Nondental Invasive Procedures and Risk of Infective Endocarditis: Time for a Revisit: A Science Advisory From the American Heart Association.

There have been no published prospective randomized clinical trials that have: (1) established an association between invasive dental and nondental invasive procedures and risk of infective endocarditis; or (2) defined the efficacy and safety of antibiotic prophylaxis administered in the setting of invasive procedures in the prevention of infective endocarditis in high-risk patients. Moreover, previous observational studies that examined the association of nondental invasive procedures with the risk of infective endocarditis have been limited by inadequate sample size. They have typically focused on a few potential at-risk surgical and nonsurgical invasive procedures. However, recent investigations from Sweden and England that used nationwide databases and demonstrated an association between nondental invasive procedures, and the subsequent development of infective endocarditis (in particular, in high-risk patients with infective endocarditis) prompted the development of the current science advisory.

Endocarditis, invasive dental procedures, and antibiotic prophylaxis efficacy in US Medicaid patients.

OBJECTIVE: Antibiotic prophylaxis is recommended before invasive dental procedures to prevent endocarditis in those at high risk, but supporting data are sparse. We therefore investigated any association between invasive dental procedures and endocarditis, and any antibiotic prophylaxis effect on endocarditis incidence. SUBJECTS AND METHODS: Cohort and case-crossover studies were performed on 1,678,190 Medicaid patients with linked medical, dental, and prescription data. RESULTS: The cohort study identified increased endocarditis incidence within 30 days of invasive dental procedures in those at high risk, particularly after extractions (OR 14.17, 95% CI 5.40-52.11, p < 0.0001) or oral surgery (OR 29.98, 95% CI 9.62-119.34, p < 0.0001). Furthermore, antibiotic prophylaxis significantly reduced endocarditis incidence following invasive dental procedures (OR 0.20, 95% CI 0.06-0.53, p < 0.0001). Case-crossover analysis confirmed the association between invasive dental procedures and endocarditis in those at high risk, particularly following extractions (OR 3.74, 95% CI 2.65-5.27, p < 0.005) and oral surgery (OR 10.66, 95% CI 5.18-21.92, p < 0.0001). The number of invasive procedures, extractions, or surgical procedures needing antibiotic prophylaxis to prevent one endocarditis case was 244, 143 and 71, respectively. CONCLUSIONS: Invasive dental procedures (particularly extractions and oral surgery) were significantly associated with endocarditis in high-risk individuals, but AP significantly reduced endocarditis incidence following these procedures, thereby supporting current guideline recommendations.

World Workshop on Oral Medicine VIII: Dentists' compliance with infective endocarditis prophylaxis guidelines for patients with high-risk cardiac conditions: a systematic review.

OBJECTIVE: To determine dentists' awareness and/or adherence to antibiotic prophylaxis (AP) guidelines for preventing infective endocarditis (IE) in patients with high-risk heart conditions. STUDY DESIGN: A systematic literature review was performed on MEDLINE/PubMed, Scopus, Web of Science, Cochrane Library, Proquest, Embase, Dentistry, and Oral Sciences Source databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Nationwide studies based on questionnaires, surveys, and interviews completed by dentists and published since 2007 were included. RESULTS: From 2907 articles screened, 28 studies were selected (across 20 countries). The quality of included studies was poor due to a lack of standard evaluation tools, low response rates, and lack of questionnaire validity and/or reliability. Approximately 75% of surveyed dentists reported being knowledgeable about AP guidelines, but only ∼25% complied. Reported compliance with American Heart Association (AHA) guidelines was 4 times higher than with the National Institute for Health and Care Excellence (NICE) recommendations. Some of the highest adherence rates were reported for other national AP guidelines. Significant geographic differences were observed in the estimated adherence to AHA guidelines and the percentage of dentists who reported seeking advice from physicians and/or cardiologists. CONCLUSION: Rates of compliance and/or adherence were substantially different from rates of knowledge and/or awareness, including relevant geographic dissimilarities. Compliance/adherence was higher for AHA than NICE.

