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A 3D-printed resin crown is a novel option for esthetic crown restoration for primary teeth, which are typically bonded with resin cement. The purpose of this study was to evaluate the bonding ability of a 3D printing resin and compare it with other indirect resin materials for crown fabrication. The shear bond strengths of two 3D printing resin materials, Graphy (GP) and NextDent (NXT), and two indirect resin materials, VIPI Block (VIPI) and MAZIC Duro (MZ), were compared in the study. For all materials, the shear bond strength at the interface between the surface of the resin material and resin cement was measured. The mean shear bond strength values of GP, NXT, MZ, and VIPI were 23.29 ± 3.88, 26.14 ± 4.67, 25.41 ± 4.03, and 18.79 ± 4.26 MPa, respectively. There was no significant difference among the SBSs of GP, NXT and MZ except for VIPI. The result of this study indicates that the 3D printing resin meets the essential requirement for clinical use by showing clinically adequate bond strength.

A buccal pit is a prominent point-like depression that appears at the cervical end of the mandibular molar developmental grooves. A defective buccal pit can be defined as a buccal pit in which the continuity of the dentinoenamel junction is broken and the pit extends to the dentinal level. This study aimed to determine the frequency of buccal pits and defective buccal pits in un-erupted mandibular first and second molars using cone-beam computed tomography (CBCT). The analysis was performed on CBCT images taken from 417 Korean children and adolescents who visited the Department of Pediatric Dentistry, Yonsei University Dental Hospital between 2004 and 2020. Based on cross-sectional views of CBCT images, buccal pits were categorized into 4 classes according to the depth of the pits. The expression rate of the buccal pits was 29.1%. The prevalence of defective buccal pits was 7.9%. The buccal pits tended to develop bilaterally. To date, this is the most comprehensive study on the frequency of buccal pits with the largest sample size. This was the first attempt worldwide to analyze the depth of the buccal pit using CBCT images and to define a defective buccal pit worldwide.

This study aimed to investigate the frequency of dental visits after coronavirus disease 2019 (COVID-19) in children and adolescents in comparison to that of adults. The data on the number of dental visits on the basis of different classification and treatment codes for all the age groups were provided by the Health Insurance Review and Assessment Service from January 2017 to December 2020. To reduce the impact of the population change, dental visits per 1000 people was used. After the start of the pandemic, dental visits per 1000 people decreased in all age groups when analyzed for the diseases of pulp and periapical tissues classification code and dental visits per 1000 people decreased over 5 years age groups when analyzed for the pulp treatment code. Regarding the restorative treatment code, visits in the 0 - 19 years age group decreased after the pandemic. Based on the comparison of the number of confirmed COVID-19 cases to that of monthly dental visits by treatment codes, the change rate of pulp and restorative treatments gradually decreased after the waves of the pandemic in February and August 2020 in Korea. Furthermore, dental visits per 1000 people for gingivitis and periodontal disease classification code increased after the pandemic in all age groups. The rate of decrease in dental visits per 1000 people for restorative treatments in children and adolescents was higher than that in adults. The rate of decrease in the number of dental visits for multi-visit pulp treatments showed a rapid decrease as compared to that of 1-visit pulp treatments after the pandemic. This study identified changes in the number of dental visits of children and adolescents after COVID-19 transmission in comparison to that observed in adults.

Black staining of the teeth in children and adolescents does not cause pain or serious illness, but it can be socially debilitating for esthetic reasons. Black staining is easily removed through periodic professional mechanical tooth cleaning and ultrasonic scaling, but it can easily recur within few months. Using essential oil-containing mouth rinses diluted at 50% twice per day could prevent the black staining from returning after it is removed, reducing the need for mechanical treatments and improving esthetics.

