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 (Ti3 C2 Tx )-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.

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.

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.

Cartilage-Inspired Inhomogeneous Salt-Hydrogel for Hydrated Drag-Reducing and Strain Sensing.

Articular cartilages exhibit load-bearing capacity and durability due to their inhomogeneous structure. Inspired by this unique structure, a tough and inhomogeneous salt-hydrogel was developed by trapping sodium acetate (NaAc) crystals in polyacrylamide (PAM) polymer networks and then partially redissolving the NaAc crystals. The compressive and tensile stresses of the salt-hydrogel increase significantly by more than 20 times when oversaturated Ac- and Na+ are introduced into the gel network. Such an enhancement in mechanical strength is primarily attributed to the formation of NaAc crystals within the gel network. Further investigations reveal that the mechanical strength of the salt-hydrogel is temperature-dependent as the NaAc crystals gradually redissolve in the gel network with increasing temperature. Furthermore, redissolving NaAc crystals in an aqueous solution can yield an inhomogeneous salt-hydrogel. The topmost soft surface of the salt-hydrogel offers hydration lubrication, while the inhomogeneous network confers load-bearing capacity and durability. Compared to regular hydrogels, the inhomogeneous salt-hydrogel surface can realize drag reduction and remain smooth without damage after the friction tests. Moreover, a salt-hydrogel coating is also fabricated to visually demonstrate its drag-reducing property. In addition, this salt-hydrogel possesses conductivity and can be utilized in the development of inhomogeneous salt-hydrogel fibers (diameter = 438 ± 7 µm) for strain detection. The produced salt-hydrogel fiber exhibits excellent durability and reproducibility as a strain sensor, capable of detecting both small strains (e.g., 1%) and large strains (e.g., 40%). This work provides fundamental insights into developing hydrogels with an inhomogeneous network and explores their potential applications (e.g., hydrated drag-reducing, strain sensing).

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.

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.

A multifunctional chitosan-based hydrogel with self-healing, antibacterial, and immunomodulatory effects as wound dressing.

Bacterial infection often leads to inflammatory responses and delays wound healing. Chitosan (CS)-based composite hydrogels can hold desirable mechanical properties and maintain excellent antibacterial abilities, and thus may be promising as wound dressings. Although CS-based hydrogels have been widely studied on the antibacterial and wound-healing abilities, their immunomodulatory abilities were rarely evaluated. Herein, we developed a multifunctional CS/Poly[2-(methacryloyloxy)ethyl] trimethyl ammonium chloride (PMETAC) hydrogel. In vitro, this hydrogel exhibited self-healing ability and excellent biocompatibility, promoted macrophage polarization towards M2 phenotype, and showed desirable antibacterial activity. In vivo, this hydrogel accelerated the wound regeneration process by reducing bacterial burden, increasing collagen deposition, stimulating angiogenesis, promoting macrophage polarization to M2 direction, and shifting the balance of T helper type 17 (Th17) cells towards anti-inflammatory regulatory T (Treg) cells. This work revealed the potential immunomodulatory effect of CS-based wound dressings and thus may provide a novel target for developing efficient wound healing tools.

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.

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.

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.

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.

Unilateral Silver-Loaded Silk Fibroin Difunctional Membranes as Antibacterial Wound Dressings.

Silk fibroin (SF) has been widely used as wound dressings due to its good biocompatibility. To enhance the antibacterial properties of the dressings, silver (Ag) is often added. However, an overdose of Ag may cause cytotoxicity and inhibit wound healing. Therefore, this study aimed to develop a two-layered membrane to reduce cytotoxicity while maintaining the antibacterial properties of Ag through a simplified layer-by-layer technique. The membranes comprised an Ag-rich SF layer (Ag-SF) and a pure SF layer. The unilateral Ag-loaded membranes showed efficient antibacterial properties at doses above 0.06 mg/mL Ag, and the antibacterial properties were comparable on both sides. In contrast, the SF sides of the membranes showed lower cytotoxicity than the Ag-SF sides of the membranes. Further studies on the thickness ratio of Ag-SF/SF layers revealed that Ag0.12-SF/SF membranes with a ratio of 1:3 had high cytocompatibility on the SF sides while holding a strong antibacterial property. Besides, the SF sides of the Ag0.12-SF/SF1:3 membranes promoted the expression levels of collagen I and transforming growth factor-ß mRNA in human foreskin fibroblasts. The SF sides of the Ag0.12-SF/SF1:3 membranes significantly promoted the healing of infected wounds in vivo. Therefore, unilateral loading with the simplified layer-by-layer preparation technique provided an effective method to balance the cytotoxicity and the antibacterial property of Ag-loaded materials and thus form a broader therapeutic window for Ag applications. The unilateral Ag-loaded silk fibroin difunctional membranes have the potential to be further preclinically explored as wound dressings.

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.

[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.

Dimethyloxallyl glycine/nanosilicates-loaded osteogenic/angiogenic difunctional fibrous structure for functional periodontal tissue regeneration.

The coupled process of osteogenesis-angiogenesis plays a crucial role in periodontal tissue regeneration. Although various cytokines or chemokines have been widely applied in periodontal in situ tissue engineering, most of them are macromolecular proteins with the drawbacks of short effective half-life, poor stability and high cost, which constrain their clinical translation. Our study aimed to develop a difunctional structure for periodontal tissue regeneration by incorporating an angiogenic small molecule, dimethyloxalylglycine (DMOG), and an osteoinductive inorganic nanomaterial, nanosilicate (nSi) into poly (lactic-co-glycolic acid) (PLGA) fibers by electrospinning. The physiochemical properties of DMOG/nSi-PLGA fibrous membranes were characterized. Thereafter, the effect of DMOG/nSi-PLGA membranes on periodontal tissue regeneration was evaluated by detecting osteogenic and angiogenic differentiation potential of periodontal ligament stem cells (PDLSCs) in vitro. Additionally, the fibrous membranes were transplanted into rat periodontal defects, and tissue regeneration was assessed with histological evaluation, micro-computed tomography (micro-CT), and immunohistochemical analysis. DMOG/nSi-PLGA membranes possessed preferable mechanical property and biocompatibility. PDLSCs seeded on the DMOG/nSi-PLGA membranes showed up-regulated expression of osteogenic and angiogenic markers, higher alkaline phosphatase (ALP) activity, and more tube formation in comparison with single application. Further, in vivo study showed that the DMOG/nSi-PLGA membranes promoted recruitment of CD90+/CD34- stromal cells, induced angiogenesis and osteogenesis, and regenerated cementum-ligament-bone complex in periodontal defects. Consequently, the combination of DMOG and nSi exerted admirable effects on periodontal tissue regeneration. DMOG/nSi-PLGA fibrous membranes could enhance and orchestrate osteogenesis-angiogenesis, and may have the potential to be translated as an effective scaffold in periodontal tissue engineering.

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.

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.

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.

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.