Electromechanical convective drug delivery devices for overcoming diffusion barriers.

Drug delivery systems which rely on diffusion for mass transport, such as hydrogels and nanoparticles, have enhanced drug targeting and extended delivery profiles to improve health outcomes for patients suffering from diseases including cancer and diabetes. However, diffusion-dependent systems often fail to provide >0.01-1% drug bioavailability when transporting macromolecules across poorly permeable physiological tissues such as the skin, solid tumors, the blood-brain barrier, and the gastrointestinal walls. Convection-enabling robotic ingestibles, wearables, and implantables physically interact with tissue walls to improve bioavailability in these settings by multiple orders of magnitude through convective mass transfer, the process of moving drug molecules via bulk fluid flow. In this Review, we compare diffusive and convective drug delivery systems, highlight engineering techniques that enhance the efficacy of convective devices, and provide examples of synergies between the two methods of drug transport.

Spiral NeuroString: High-Density Soft Bioelectronic Fibers for Multimodal Sensing and Stimulation.

Bioelectronic fibers hold promise for both research and clinical applications due to their compactness, ease of implantation, and ability to incorporate various functionalities such as sensing and stimulation. However, existing devices suffer from bulkiness, rigidity, limited functionality, and low density of active components. These limitations stem from the difficulty to incorporate many components on one-dimensional (1D) fiber devices due to the incompatibility of conventional microfabrication methods (e.g., photolithography) with curved, thin and long fiber structures. Herein, we introduce a fabrication approach, ‶spiral transformation″, to convert two-dimensional (2D) films containing microfabricated devices into 1D soft fibers. This approach allows for the creation of high density multimodal soft bioelectronic fibers, termed Spiral NeuroString (S-NeuroString), while enabling precise control over the longitudinal, angular, and radial positioning and distribution of the functional components. We show the utility of S-NeuroString for motility mapping, serotonin sensing, and tissue stimulation within the dynamic and soft gastrointestinal (GI) system, as well as for single-unit recordings in the brain. The described bioelectronic fibers hold great promises for next-generation multifunctional implantable electronics.

Efficacy of Ultrasound Shear Wave Elastography in the Diagnosis of Salivary Gland Tumors.

PURPOSE: Diagnostic accuracy of fine-needle aspiration cytology (FNAC) to discriminate between the target condition and health in the evaluation of salivary gland tumors is not perfected yet and thus, false-negative results are possible. The purpose of the present study was to measure and compare the diagnostic accuracy of FNAC performed with conventional B-mode ultrasound and ultrasound with shear wave elastography (SWE) FNAC navigation. METHODS: The investigators implemented a single-blind randomized study (sealed envelope method). The study population was composed of all patients presenting for evaluation and management of suspected benign or malignant tumors of the major salivary glands between July 2013 and December 2020. The involvement of SWE navigation was the primary predictor variable affecting FNA targeting. The method involved analysis of redistribution of SWE values within the affected gland expressed in kilopascals (kPa) and the four-point ES1 (soft tissue) to ES4 (stiff) scoring. The primary outcome variable was the success in obtaining diagnostic tissue resulting in a histologically confirmed FNAC diagnosis and coded as yes/no. Age and sex of the patients and topographical locations of lesions were covariates. Descriptive and bivariate statistics were computed and the P value was set at .05. RESULTS: The sample included 132 subjects (male/female 59/73; mean age 54 ± 11 years; 144 tumors). SWE + Group (n = 66) consisted of patients presurgically diagnosed with salivary tumors SWE-guided FNAC and SWE- Group (n = 66) was diagnosed with tumors by conventional ultrasound-(B-mode)-guided FNAC. The SWE-guided FNAC statistically significantly reduced the incidence of false-negative results (n = 0; P = .001) and nondiagnostic cases (n = 3 SWE FNAC vs n = 7 B-mode US FNAC; P = .04). For SWE + Group, the FNAC diagnosis was confirmed by postsurgical histology in 95.5% with 91.0% sensitivity (confidence interval [CI] 0.62 to 0.97) and 84.4% specificity (CI 0.58 to 0.96). For SWE- Group, 81.8% confirmation was obtained (P = .05) with 82.3% sensitivity (CI 0.54 to 0.90) and 74.0% specificity. CONCLUSION: SWE can increase success in obtaining diagnostic tissue when used for FNAC navigation purposes. We suggest combining both SWE and standard B-mode ultrasonography methods when the FNAC procedure is performed.