The aim of this study was to evaluate the accuracy of 3 different automatic landmark identification programs on lateral cephalgrams and the clinical acceptability in pediatric dentistry. Sixty digital cephalometric radiographs of 7 to 12 years old healthy children were randomly selected. Fourteen landmarks were chosen for assessment and the mean of 3 measurements of each landmark by a single examiner was defined as the baseline landmarks. The mean difference between an automatically identified landmark and the baseline landmark was measured for each landmark on each image. The total mean difference of 3 automatic programs compared to the baseline landmarks were 2.53 ± 1.63 mm. Errors among 3 programs were not significantly different for 12 of 14 landmarks except Orbitale and Gonion. The automatic landmark identification programs showed significant higher mean detection errors than the manual method. The programs couldn’t be used as the 1st tool to replace human examiners. But considering short consuming time, these results indicate that all 3 programs have sufficient validity to be used in pediatric dental clinic.

The aim of this study was to investigate the relationships between the stages of calcification of various teeth and skeletal maturity stages among Korean subjects. The samples were derived from hand-wrist, panoramic radiographs, and lateral cephalograms of 743 subjects (359 males and 384 females) with ages ranging from 6 to 14 years. Calcification of seven permanent mandibular teeth on the left side were rated according to the system of Demirjian. To evaluate the stage of skeletal maturation, hand-wrist radiographs were analyzed by skeletal maturity indicators (SMI) system of Fishman and lateral cephalograms by cervical vertebral maturation (CVM) method of Baccetti. Statistically significant relationships were found between dental calcification and skeletal maturity stages according to Spearman rank-order correlation coefficients (r = 0.40-0.84, p < 0.001). The second molar showed the highest correlation and central incisor showed the lowest correlation for female and male subjects. For both sexes, canine stage G and second molar stage F were related to SMI 6 and CS 3. Because of the high correlation coefficients, this study suggests that tooth calcification stages from panoramic radiographs might be clinically useful as a maturity indicator of the pubertal growth period in Korean patients.

Dental clinics are exposed to various uncomfortable noises. The aim of this study was to quantify the effectiveness of active noise control devices in dental treatment conditions. Two types of commercial headsets (Airpods Pro, QC30) and two types of dental headsets (Alltalk, Quieton Dental) were used for the experiment. Three sounds (high-speed handpiece, low-speed handpiece, and suction system) were measured at three different distances from the dental teeth model, typodont. The distances of 10, 40, and 70 cm reflected the positions of the patient, assistant, and practitioner’s ears, respectively. Sound analysis was performed, and the significance of differences in the maximum noise level using each device was determined with the Kruskal–Wallis test. Dental noise was characterized by the peak in sound pressure level (SPL) at 4–5 kHz and >15 kHz frequencies. The commercial headsets efficiently blocked 1 kHz and 10 kHz of noise. The dental headsets efficiently reduced 4–6 and >15 kHz noise. Quieton had the highest maximum SPL in all situations and positions among the four devices. For a better dental clinic, however, active noise control devices more suitable for the characteristics of dental noise should be developed.

The noise is defined as unwanted sound that causes discomfort and physical changes. This study was conducted to evaluate intensity of noise in the pediatric dental clinic and to investigate noise environment of a pediatric dentist. Human ear shaped microphone and mobile noise level meter were used for recording noise and calculating intensity of noise.By recording according to the method specified by Korea Occupational Safety and Health Agency (KOSHA) of Korea Ministry of labor and employment, the following results were obtained. For 16 experimental days, 8 hour time weighted average (8hr-TWA) was 49.33 dBA (A-weighted deci-Bell) on daily average with maximum 58.54 dBA and minimum 33.97 dBA. And Dose was 0.49% on daily average with maximum 1.28%, minimum 0.04%. These values are less than criteria of KOSHA standard (85 dBA, 100%). Comparing the highest noise level for each patient, pulp therapy group and Frankel grade I group were the highest.The intensity of dental noise of pediatric dental clinic didn’t meet standard of KOSHA. It is necessary to re-evaluate noise environment by establishing new standards considering environment of pediatric dental clinic.