Oral hygiene and infective endocarditis: a case control study.

OBJECTIVE: To determine if oral hygiene is associated with infective endocarditis (IE) among those at moderate risk for IE. STUDY DESIGN: This is a case control study of oral hygiene among hospitalized patients with IE (cases) and outpatients with heart valve disease but without IE (controls). The primary outcome was the mean dental calculus index. Secondary outcomes included other measures of oral hygiene and periodontal disease (e.g., dental plaque, gingivitis) and categorization of blood culture bacterial species in case participants. RESULTS: The 62 case participants had 53% greater mean dental calculus index than the 119 control participants (0.84, 0.55, respectively; difference = 0.29, 95% CI: 0.11, 0.48; P = .002) and 26% greater mean dental plaque index (0.88, 0.70, respectively; difference = 0.18, 95% CI: 0.01.0.36; P = .043). Overall, cases reported fewer dentist and dental hygiene visits (P = .013) and fewer dental visits in the 12 weeks before enrollment than controls (P = .007). Common oral bacteria were identified from blood cultures in 27 of 62 cases (44%). CONCLUSIONS: These data provide evidence to support and strengthen current American Heart Association guidance that those at risk for IE can reduce potential sources of IE-related bacteremia by maintaining optimal oral health through regular professional dental care and oral hygiene procedures.

Temporal association between invasive procedures and infective endocarditis.

OBJECTIVE: Antibiotic prophylaxis has been recommended for patients at increased risk of infective endocarditis (IE) undergoing specific invasive procedures (IPs) despite a lack of data supporting its use. Therefore, antibiotic prophylaxis recommendations ceased in the mid-2000s for all but those at high IE risk undergoing invasive dental procedures. We aimed to quantify any association between IPs and IE. METHODS: All 14 731 IE hospital admissions in England between April 2010 and March 2016 were identified from national admissions data, and medical records were searched for IP performed during the 15-month period before IE admission. We compared the incidence of IP during the 3 months immediately before IE admission (case period) with the incidence during the preceding 12 months (control period) to determine whether the odds of developing IE were increased in the 3 months after certain IP. RESULTS: The odds of IE were increased following permanent pacemaker and defibrillator implantation (OR 1.54, 95% CI 1.27 to 1.85, p<0.001), extractions/surgical tooth removal (OR 2.14, 95% CI 1.22 to 3.76, p=0.047), upper (OR 1.58, 95% CI 1.34 to 1.85, p<0.001) and lower gastrointestinal endoscopy (OR 1.66, 95% CI 1.35 to 2.04, p<0.001) and bone marrow biopsy (OR 1.76, 95% CI 1.16 to 2.69, p=0.039). Using an alternative analysis, bronchoscopy (OR 1.33, 95% CI 1.06 to 1.68, p=0.049) and blood transfusions/red cell/plasma exchange (OR 1.2, 95% CI 1.07 to 1.35, p=0.012) were also associated with IE. CONCLUSIONS: This study identifies a significant association between specific IPs (permanent pacemaker and defibrillator implantation, dental extraction, gastrointestinal endoscopy and bronchoscopy) and subsequent IE that warrants re-evaluation of current antibiotic prophylaxis recommendations to prevent IE in high IE risk individuals.

Temporal Trends of Infective Endocarditis in North America From 2000 to 2017-A Systematic Review.