Communication Protocols Integrating Wearables, Ingestibles, and Implantables for Closed-Loop Therapies.

Body-conformal sensors and tissue interfacing robotic therapeutics enable the real-time monitoring and treatment of diabetes, wound healing, and other critical conditions. By integrating sensors and drug delivery devices, scientists and engineers have developed closed-loop drug delivery systems with on-demand therapeutic capabilities to provide just-in-time treatments that correspond to chemical, electrical, and physical signals of a target morbidity. To enable closed-loop functionality in vivo, engineers utilize various low-power means of communication that reduce the size of implants by orders of magnitude, increase device lifetime from hours to months, and ensure the secure high-speed transfer of data. In this review, we highlight how communication protocols used to integrate sensors and drug delivery devices, such as radio frequency communication (e.g., Bluetooth, near-field communication), in-body communication, and ultrasound, enable improved treatment outcomes.

Topographic Positions of the Wharton's Duct Orifice in Children.

PURPOSE: Sialoendoscopic, orthodontic, and surgical interventions within the floor of the mouth require precise knowledge of the topography of the Wharton's duct orifices which is still lacking for the pediatric population. We aimed to establish a normative database for the topography of these orifices in children. METHODS: The prospective cross-sectional analytic study was performed during January to December 2021. The distances between the mandible gonions and each orifice and the lingual frenulum were defined as primary outcome variables. The secondary outcome variables were the inter-position of the orifices and their location against the base of the tongue and the mandibular alveolar ridge. The segments of the cohort were classified by sex and age groups (4 to 7, 8 to 14, 15 to 17 years old) as the primary predictor variables. The data were evaluated by a 3-way ANOVA for analysis of selected distances with the level of significance at P ≤ .05. The correlation analysis between sex and locations of the orifices was performed using χ2 criterion (95% confidence interval) and r ≥ 0.60 was counted as a strong correlation. RESULTS: The study involved 3,000 healthy children from 4 to 17 years of age. The orifices were symmetrical (89.3%), frenulum-independent (78.0%) openings that were usually located in the middle part of the floor of the mouth. The distance between the orifices varied from 0 mm in the frenulum-attached cases to 4.6 ± 1.8 mm for 4 to 7 years old, 7.6 ± 1.9 mm for 8 to 14 years old, and 9.1 ± 2.6 mm for 15 to 17 years old individuals. The orifices were attached to the frenulum (5.7%), were frenulum-related (16.3%), and frenulum-independent (78.0%). The sagittal asymmetry of the orifices was noted in 10.7%, and in 1.6% the lateral asymmetry was detected. No statistically significant sex-related differences were noted. CONCLUSION: In the pediatric population, the Wharton's duct orifices are usually symmetrical frenulum-independent openings that are located in the middle part of the floor of the mouth. The distance between the orifices normatively varies according to sex and age. The size of the mandible does not influence the positions of the orifices. The position of the duct orifices must be established prior to submandibular sialoendoscopy, orthodontic interventions, frenotomy, and other oral surgeries.

A flexible electronic strain sensor for the real-time monitoring of tumor regression.

Assessing the efficacy of cancer therapeutics in mouse models is a critical step in treatment development. However, low-resolution measurement tools and small sample sizes make determining drug efficacy in vivo a difficult and time-intensive task. Here, we present a commercially scalable wearable electronic strain sensor that automates the in vivo testing of cancer therapeutics by continuously monitoring the micrometer-scale progression or regression of subcutaneously implanted tumors at the minute time scale. In two in vivo cancer mouse models, our sensor discerned differences in tumor volume dynamics between drug- and vehicle-treated tumors within 5 hours following therapy initiation. These short-term regression measurements were validated through histology, and caliper and bioluminescence measurements taken over weeklong treatment periods demonstrated the correlation with longer-term treatment response. We anticipate that real-time tumor regression datasets could help expedite and automate the process of screening cancer therapies in vivo.

The Normative Topographic Position of the Wharton's Duct Orifice in Adults.