Uncontrolled proliferative diseases, such as fibrosis or cancer, can be fatal. We previously found that a compound containing the chromone scaffold (CS), ONG41008, had potent antifibrogenic effects associated with EMT or cell-cycle control resembling tumorigenesis. We investigated the effects of ONG41008 on tumor cells and compared these effects with those in pathogenic myofibroblasts. Stimulation of A549 (lung carcinoma epithelial cells) or PANC1 (pancreatic ductal carcinoma cells) with ONG41008 resulted in robust cellular senescence, indicating that dysregulated cell proliferation is common to fibrotic cells and tumor cells. The senescence was followed by multinucleation, a manifestation of mitotic slippage. There was significant upregulation of expression and rapid nuclear translocation of p-TP53 and p16 in the treated cancer cells, which thereafter died after 72 h confirmed by 6 day live imaging. ONG41008 exhibited a comparable senogenic potential to that of dasatinib. Interestingly, ONG41008 was only able to activate caspase-3, 7 in comparison with quercetin and fisetin, also containing CS in PANC1. ONG41008 did not seem to be essentially toxic to normal human lung fibroblasts or primary prostate epithelial cells, suggesting ONG41008 can distinguish the intracellular microenvironment between normal cells and aged or diseased cells. This effect might occur as a result of the increased NAD/NADH ratio, because ONG41008 restored this important metabolic ratio in cancer cells. Taken together, this is the first study to demonstrate that a small molecule can arrest uncontrolled proliferation during fibrogenesis or tumorigenesis via both senogenic and senolytic potential. ONG41008 could be a potential drug for a broad range of fibrotic or tumorigenic diseases.

Background/purpose ProRoot MTA, Vitapex, and Metapex are widely used for pulp treatment of primary tooth. The aim of this study was to compare the pulpal responses to ProRoot MTA, Vitapex, and Metapex in a canine model of pulpotomy. Materials and methods Pulpotomy procedure was performed to 34 teeth (21 incisors and 13 premolars) and ProRoot MTA, Vitapex or Metapex was applicated to artificially exposed pulp tissues. After 13 weeks, the teeth were extracted and processed with hematoxylin-eosin staining for histologic evaluation. All specimens were evaluated in several categorys related to calcific barrier, inflammatory responses and the area of calcific barrier formation was measured. Results Most of the specimens in the ProRoot MTA group developed a calcific barrier at the pulp amputation site and showed a low level of inflammatory response. However, in comparison to ProRoot MTA group, a small amount of calcific barrier formed in Vitapex and Metapex groups. Conclusion This in vivo study found that Vitapex and Metapex induced similar pulpal responses but showed poor outcomes compared with using ProRoot MTA. Vitapex and Metapex are therefore not good substitutes for ProRoot MTA in direct pulp capping and pulpotomy.

Taurodontism is an anomaly characterized by a long and broad pulpal cavity and consumed apical location of the furcation area. This study aimed to determine the prevalence of taurodontism in deciduous molars based on digital panoramic radiographs of children. The study was performed on a sample of panoramic radiographs taken from 2,473 Korean children who visited the department of pediatric dentistry, Yonsei University Dental Hospital between Nov. 2005 and Mar. 2018. Taurodontism was mainly categorized by Daito’s method. Using panoramic radiographs, taurodontism was also categorized into mesotaurodontism, hypotaurodontism, and hypertaurodontism. Mesotaurodontism was the most prevalent type. A total of 2,473 panoramic radiographs were evaluated. The prevalence of taurodontism was 5.7% in general, 51.5% in the left quadrant, 48.5% in the right quadrant, 6.3% in the maxilla, and 93.7% in the mandible. The distribution of taurodontism stratified by gender showed a higher prevalence in males. This is a comprehensive study on the prevalence of taurodontism in children using the largest sample size to date.

The pulp treatment of primary and immature teeth in the children and adolescents is affected by the environment of the patients, clinical careers and dentists performing the techniques, as well as clinical modalities and pulpal diagnosis. The purpose of this study was to investigate the current status of pulp treatment performed in real clinical practice, as well as the reasons behind the choice of treatment methods.The study was conducted on a total of 153 members of the Korean Academy of Pediatric Dentistry, and statistical data from the Health Insurance Review and Assessment Service (HIRA) from 2010 to 2018 were analyzed together. Both the survey results and the statistics from the HIRA showed that 1-visit pulpectomies of primary teeth were most common, and the frequency of the use of the Ni-Ti file was increased in children with primary or mixed-dentition. In the treatment of immature permanent teeth, regenerative endodontic treatment by individual dentists was found to be less frequent than in university hospitals.