BACKGROUND: The objective of this paper was to examine temporal changes of infective endocarditis (IE) incidence and epidemiology in North America. METHODS: A systematic review was conducted at Mayo Clinic, Rochester. Ovid EBM Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science were searched for studies published between January 1, 2000, and May 31, 2020. Four referees independently reviewed all studies, and those that reported a population-based incidence of IE in patients aged 18 years and older in North America were included. RESULTS: Of 8588 articles screened, 14 were included. Overall, IE incidence remained largely unchanged throughout the study period, except for 2 studies that demonstrated a rise in incidence after 2014. Five studies reported temporal trends of injection drug use (IDU) prevalence among IE patients with a notable increase in prevalence observed. Staphylococcus aureus was the most common pathogen in 7 of 9 studies that included microbiologic findings. In-patient mortality ranged from 3.7% to 14.4%, while the percentage of patients who underwent surgery ranged from 6.4% to 16.0%. CONCLUSIONS: The overall incidence of IE has remained stable among the 14 population-based investigations in North America identified in our systematic review. Standardization of study design for future population-based investigations has been highlighted for use in subsequent systematic reviews of IE.

Methodology for the development of a national Dental Practice-Based Research Network survey on dentist's beliefs and behaviors concerning antibiotic prophylaxis.

BACKGROUND: Dentists are high prescribers of antibiotics for both treatment and prevention of infection, although there are few guidelines to aid clinicians. Given the worldwide concerns about unnecessary use of antibiotics, there is a need for a better understanding of dentists' use of these drugs for antibiotic prophylaxis (AP) to prevent distant site infections (i.e., infective endocarditis and prosthetic joint infection). OBJECTIVE: The aim of this study was to develop and implement an effective, self-reporting, cross-sectional, survey instrument that optimized the response rate and maximized reliability and validity for determining the beliefs and behaviors of a large and nationally representative group of generalist and specialist dentists concerning their use of AP. STUDY DESIGN: A 15-question survey (58 items) was developed in a structured process by a multidisciplinary team and configured for automated online dissemination to 3584 national Dental Practice-Based Research Network (DPBRN; hitherto referred to as "Network") practitioners. The implementation phase consisted of 3 waves of greater than 1000 Network members. Additionally, 47 randomly selected dentists were surveyed twice to assess test-retest reliability. RESULTS: Of 3584 eligible Network members, 2169 (60.5%) completed the survey. The age and geographic distributions of responders was similar to those of dentists in the 2019 American Dental Association census. Furthermore, test-retest weighted kappa values for the survey were acceptable (median 0.56; interquartile range 0.42-0.64). CONCLUSIONS: We developed a highly structured survey with a high response rate and good reliability that will allow us to obtain unique data on dentists' beliefs and practices regarding AP prescribing.

Point-of-care oral cytology tool for the screening and assessment of potentially malignant oral lesions.

BACKGROUND: The effective detection and monitoring of potentially malignant oral lesions (PMOL) are critical to identifying early-stage cancer and improving outcomes. In the current study, the authors described cytopathology tools, including machine learning algorithms, clinical algorithms, and test reports developed to assist pathologists and clinicians with PMOL evaluation. METHODS: Data were acquired from a multisite clinical validation study of 999 subjects with PMOLs and oral squamous cell carcinoma (OSCC) using a cytology-on-a-chip approach. A machine learning model was trained to recognize and quantify the distributions of 4 cell phenotypes. A least absolute shrinkage and selection operator (lasso) logistic regression model was trained to distinguish PMOLs and cancer across a spectrum of histopathologic diagnoses ranging from benign, to increasing grades of oral epithelial dysplasia (OED), to OSCC using demographics, lesion characteristics, and cell phenotypes. Cytopathology software was developed to assist pathologists in reviewing brush cytology test results, including high-content cell analyses, data visualization tools, and results reporting. RESULTS: Cell phenotypes were determined accurately through an automated cytological assay and machine learning approach (99.3% accuracy). Significant differences in cell phenotype distributions across diagnostic categories were found in 3 phenotypes (type 1 ["mature squamous"], type 2 ["small round"], and type 3 ["leukocytes"]). The clinical algorithms resulted in acceptable performance characteristics (area under the curve of 0.81 for benign vs mild dysplasia and 0.95 for benign vs malignancy). CONCLUSIONS: These new cytopathology tools represent a practical solution for rapid PMOL assessment, with the potential to facilitate screening and longitudinal monitoring in primary, secondary, and tertiary clinical care settings.