PURPOSE: We aimed to establish a normative database for the topography of Wharton's duct orifices and to indicate the localization and distances of the orifices against other oral structures. METHODS: The prospective study involved 3,000 healthy adults. We measured the cranial index, the distances between the mandible gonions and the orifices and between each orifice and the lingual frenulum, the position of the orifices against each other, and against the base of the tongue and the mandibular alveolar ridge. The segments of the cohort were classified by sex and the headform (dolichocephalic, brachycephalic, and mesocephalic). RESULTS: The distance between the orifices varied from 0 mm in the frenulum-attached cases to11.0 ± 2.3 mm in cases of the male brachycephalic skull. The correlation with sex was found for the localization of the frenulum-related orifices (r = 0.64 for females). The orifices were attached to the frenulum (5.9%), were frenulum-related (16.2%), and frenulum-independent (77.9%). The sagittal asymmetry of the orifices was noted in 11.8%, and in 2.1%, the lateral asymmetry was detected. CONCLUSION: In most of the cases, the Wharton's duct orifices are symmetrical frenulum-independent openings that are usually located in the middle part of the floor of the mouth or close to the mandibular alveolar ridge. The distance between the orifices varies according to sex and the type of the skull. The precise position of the duct orifices must be established prior to sialoendoscopy of the submandibular glands, a botulinum toxin injection around the mandible, tongue traction maneuvers, frenotomy, and other oral surgeries.

The Impact of the COVID-19 Pandemic on Israeli Orthodontic Practice: A Clinic's Activity and Patients' Attitudes.

The current study aimed to characterize the activity in orthodontic clinics during the COVID-19-induced lockdown and the inter-lockdown periods, as well as to evaluate patients' perspectives with respect to their fears, their extent of cooperation with treatment, and their emergency needs during the lockdown. The data were gathered from 11 private orthodontic clinics from 1 January 2020 to 8 March 2021, which included three lockdowns and inter-lockdowns. Information specifying the number of admissions, missed appointments, and emergency visits was gathered. Four hundred and twenty-nine orthodontic patients treated in those clinics agreed to complete a questionnaire that evaluated their concerns and expectations, the treatment emergency issues, implementation of the orthodontist's instructions, and contact with the clinical staff during lockdowns. There was a significant increase in the number of scheduled appointments during the inter-lockdown periods, compared with the pre-pandemic period (p = 0.001). No difference in the number of missed/canceled or emergency appointments was found between the different periods (p > 0.420). The majority (89.6%) of the emergency visits involved issues with appliances; 68.7% of the subjects were advised to present themselves at clinics. During the peaks of the waves of the COVID-19 pandemic, a sharp rise in the number of missed and urgent appointments was not found. Reducing the number of orthodontic emergencies may assist in reducing patient fears.

COVID-19 knowledge and adherence of dental practitioners to health authority safety guidelines during a pandemic.

OBJECTIVES: This study aimed to assess the degree of dental practitioner adherence to recommendations made during the COVID-19 pandemic. METHOD AND MATERIALS: An online questionnaire was distributed via social media among dental practitioners in Israel who worked during the COVID-19 outbreak. RESULTS: In total, 144 dental practitioners completed the survey; it was found that dental practitioner adherence to all the official PPE use recommendations was 69.8%, whereas 36.8% of dental practitioners reported the use of N95 when needed. Knowledge of self-protection against COVID-19 was rated as "very good" by 37.5% of responders. However, only 25.7% felt "highly protected" by personal protective equipment. Interestingly, many dental practitioners (46.8%) reported adherence to extra protection in addition to the required PPE communicated by the Ministry of Health guidelines. CONCLUSION: Stricter regimens should be applied for dealing with the current challenging pandemic, especially in clinical work with a higher risk for viral transmission. Specific strategies should be followed to ensure good practice to improve dental practitioners' and patients' safety.

Oral delivery of systemic monoclonal antibodies, peptides and small molecules using gastric auto-injectors.

Oral administration provides a simple and non-invasive approach for drug delivery. However, due to poor absorption and swift enzymatic degradation in the gastrointestinal tract, a wide range of molecules must be parenterally injected to attain required doses and pharmacokinetics. Here we present an orally dosed liquid auto-injector capable of delivering up to 4-mg doses of a bioavailable drug with the rapid pharmacokinetics of an injection, reaching an absolute bioavailability of up to 80% and a maximum plasma drug concentration within 30 min after dosing. This approach improves dosing efficiencies and pharmacokinetics an order of magnitude over our previously designed injector capsules and up to two orders of magnitude over clinically available and preclinical chemical permeation enhancement technologies. We administered the capsules to swine for delivery of clinically relevant doses of four commonly injected medications, including adalimumab, a GLP-1 analog, recombinant human insulin and epinephrine. These multi-day dosing experiments and oral administration in awake animal models support the translational potential of the system.