Precocious puberty (PP) is defined as the early development of secondary sexual characteristics (before the ages of 8 years in girls and 9 years in boys). The aim of this study is to identify characteristics of the dental maturity in girls with PP that discriminate them from normal healthy girls.This study included 99 girls aged 6 - 8 years with PP and 99 girls without past medical history of same chronological age (control group). The study was performed on 198 panoramic radiographs (99 PP girls, 99 control group girls). Demirjian method was used to evaluate the panoramic radiographs and determine dental maturity. Difference in dental maturity score and tooth formation stages between the two groups were analyzed.The PP group showed significant higher maturity score than control group. Among mandibular teeth, mandibular 2nd premolar and 2nd molar were significantly more mature in the PP group than control group. Logistic regression analysis showed that mandibular 2nd molar was only significant predictor for PP girls.

The aim of the present study was to evaluate potential factors influencing the success rates of mineral trioxide aggregate (MTA) pulpotomy performed in primary molars. A total of 347 teeth treated between March 2012 and December 2016 in 258 patients, with a mean age of 5.3 ± 1.7 years, were included in the analysis. Kaplan-Meier analyses were used to analyze were used time to failure. Multivariate Cox regression analysis with shared frailty was used to evaluate the clinical factors associated with failures. The mean (standard deviation) follow-up period was 35.8 (19.6) months. Within 84 months, the survival rate was 87.1%. In multivariate Cox regression, treatment performed in lower primary molars had a lower survival rate than upper primary molars (hazard ratio [HR] = 3.38, P = 0.012). Caries extension below the cemento-enamel junction had more risk of failure (HR = 10.9, P

The aim of this study is to investigate visual exploration of children and adolescents during dental treatment by examining time ratio of eye opening in various age groups.This study reviewed 5 - 15 year-old patients who visited the department of pediatric dentistry of Yonsei University Dental Hospital from March to October 2018. Restorative treatment or sealant application was done by one pediatric dentist. A trained observer used 2 stopwatches to measure total treatment time and time of open eye. Average ratios of eye opening were calculated and compared.60 patients were investigated, with 15 patients in each age group. Average ratio of eye opening increased as age decreased (p < .001). The average of 13 - 15 year-olds was significantly shorter than that of children younger than 12 years (p < .005).This study indicated that children have higher rates of eye opening during dental treatment than adolescents.

This study intended to evaluate noise level of dental handpieces and the effects of noise cancelling devices. An ear model was designed to measure the level of the noise delivered to the inner ear during dental handpiece operation. The level of noise was measured in various conditions using the ear model and the portable noise meter. Noise level was measured again after applying of 4 different noise cancelling devices to the model ear.The noise level of dental handpieces was 82.5 - 84.4 dB. When 4 types of noise canceling devices were applied, the noise level reduced to 67.4 - 73.8 dB. All 4 devices had statistically significant effect in reducing the noise of the handpiece.Considering the intensity and exposure time, noise in dental clinics can cause hearing damage to dentists. For protection from the risk of occupational hearing damages, noise canceling devices can be recommended.

To circumvent the limitations of conventional cancer immunotherapy, it is critical to prime antigen-presenting cells (APCs) to initiate the cancer-immune cycle. Here, the authors develop a metal-phenolic network (MPN)-based immunoactive nanoparticle in combination with irreversible electroporation (IRE) for an effective cancer immunotherapy. The MPN nanoparticles are synthesized by coordinating tannic acid with manganese (Mn) ions, and subsequent coating with CpG-oligodeoxynucleotides (CpG-ODNs) via hydrogen bonding. The CpG-ODN-coated Mn-phenolic network (CMP) nanoparticles are effectively internalized into macrophages, a type of APCs, and successfully trigger M1 polarization to promote release of proinflammatory cytokines. Notably, the CMP nanoparticles demonstrate an extended retention time period than the free CpG-ODN in the tumor. The tumor microenvironment tailored bipolar IRE, enhances the therapeutic efficacy by significantly broadening the ablation zone, which further increases immunogenic cell death (ICD). Ultimately, the simultaneous CMP nanoparticles and IRE treatment successfully inhibit tumor growth and prolong survival in a mouse tumor model. Thus, CMP nanoparticles are empowered with Mn and CpG-ODN immunomodulators and the tumor microenvironment tailored bipolar IRE will be a new tool for effective cancer immunotherapy to treat intractable malignancies.