Development of a cytology-based multivariate analytical risk index for oral cancer.

OBJECTIVES: The diagnosis and management of oral cavity cancers are often complicated by the uncertainty of which patients will undergo malignant transformation, obligating close surveillance over time. However, serial biopsies are undesirable, highly invasive, and subject to inherent issues with poor inter-pathologist agreement and unpredictability as a surrogate for malignant transformation and clinical outcomes. The goal of this study was to develop and evaluate a Multivariate Analytical Risk Index for Oral Cancer (MARIO) with potential to provide non-invasive, sensitive, and quantitative risk assessments for monitoring lesion progression. MATERIALS AND METHODS: A series of predictive models were developed and validated using previously recorded single-cell data from oral cytology samples resulting in a "continuous risk score". Model development consisted of: (1) training base classification models for each diagnostic class pair, (2) pairwise coupling to obtain diagnostic class probabilities, and (3) a weighted aggregation resulting in a continuous MARIO. RESULTS AND CONCLUSIONS: Diagnostic accuracy based on optimized cut-points for the test dataset ranged from 76.0% for Benign, to 82.4% for Dysplastic, 89.6% for Malignant, and 97.6% for Normal controls for an overall MARIO accuracy of 72.8%. Furthermore, a strong positive relationship with diagnostic severity was demonstrated (Pearson's coefficient = 0.805 for test dataset) as well as the ability of the MARIO to respond to subtle changes in cell composition. The development of a continuous MARIO for PMOL is presented, resulting in a sensitive, accurate, and non-invasive method with potential for enabling monitoring disease progression, recurrence, and the need for therapeutic intervention of these lesions.

Quantifying infective endocarditis risk in patients with predisposing cardiac conditions.

Aims: There are scant comparative data quantifying the risk of infective endocarditis (IE) and associated mortality in individuals with predisposing cardiac conditions. Methods and results: English hospital admissions for conditions associated with increased IE risk were followed for 5 years to quantify subsequent IE admissions. The 5-year risk of IE or dying during an IE admission was calculated for each condition and compared with the entire English population as a control. Infective endocarditis incidence in the English population was 36.2/million/year. In comparison, patients with a previous history of IE had the highest risk of recurrence or dying during an IE admission [odds ratio (OR) 266 and 215, respectively]. These risks were also high in patients with prosthetic valves (OR 70 and 62) and previous valve repair (OR 77 and 60). Patients with congenital valve anomalies (currently considered 'moderate risk') had similar levels of risk (OR 66 and 57) and risks in other 'moderate-risk' conditions were not much lower. Congenital heart conditions (CHCs) repaired with prosthetic material (currently considered 'high risk' for 6 months following surgery) had lower risk than all 'moderate-risk' conditions-even in the first 6 months. Infective endocarditis risk was also significant in patients with cardiovascular implantable electronic devices. Conclusion: These data confirm the high IE risk of patients with a history of previous IE, valve replacement, or repair. However, IE risk in some 'moderate-risk' patients was similar to that of several 'high-risk' conditions and higher than repaired CHC. Guidelines for the risk stratification of conditions predisposing to IE may require re-evaluation.

Fabrication of Electrospun Mucoadhesive Membranes for Therapeutic Applications in Oral Medicine.