Surgical approach to a severe case of sodium hypochlorite accident: a case report and review of the literature.

Sodium hypochlorite (NaOCl) is the most common irrigant used in modern endodontics due to the antimicrobial properties against bacteria, the powerful oxidative activity, and the ability to dissolve organic soft tissues. When NaOCl extrudes the apex of the root, commonly referred as "sodium hypochlorite accident," it can lead to devastating outcomes leading to long-term functional and esthetic deficits. Currently, no clear guidelines exist as to how these patients should be managed. The purpose of this paper is to present a case report and a review of literature and to propose an adequate surgical treatment protocol for this unfortunate event.

Transoral Endoscopic Plating for Orbital Blowout Fractures.

ABSTRACT: Orbital fractures account for up to 40% of craniofacial injuries. In this article, the authors present the transoral endoscopy-assisted plating technique for treating orbital blowout fractures (OBF). A retrospective analysis of 56 cases treated with transoral endoscopy-assisted approach was performed. Immediate versus delayed surgery decision-making was performed by using our 2-week algorithm. The surgical technique included only transoral incisions, forced duction and "pulse" tests, osteotomy, endoscopic inspections, the reduction with a curved elevator and an indwelling balloon, the retrieval of prolapsed fatty tissue back into the orbit, removal of sharp bony fragments, adaptation of the titanium mesh to the orbital floor and its fixation with screws to stable bony structures, reattachment of the osteotomized lateral wall, and postoperative computed tomography (CT) scan with 3D CT reconstruction. The overall success rate of surgeries was 96%. The resolution of comorbidities resulted in a normal globe position, normal eye movement, and the resolution of diplopia. Postoperative complications were insignificant with one case of surgical edema and one case of infection and sequestration that appeared six months after surgery. These results remained unchanged after 20 to 24 months of follow-up. The suggested minimally invasive transoral technique can be effectively implemented in cases of OBF as well as in cases when the medial wall of the orbit is involved. Our results presented a high success rate with minimal rate of complications, thus our technique is a safe way with minimal morbidity for treating OBF.

Ingestible transiently anchoring electronics for microstimulation and conductive signaling.

Ingestible electronic devices enable noninvasive evaluation and diagnosis of pathologies in the gastrointestinal (GI) tract but generally cannot therapeutically interact with the tissue wall. Here, we report the development of an orally administered electrical stimulation device characterized in ex vivo human tissue and in in vivo swine models, which transiently anchored itself to the stomach by autonomously inserting electrically conductive, hooked probes. The probes provided stimulation to the tissue via timed electrical pulses that could be used as a treatment for gastric motility disorders. To demonstrate interaction with stomach muscle tissue, we used the electrical stimulation to induce acute muscular contractions. Pulses conductively signaled the probes' successful anchoring and detachment events to a parenterally placed device. The ability to anchor into and electrically interact with targeted GI tissues controlled by the enteric nervous system introduces opportunities to treat a multitude of associated pathologies.

A luminal unfolding microneedle injector for oral delivery of macromolecules.

Insulin and other injectable biologic drugs have transformed the treatment of patients suffering from diabetes1,2, yet patients and healthcare providers often prefer to use and prescribe less effective orally dosed medications3-5. Compared with subcutaneously administered drugs, oral formulations create less patient discomfort4, show greater chemical stability at high temperatures6, and do not generate biohazardous needle waste7. An oral dosage form for biologic medications is ideal; however, macromolecule drugs are not readily absorbed into the bloodstream through the gastrointestinal tract8. We developed an ingestible capsule, termed the luminal unfolding microneedle injector, which allows for the oral delivery of biologic drugs by rapidly propelling dissolvable drug-loaded microneedles into intestinal tissue using a set of unfolding arms. During ex vivo human and in vivo swine studies, the device consistently delivered the microneedles to the tissue without causing complete thickness perforations. Using insulin as a model drug, we showed that, when actuated, the luminal unfolding microneedle injector provided a faster pharmacokinetic uptake profile and a systemic uptake >10% of that of a subcutaneous injection over a 4-h sampling period. With the ability to load a multitude of microneedle formulations, the device can serve as a platform to orally deliver therapeutic doses of macromolecule drugs.

Graftless sinus floor augmentation with an internal-port implant: long-term experience.