Poly(lactic-co-glycolic acid) (PLGA) has been widely used as a biomaterial for pharmaceutical and medical applications. However, the decomposition products of PLGA are known to acidify the surrounding tissue of the implanted site, causing an inflammatory response. Previously, we developed PLGA/inorganic nanocomposites and optimized the amounts of inorganic compounds, β-tricalcium phosphate (β-TCP) and magnesium hydroxide [Mg(OH)2], in terms of osteogenesis of normal human osteoblasts and anti-inflammatory responses of preosteoclastic cells in vitro. In this study, the potential of the optimized PLGA/β-TCP/Mg(OH)2 nanocomposite (TCP/MH) to promote bone repair through osteoinductive, osteoconductive, and anti-inflammatory abilities was assessed using a bone defect in a rat humeral defect model. PLGA nanocomposites with or without inorganic compounds, PLGA, β-TCP, MH, and TCP/MH were prepared through one-step bulk modification using a twin-screw extruder. The resulting TCP/MH nanocomposite successfully enhanced the bone regeneration rate for allowing complete bone defect healing with significantly suppressed inflammatory responses. Taken together, the organic and inorganic bioactive nanocomposite developed in this study, TCP/MH, is a promising material in orthopedic implantation.

Polymeric microspheres containing magnesium hydroxide (MH) was developed as a functional dermal filler with enhanced physicochemical and biological performances. In this study, polycaprolactone (PCL) and MH microspheres (PCL/MH) were uniformly produced with approximately 50 μm in size through a simple fluidic device. In the PCL/MH composite, MH effectively neutralized the acidic degradation products generated by polymer degradation. In in vitro cell experiments, when MH was treated with acidic decomposition product (i.e., 6-hydroxycaproic acid, HCA), the acidic pH was neutralized to induce wound healing along with inhibition of inflammation and senescence. Furthermore, MH promoted the production of collagen. These results suggest that the PCL/MH microspheres have great potential as a functional dermal filler for skin esthetics and facial plastic surgery.

Objective: The aim of this study was to determine relationships between dental maturity and body mass index (BMI) in Korean children. Study Design: 600 Korean children aged between 5 and 10 years for whom panoramic radiographs have been obtained between 2010 and 2017 were selected. Subjects were divided into four weight-status groups: underweight, normal weight, overweight, and obese. Five lower-left permanent teeth were observed and rated. The stage of each tooth was converted into a score using the table suggested by Demirjian, and the sum of these scores was designated as the ‘maturity score’. Results: This study found statistically significant differences in dental maturity between the weight groups (analysis of variance, P=0.003), with the maturity score being higher in the obese group than in normal-weight subjects (Tukey’s post-hoc test, P=0.004). The linear regression showed a positive association between BMI and the maturity score after adjusting for sex and age (β=0.34, P

Cancer immunotherapy is a next-generation treatment strategy; however, its side effects limit its clinical translation. Here, a novel combination of a multi-functional nano-adjuvant (M-NA) prepared with an iron oxide/gold core and a cationic polymer shell via multilayer synthesis with CpG oligodeoxynucleotide (CpG-ODN) electrostatically complexed on its surface, and irreversible electroporation (IRE) technique was developed for effective image-guided in situ cancer vaccination. The M-NA can be retained long-term in the dense tumoral extracellular matrix after intratumoral injection and internalized by antigen-presenting cells (APCs). The IRE can induce immunogenic cell death. Indeed, in a mouse tumor model, the M-NA showed longer tumor retention time than free CpG-ODN. Compared with other treatments, the combined treatment significantly inhibited tumor growth with 100% survival rate for ∼60 days. The therapy induced the activation of cytotoxic lymphocytes and the maturation of APCs in vivo. This treatment could be effective in image-guided local cancer immunotherapy.