Oral mucosal lesions are related to several etiologies, including trauma, infection, and immunologic and neoplastic diseases. Their prevalence varies greatly depending on ethnicity, gender, and exposure to risk factors. Currently, most oral mucosal lesions are treated with creams, mouthwashes, or gels containing suitable drugs. However, topical medications may be relatively ineffective as they are removed rapidly from oral surfaces, limiting drug contact times. Systemic medications might be more effective but are associated with unacceptable off-target side effects. The aim of this study was to produce novel polymeric mucoadhesive membranes for therapeutic applications on the oral mucosa using electrospinning. Poly(vinylpyrrolidone) (PVP) and Eudragit RS100 (RS100) were used for the fabrication of membranes, whereas dextran (Dex) or poly(ethylene oxide) (PEO) particles were incorporated to enhance their mucoadhesive properties. An electrospun poly(caprolactone) (PCL) backing layer (BL) was added to create a dual-layer system. Solution properties were studied using rheometry, and membranes were characterized using differential thermal analysis and scanning electron microscopy. Solubility, surface hydrophobicity, and adhesion properties were also investigated. The solution viscosity varied depending on the composition and concentration, affecting fiber production. The addition of RS100 to PVP resulted in reduced membrane porosity and solubility, and increased surface hydrophobicity and in vitro adhesion times. Dex and PEO particles were located on the surface of the fibers. A PCL BL was successfully produced, with enhanced attachment between layers achieved through thermal treatment. PVP homopolymer membranes did not adhere to plastic or porcine mucosa, whereas PVP/RS100 membranes with and without PEO or Dex were tightly adherent. In conclusion, PVP and RS100 may be combined to tailor membrane properties. Furthermore, electrospinning facilitated the production of membranes consisting of mucoadhesive-fabricated fibers displaying increased surface area and long-lasting adhesive properties. These novel compositions exhibit great potential for the fabrication of mucoadhesive patches for therapeutic applications in oral medicine.

Effect of cigarette smoking on subgingival bacteria in healthy subjects and patients with chronic periodontitis.

BACKGROUND: Cigarette smoking is known to increase the risk of periodontal destruction and developing chronic periodontitis (CP). It is also reported to affect the subgingival bacterial profile among CP patients. However, studies on the effect of smoking on the bacterial profile among healthy subjects are still limited. Therefore, the aim of this study was to investigate the impact of smoking on the subgingival bacterial profile in both healthy adults and CP patients. METHODS: Subgingival plaque samples were collected from CP patients (30 nonsmokers and 9 smokers) and healthy subjects (37 non-smokers and 18 smokers). Genomic DNA was extracted and 25 bacterial species were detected using PCR of 16S rRNA. Comparing smokers to non-smokers from each group was conducted using chi2 and binary logistic regression analysis. RESULTS: After correcting for confounding factors, the odds of having Slackia exigua, Selenomonas sputigena and Campylobacter rectus was higher among healthy smokers (ORadj = 10.1, 6.62 and 5.62 respectively). While for CP group, the highest odds were observed for Treponema amylovorum, Treponema medium, Slackia exigua and Treponema vincentii (ORadj = 20.7, 7.97, 6.37 and 5.37 respectively) and the increase in Treponema amylovorum was statistically significant (p = 0.05). CONCLUSION: Smoking affects the subgingival bacterial profile in healthy individuals and is responsible for the depletion of beneficial bacteria and the increase in periodontopathogenic bacteria. In the CP patient group, our study suggests that subgingival bacteria (particularly Treponema species) make a more substantial contribution in the etiology of CP among non-smokers. Further studies using a larger sample set and more sensitive and quantitative techniques (such as real -time PCR) are needed to enhance our understanding of the exact effect of smoking on subgingival biofilm.

'Cytology-on-a-chip' based sensors for monitoring of potentially malignant oral lesions.

UNLABELLED: Despite significant advances in surgical procedures and treatment, long-term prognosis for patients with oral cancer remains poor, with survival rates among the lowest of major cancers. Better methods are desperately needed to identify potential malignancies early when treatments are more effective. OBJECTIVE: To develop robust classification models from cytology-on-a-chip measurements that mirror diagnostic performance of gold standard approach involving tissue biopsy. MATERIALS AND METHODS: Measurements were recorded from 714 prospectively recruited patients with suspicious lesions across 6 diagnostic categories (each confirmed by tissue biopsy -histopathology) using a powerful new 'cytology-on-a-chip' approach capable of executing high content analysis at a single cell level. Over 200 cellular features related to biomarker expression, nuclear parameters and cellular morphology were recorded per cell. By cataloging an average of 2000 cells per patient, these efforts resulted in nearly 13 million indexed objects. RESULTS: Binary "low-risk"/"high-risk" models yielded AUC values of 0.88 and 0.84 for training and validation models, respectively, with an accompanying difference in sensitivity+specificity of 6.2%. In terms of accuracy, this model accurately predicted the correct diagnosis approximately 70% of the time, compared to the 69% initial agreement rate of the pool of expert pathologists. Key parameters identified in these models included cell circularity, Ki67 and EGFR expression, nuclear-cytoplasmic ratio, nuclear area, and cell area. CONCLUSIONS: This chip-based approach yields objective data that can be leveraged for diagnosis and management of patients with PMOL as well as uncovering new molecular-level insights behind cytological differences across the OED spectrum.

