodontal Regeneration: A Systematic Review and Meta-Analysis.

Background: Over the past decades, locally delivered host-modulating pharmacological agents have been extensively investigated to treat periodontitis. Although a small category of agents has been tested in clinical trials, most of them were reported in the animal experiments. This systematic review evaluates the efficacy of local application of currently available host-modulating agents, with or without mechanical removal of plaque, in animal models with periodontitis or periodontal defect. Methods: PubMed and Embase were searched on February 11, 2019. The inclusion criteria were as follows: (1) experiments were performed in healthy animals (all ages, sexes, and species) with periodontitis, and (2) outcome data for the local application of host-modulating approaches were presented for bone quantity, bone loss, and attachment loss and compared with a vehicle control group. Study characteristics and outcome data were extracted and internal validity was assessed. The efficacy of host-modulating agents was analyzed in a meta-analysis. A standardized mean difference (SMD) and its 95% confidence intervals for each individual comparison were calculated to estimate the overall effect. Subgroup analyses were conducted on animal species and different types of agents. Results: Forty-eight articles were included in the review, of which 42 were included in meta-analysis on bone quantity, bone loss, and attachment loss. The results showed that host-modulating therapy significantly increased bone formation (SMD: 2.200 [1.560-2.840], n = 24), and decreased bone loss (SMD: -1.659 [-1.969 to -1.348], n = 51) and attachment loss (SMD: -1.572 [-2.211 to -0.933], n = 17). No significant subgroup effects were identified, indicating that the effects are similar across species and drug types. Conclusions: The current scientific evidence supports the use of local host-modulation therapy in the treatment of periodontitis in experimental animals. Our findings seem robust for various animal models and designs included in this review, which increases our confidence of the translational value of the results to the clinical situation. Impact Statement Over the past decades, locally delivered host-modulating pharmacological agents have been extensively investigated for periodontal regeneration. Although a small category of agents has been tested in clinical trials, most of them were reported in the animal experiments. Considering the increasing amount of preclinical evidence and the need for future clinical trials, a systematic review and meta-analysis of all preclinical data was performed to determine the translational value of host-modulating drugs for human application. The results showed that host-modulating therapy significantly increased bone formation and decreased bone and attachment loss. This study contributes to researchers working on the periodontal translational research.

Application of BMP-Bone Cement and FGF-Gel on Periodontal Tissue Regeneration in Nonhuman Primates.

The ultimate challenge of tissue engineering research is the translation of experimental knowledge into clinical application. In the preclinical testing phase of any new therapy, animal models remain the gold standard. Therefore, the methodological choice of a suitable model is critical to meet the requirements for a safe clinical application of the developed treatment. For instance, we have shown in rats that the application of calcium phosphate cement (CPC)/propylene glycol alginate (PGA) with bone morphogenetic protein (BMP)-2 or fibroblast growth factor (FGF)-2 resulted in the regeneration of periodontal defects. However, it is debated whether using small models form a predictive method for translation to larger species. At the same time, the 3R framework is encouraged as guiding principles of the ethical use of animal testing. Therefore, based on the successful rat study, the objective of this study was to further investigate the periodontal regenerative efficacy of the CPC/BMP and PGA/FGF system in a periodontal defect model with a low number of nonhuman primates (NHPs). Three Macaca fascicularis-overstocked from breeding for other purposes-were used (reuse of animals and appropriateness of the experimental animal species according to 3R framework). Three-wall periodontal defects were surgically created in the mandible. In total, 10 defects were created and distributed over two groups: (1) control group: PGA+CPC (n = 5) and (2) experimental group: PGA/FGF+CPC/BMP (n = 5). After 3 months, tissue regeneration was evaluated by histomorphometry and radiographic measurements. Data showed that epithelial downgrowth, cementum, and ligament regeneration were significantly enhanced in the experimental group compared with the control group (n = 5; p = 0.013, p = 0.028, and p = 0.018, respectively). However, the amount of newly formed bone did not differ (p = 0.146). Overall, as a translational proof-of-principle study, the hybrid periodontal regenerative method of CPC/BMP+PGA/FGF promoted periodontal regeneration in NHPs. This study warrants the application of CPC/BMP/PGA/FGF in clinical trials. Impact Statement This study validated an earlier successful periodontal regeneration strategy from a rat model into a few spare nonhuman primates (NHPs). The hybrid periodontal regenerative method of calcium phosphate cement (CPC)/bone morphogenetic protein (BMP)-2/propylene glycol alginate (PGA)/fibroblast growth factor (FGF)-2 promoted periodontal regeneration in NHPs, which corroborated the previous rat results. This translational approach was a very practical option and thus reduced the number and species of experimental animals in translational research. These results found in NHPs indicate a consistent conclusion with the earlier findings in the rat model. It further warrants the application of CPC/BMP-2+PGA/FGF-2 in human clinical trials.

Combinatorial Surface Roughness Effects on Osteoclastogenesis and Osteogenesis.

Implant surface properties are a key factor in bone responses to metallic bone implants. In view of the emerging evidence on the important role of osteoclasts in bone regeneration, we here studied how surface roughness affects osteoclastic differentiation and to what extent these osteoclasts have stimulatory effects on osteogenic differentiation of osteoprogenitor cells. For this, we induced osteoclasts derived from RAW264.7 cell line and primary mouse macrophages on titanium surfaces with different roughness ( Ra 0.02-3.63 µm) and analyzed osteoclast behavior in terms of cell number, morphology, differentiation, and further anabolic effect on osteoblastic cells. Surfaces with different roughness induced the formation of osteoclasts with distinct phenotypes, based on total osteoclast numbers, morphology, size, cytoskeletal organization, nuclearity, and osteoclastic features. Furthermore, these different osteoclast phenotypes displayed differential anabolic effects toward the osteogenic differentiation of osteoblastic cells, for which the clastokine CTHRC1 was identified as a causative factor. Morphologically, osteoclast potency to stimulate osteogenic differentiation of osteoblastic cells was found to logarithmically correlate with the nuclei number per osteoclast. Our results demonstrate the existence of a combinatorial effect of surface roughness, osteoclastogenesis, and osteogenic differentiation. These insights open up a new dimension for designing and producing metallic implants by considering the implant roughness to locally regulate osseointegration through coupling osteoclastogenesis with osteogenesis.