BackgroundUncontrolled proliferative diseases such as fibrosis or cancer can be fatal. We previously found that a compound containing a chromone scaffold, ONG41008, had potent anti-fibrotic effects in diseased human lung myofibroblasts but not normal human lung fibroblasts.MethodsWe investigated the effects of ONG41008 on tumor cells, and compared these effects with those in pathogenic myofibrotic cells and normal fibroblasts cells.FindingsStimulation of A549 lung carcinoma epithelial cells with ONG41008 resulted in cellular senescence, indicating that dysregulated cell proliferation is common to fibrotic cells and tumor cells. Replicative senescence of A549 cells resulted in multinucleation, which was followed by oncogene-induced senescence. There was significant upregulation of expression and nuclear translocation of p-TP53 and p16 in ONG41008-treated A549 cells, and all cells died after 72 hr. Similar effects occurred after ONG41008 treatment in several human aggressive cancer cell lines such as PANC1, MCF7, PC3, or primary non-small cell lung carcinoma cells. Unlike cisplatin, ONG41008 was not toxic to normal human lung fibroblasts or primary prostate epithelial cells, suggesting ONG41008 can distinguish the intracellular microenvironment between normal cells and aged or diseased cells. This effect might occur as a result of the increased NAD/NADH ratio or increased lactate dehydrogenase levels in aged or diseased cells.InterpretationTo our best knowledge, this is the first study to show that a small molecule can arrest uncontrolled proliferation during fibrogenesis or tumorigenesis in vitro. ONG41008 could be a potential drug for a broad range of fibrotic or tumorigenic diseases.Research in ContextEvidence before this studyThe notion that aging is a disease and that diseases occur as a consequence of aging was first put forward by David Sinclair and colleagues (Aging Cell;14(4):497-510). There are biological systems that provide evidence for this notion; for example, somatic cells can revert to embryonic cells, producing younger somatic cells. This phenomenon underlies induced pluripotent stem cells. Another example is that some types of jellyfish can live forever. These examples suggest that a counter-aging program exists in animals. Human diseases are the manifestations of cell aging generated by the accumulation of somatic mutations. Aged and pathogenic cells are senescent, so a drug that specifically targeted senescent cells might initiate a cellular program that could ameliorate age-associated disease. Indeed, the kinase inhibitor dasatinib induces cellular senescence (Clin Ther 2007 29:2289-2308). In 2017, two drugs that target senescent cells were identified: quercetin and fisetin. These drugs selectively kill senescent cells, and are referred to as senolytic drugs or senotherapeutics (Aging 2017 8;9(3):955-963). Although it is established that senescent cells accumulate in cancer and idiopathic pulmonary fibrosis (Nat Commun 2017 23;8 :14532), the effect of senolytic drugs in these diseases is largely unknown.Added value of this studyThis study characterized a novel drug, termed ONG41008, which was found to have both senogenic and senolytic effects in cell-based assays. ONG41008 induced senescence in myofibroblasts and several cancer cell lines representative of aggressive human cancers, which was followed by cell death. Importantly, ONG41008 exhibited essentially no toxicity on normal human lung fibroblasts or primary prostate epithelial cells.Implication of all the evidenceBased on our results, we believe that ONG41008 is a potent inducer of cellular senescence (replicative senescence and oncogene-induced senescence) and causes arrest of uncontrolled, pathogenic proliferation of myofibroblasts or cancer cells.

Envelope tracking (ET) is a key technology improving efficiency of RF power amplifiers (PAs) and battery lifetime in mobile handsets. It has been commercialized since 4G LTE era, and is also being employed in 5G NR handsets. A supply modulator (SM) is a circuit generating power supplies of RF PAs for ET and average power tracking (APT) operations. Currently, the maximum channel BW and supported ET BW of 5G NR handset is 100MHz [1]–[4]. In a short time, over 100MHz BW will be necessary to support intra-band contiguous carrier aggregation cases of n77C/n78C/n79C in 3GPP standard [5]. The required instantaneous maximum output power of SM is about 10W which is calculated by the following parameters: 26dBm output power by power class 2 (PC2), 2dB loss of RF front-end module (FEM) due to complex operating band combinations (EN-DC for non-standalone mode, NE-DC, 2CA/3CA), 6dB higher instantaneous power due to peak-to-average power ratio (PAPR) at 1 resource block (RB), 1dB margin, and poor PA efficiency of around 33% (worst example) due to high carrier frequency of 5GHz at n79 band. The poor PA efficiency can be relaxed by high voltage PA design beyond 5V. In [1], a supply modulator with boosted output larger than battery voltage $(V_{BAT})$ is proposed, and the designed PA with 30% higher voltage shows 10% higher efficiency and broader BW owing to low impedance transformation ratio from $50 \Omega$ and small parasitic output capacitance of power cell. The challenge is how to design a supply modulator for 5G NR that can achieve both wide ET BW and high output voltage/power capability, while satisfying high efficiency, low receiver-band noise, short transition time, and multi-mode/standard operation.