Interobserver agreement in dysplasia grading: toward an enhanced gold standard for clinical pathology trials.

OBJECTIVE: Interobserver agreement in the context of oral epithelial dysplasia (OED) grading has been notoriously unreliable and can impose barriers for developing new molecular markers and diagnostic technologies. This paper aimed to report the details of a 3-stage histopathology review and adjudication process with the goal of achieving a consensus histopathologic diagnosis of each biopsy. STUDY DESIGN: Two adjacent serial histologic sections of oral lesions from 846 patients were independently scored by 2 different pathologists from a pool of 4. In instances where the original 2 pathologists disagreed, a third, independent adjudicating pathologist conducted a review of both sections. If a majority agreement was not achieved, the third stage involved a face-to-face consensus review. RESULTS: Individual pathologist pair κ values ranged from 0.251 to 0.706 (fair-good) before the 3-stage review process. During the initial review phase, the 2 pathologists agreed on a diagnosis for 69.9% of the cases. After the adjudication review by a third pathologist, an additional 22.8% of cases were given a consensus diagnosis (agreement of 2 out of 3 pathologists). After the face-to-face review, the remaining 7.3% of cases had a consensus diagnosis. CONCLUSIONS: The use of the defined protocol resulted in a substantial increase (30%) in diagnostic agreement and has the potential to improve the level of agreement for establishing gold standards for studies based on histopathologic diagnosis.

Use of electrical impedance spectroscopy to detect malignant and potentially malignant oral lesions.

The electrical properties of tissues depend on their architecture and cellular composition. We have previously shown that changes in electrical impedance can be used to differentiate between different degrees of cervical dysplasia and cancer of the cervix. In this proof-of-concept study, we aimed to determine whether electrical impedance spectroscopy (EIS) could distinguish between normal oral mucosa; benign, potentially malignant lesions (PML); and oral cancer. EIS data were collected from oral cancer (n=10), PML (n=27), and benign (n=10) lesions. EIS from lesions was compared with the EIS reading from the normal mucosa on the contralateral side of the mouth or with reference spectra from mucosal sites of control subjects (n=51). Healthy controls displayed significant differences in the EIS obtained from different oral sites. In addition, there were significant differences in the EIS of cancer and high-risk PML versus low-risk PML and controls. There was no significant difference between benign lesions and normal controls. Study subjects also deemed the EIS procedure considerably less painful and more convenient than the scalpel biopsy procedure. EIS shows promise at distinguishing among malignant, PML, and normal oral mucosa and has the potential to be developed into a clinical diagnostic tool.

Polymersome-mediated delivery of combination anticancer therapy to head and neck cancer cells: 2D and 3D in vitro evaluation.