Natural killer (NK) cells have been recognized as a next-generation therapy for cancer as they are less likely to trigger adverse events (e.g., cytokine storm or graft-versus-host disease) than T cell-based therapeutics. Although NK cell activation strategies through genetic engineering and cytokine treatment have been actively studied for successful cancer treatment, the approaches are inefficient, expensive, and involve complex processing. Here, we developed a facile and efficient method of activating NK cells using cationic nanoparticles (cNPs). The cytotoxic activity of cNP-treated primary NK and NK-92MI cells against triple-negative breast cancer cells was over 2-fold higher than that of control NK cells in vitro. Molecular biological analyses confirmed that cNPs altered the expression of CCR4 and CXCR4 of NK cells that function as chemokine receptors. In vitro live cell imaging showed that the NK cells treated with cNPs were better than control NK cells at interacting with cancer cells. Consistent with these in vitro results, cNP-treated NK cells effectively inhibited tumor growth in an in vivo tumor animal model of triple-negative breast cancer. Additionally, NK cells treated with cNPs were tracked effectively in vivo by magnetic resonance imaging. Thus, cNP-mediated activation of NK cells has great potential as an NK cell-based cancer immunotherapy. Most of all, activating NK cells using cNPs has a great advantage over conventional methods in that immune cells can be activated by a one-step facile process with exogenously charged nanomaterials, without the need for genetic engineering or cytokine treatment.

Background Extracellular matrix (ECM) has a profound effect on cell behaviors. In this study, we prepare a decellularized human nasal septal chondrocyte (NSC)-derived ECM (CHDM), as a natural (N-CHDM) or soluble form (S-CHDM), and investigate their impact on NSCs differentiation. Methods N-CHDM, S-CHDM were obtained from NSC. To evaluate function of NSC cultured on each substrate, gene expression using chondrogenic marker, and chondrogenic protein expression were tested. Preconditioned NSCs-loaded scaffolds were transplanted in nude mice for 3 weeks and analyzed. Results When cultivated on each substrate, NSCs exhibited similar cell spread area but showed distinct morphology on N-CHDM with significantly lower cell circularity. They were highly proliferative on N-CHDM than S-CHDM and tissue culture plastic (TCP), and showed more improved cell differentiation, as assessed via chondrogenic marker (Col2, Sox9, and Aggrecan) expression and immunofluorescence of COL II. We also investigated the effect of NSCs preconditioning on three different 2D substrates while NSCs were isolated from those substrates, subsequently transferred to 3D mesh scaffold, then cultivated them in vitro or transplanted in vivo. The number of cells in the scaffolds was similar to each other at 5 days but cell differentiation was notably better with NSCs preconditioned on N-CHDM, as assessed via real-time q-PCR, Western blot, and immunofluorescence. Moreover, when those NSCs-loaded polymer scaffolds were transplanted subcutaneously in nude mice for 3 weeks and analyzed, the NSCs preconditioned on the N-CHDM showed significantly advanced cell retention in the scaffold, more cells with a chondrocyte lacunae structure, and larger production of cartilage ECM (COL II, glycosaminoglycan). Conclusions Taken together, a natural form of decellularized ECM, N-CHDM would present an advanced chondrogenic potential over a reformulated ECM (S-CHDM) or TCP substrate, suggesting that N-CHDM may hold more diverse signaling cues, not just limited to ECM component.

Background Myofibroblasts are known to play a key role in the development of idiopathic pulmonary fibrosis (IPF). Two drugs, pirfenidone and nintedanib, are the only approved therapeutic options for IPF, but their applications are limited due to their side effects. Thus, curative IPF drugs represent a huge unmet medical need. Methods A mouse hepatic stellate cell (HSC) line was established that could robustly differentiate into myofibroblasts upon treatment with TGF-β. Eupatilin was assessed in diseased human lung fibroblasts from IPF patients (DHLFs) as well as in human lung epithelial cells (HLECs). The drug's performance was extensively tested in a bleomycin-induced lung fibrosis model (BLM). Global gene expression studies and proteome analysis were performed. Findings Eupatilin attenuated disease severity of BLM in both preventative and therapeutic studies. The drug inhibited the in vitro transdifferantiation of DHLFs to myofibroblasts upon stimulation with TGF-β. No such induction of the in vitro transdifferantiation was observed in TGF-β treated HLECs. Specific carbons of eupatilin were essential for its anti-fibrotic activity. Eupatilin was capable of dismantling latent TGF-β complex, specifically by eliminating expression of the latent TGF-β binding protein 1 (LTBP1), in ECM upon actin depolymerization. Unlike eupatilin, pirfenidone was unable to block fibrosis of DHLFs or HSCs stimulated with TGF-β. Eupatilin attenuated phosphorylation of Smad3 by TGF-β. Eupatilin induced myofibroblasts to dedifferentiate into intermediate HCS-like cells. Interpretation Eupatilin may act directly on pathogenic myofibroblasts, disarming them, whereas the anti-fibrotic effect of pirfenidone may be indirect. Eupatilin could increase the efficacy of IPF treatment to curative levels.

Drug-eluting stents (DESs) have been widely used as a treatment approach for coronary artery diseases. Generally, conventional DESs were fully covered with drugs and biodegradable polymers on both abluminal and luminal layers (i.e., conformal coating). However, uncontrolled drug release from the luminal drug-coating layer of the stent is known to inhibit re-endothelialization. Furthermore, the acidification of the surrounding tissue by the decomposed coating polymer causes inflammation, resulting in restenosis and late thrombosis. To overcome these limitations, here we demonstrated a functional DES coated with poly(lactic-co-glycolic acid) (PLGA), sirolimus (SRL), and magnesium hydroxide (Mg(OH)2, MH) precisely only on the abluminal layer. The acidic neutralization effect of MH was elucidated by measuring the pH change of the fabricated film in PBS solution. In an in vitro cell study, the stent coated with MH exhibited higher compatibility with human coronary artery endothelial cells (ECs) and a lower inflammation score as compared to the control stent. Finally, in an in vivo large porcine model, the abluminal coated DES with SRL and MH showed excellent re-endothelialization and anti-inflammatory and anti-thrombotic effects. In conclusion, it is believed that this approach has great potential for the development of functional DES for the treatment of cardiovascular diseases.

Synthetic biodegradable polymers including poly(lactide-co-glycolide) (PLGA) have been widely used as alternatives to metallic implantable materials in the orthopedic field due to their superior biocompatibility and biodegradability. However, weak mechanical properties of the biodegradable polymers and inflammatory reaction caused by the acidic degradation products have limited their biomedical applications. In this study, we have developed a PLGA composite containing beta-tricalcium phosphate (β-TCP) and magnesium hydroxide (Mg(OH)2) as additives to improve mechanical, osteoconductivity, and anti-inflammation property of the biopolymer composite simultaneously. The β-TCP has an osteoconductive effect and the Mg(OH)2 has a pH neutralizing effect. The PLGA/inorganic composites were uniformly blended via a twin extrusion process. The mechanical property of the PLGA/β-TCP/Mg(OH)2 composite was improved compared to the pure PLGA. In particular, the addition of Mg(OH)2 suppressed the inflammatory reaction of normal human osteoblast (NHOst) cells and also inhibited the differentiation of pre-osteoclastic cells into osteoclasts. Moreover, synergistically upregulated late osteogenic differentiation of NHOst cells was observed on the PLGA/β-TCP/Mg(OH)2 composite. Taken all together, we believe that the use of β-TCP and Mg(OH)2 as additives with synthetic biodegradable polymers has great potential by the synergistic effect in orthopedic applications.