Polymersomes have the potential to encapsulate and deliver chemotherapeutic drugs into tumor cells, reducing off-target toxicity that often compromises anticancer treatment. Here, we assess the ability of the pH-sensitive poly 2-(methacryloyloxy)ethyl phosphorylcholine (PMPC)- poly 2-(diisopropylamino)ethyl methacrylate (PDPA) polymersomes to encapsulate chemotherapeutic agents for effective combinational anticancer therapy. Polymersome uptake and ability to deliver encapsulated drugs into healthy normal oral cells and oral head and neck squamous cell carcinoma (HNSCC) cells was measured in two and three-dimensional culture systems. PMPC-PDPA polymersomes were more rapidly internalized by HNSCC cells compared to normal oral cells. Polymersome cellular uptake was found to be mediated by class B scavenger receptors. We also observed that these receptors are more highly expressed by cancer cells compared to normal oral cells, enabling polymersome-mediated targeting. Doxorubicin and paclitaxel were encapsulated into pH-sensitive PMPC-PDPA polymersomes with high efficiencies either in isolation or as a dual-load for both singular and combinational delivery. In monolayer culture, only a short exposure to drug-loaded polymersomes was required to elicit a strong cytotoxic effect. When delivered to three-dimensional tumor models, PMPC-PDPA polymersomes were able to penetrate deep into the center of the spheroid resulting in extensive cell damage when loaded with both singular and dual-loaded chemotherapeutics. PMPC-PDPA polymersomes offer a novel system for the effective delivery of chemotherapeutics for the treatment of HNSCC. Moreover, the preferential internalization of PMPC polymersomes by exploiting elevated scavenger receptor expression on cancer cells opens up the opportunity to target polymersomes to tumors.

Combined mathematical modelling and experimentation to predict polymersome uptake by oral cancer cells.

This study is motivated by understanding and controlling the key physical properties underlying internalisation of nano drug delivery. We consider the internalisation of specific nanometre size delivery vehicles, comprised of self-assembling amphiphilic block copolymers, called polymersomes that have the potential to specifically deliver anticancer therapeutics to tumour cells. The possible benefits of targeted polymersome drug delivery include reduced off-target toxic effects in healthy tissue and increased drug uptake by diseased tissue. Through a combination of in vitro experimentation and mathematical modelling, we develop a validated model of nanoparticle uptake by cells via the clathrin-mediated endocytotic pathway, incorporating receptor binding, clustering and recycling. The model predicts how the characteristics of receptor targeting, and the size and concentration of polymersomes alter uptake by tumour cells. The number of receptors per cell was identified as being the dominant mechanism accounting for the difference between cell types in polymersome uptake rate. FROM THE CLINICAL EDITOR: This article reports on a validated model developed through a combination of in vitro experimentation and mathematical modeling of nanoparticle uptake by cells via the clathrin-mediated endocytotic pathway. The model incorporates receptor binding, clustering, and recycling and predicts how the characteristics of receptor targeting, the size and concentration alter polymersome uptake by cancer cells.

Tissue-engineered oral mucosa to study radiotherapy-induced oral mucositis.

PURPOSE: Oral mucositis is a severe and often dose-limiting side-effect of cancer therapy that occurs in patients receiving radiotherapy for head and neck cancers. Although radiation-induced effects on keratinocytes have been studied, little is known about its effect on fibroblasts or endothelial cells or, more importantly, when all these cells are combined in an engineered oral mucosal model. MATERIALS AND METHODS: Monolayer cultures of normal oral keratinocytes, normal oral fibroblasts, human dermal microvascular endothelial cells or tissue-engineered oral mucosa (TEOM) were exposed to 20 Gy irradiation. Cell damage and cytokine release was measured for 72 h for monolayer cultures and for up to 21 d for TEOM. RESULTS: Compared to non-irradiated cells, the viability of all monolayer and co-cultures was significantly reduced 72 h post-irradiation while levels of secreted interleukin IL-6 and CXCL8 were increased. The viability of irradiated TEOM models was significantly reduced compared to controls at all time-points. Histologically, irradiated TEOM displayed thinner epithelium, increased apoptosis and more extensive damage than non-irradiated models. IL-6, CXCL8 and granulocyte macrophage colony-stimulating factor release was reduced whereas IL-1α levels were increased in irradiated TEOM models compared to controls. CONCLUSIONS: TEOM models comprising of mixed cell populations may prove useful in examining the pathobiology of radiation-induced mucositis.