OBJECTIVE: The objective was to assess the outcome of graftless sinus floor augmentation associated with dental implant placement performed with an implant system that has an internal port and screw, combined with the osteotome technique. METHOD AND MATERIALS: Between 2012 and 2018, 722 titanium-aluminum-vanadium implants (Ti-6Al-4V ELI, diameter 3.75/4.20 mm) were placed in 331 patients. Implants 11.5 mm in length were inserted in maxillae with bone level ≤ 5 mm, and 13.0-mm-long implants were inserted in maxillae with bone level of > 5 to 8 mm. In all cases, no graft materials or bone substitutes were used for the sinus elevation. Implant condition was assessed at three different centers and the follow-up period ranged from 6 months to 7 years. RESULTS: In total, 412 11.5-mm-long implants and 310 13-mm-long implants were inserted. Implantation was successful in 689 implants (95.4%), based on cone beam computed tomography and clinical evaluation as well as the patients' experience, with no statistically significant difference between the 11.5-mm and 13.0-mm implants. The complication rates were comparable between cases with bone levels from 3 to 5 mm and the > 5- to 8-mm bone level cases. CONCLUSIONS: The port and screw implant system may allow maxillary sinus augmentation without grafting or bony substitute. This can simplify relatively major surgery, such as a sinus augmentation procedure, to a less invasive procedure and potentially reduce the risk of complications.

Quantifying the Value of Orally Delivered Biologic Therapies: A Cost-Effectiveness Analysis of Oral Semaglutide.

Oral semaglutide, which has undergone multiple phase 3 clinical trials, represents the first oral biologic medication for type 2 diabetes in the form of a daily capsule. It provides similar efficacy compared with its weekly injection counterpart, but it demands a dose on the order of 100 times as high and requires more frequent administration. We perform a cost effectiveness analysis using a first and second order Monte Carlo simulation to estimate quality-adjusted life expectancies associated with an oral daily capsule, oral weekly capsule, daily injection, and weekly injection of semaglutide. We conclude that the additional costs incurred to produce extra semaglutide for the oral formulation are cost effective, given the greater quality of life experienced when taking a capsule over a weekly injection. We also demonstrate that the potency of semaglutide allows the formulation to be cost effective, and less potent drugs will require increased oral bioavailability to make a cost effective oral formulation.

An ingestible self-orienting system for oral delivery of macromolecules.

Biomacromolecules have transformed our capacity to effectively treat diseases; however, their rapid degradation and poor absorption in the gastrointestinal (GI) tract generally limit their administration to parenteral routes. An oral biologic delivery system must aid in both localization and permeation to achieve systemic drug uptake. Inspired by the leopard tortoise's ability to passively reorient, we developed an ingestible self-orienting millimeter-scale applicator (SOMA) that autonomously positions itself to engage with GI tissue. It then deploys milliposts fabricated from active pharmaceutical ingredients directly through the gastric mucosa while avoiding perforation. We conducted in vivo studies in rats and swine that support the applicator's safety and, using insulin as a model drug, demonstrated that the SOMA delivers active pharmaceutical ingredient plasma levels comparable to those achieved with subcutaneous millipost administration.

Oral delivery of biologics using drug-device combinations.

Orally administered devices could enable the systemic uptake of biologic therapeutics by engineering around the physiological barriers present in the gastrointestinal (GI) tract. Such devices aim to shield cargo from degradative enzymes and increase the diffusion rate of medication through the GI mucosa. In order to achieve clinical relevance, these designs must significantly increase systemic drug bioavailability, deliver a clinically relevant dose and remain safe when taken frequently. Such an achievement stands to reduce our dependence on needle injections, potentially increasing patient adherence and reducing needle-associated complications. Here we discuss the physical and chemical constraints imposed by the GI organs and use these to develop a set of boundary conditions on oral device designs for the delivery of macromolecules. We critically examine how device size affects the rate of intestinal obstruction and hinders the loading capacity of poorly soluble protein drugs. We then discuss how current orally administered devices could solve the problem of tissue permeation and conclude that these physical methods stand to provide an efficacious set of alternatives to the classic hypodermic needle.

A phosphopantetheinyl transferase that is essential for mitochondrial fatty acid biosynthesis.

In this study we report the molecular genetic characterization of the Arabidopsis mitochondrial phosphopantetheinyl transferase (mtPPT), which catalyzes the phosphopantetheinylation and thus activation of mitochondrial acyl carrier protein (mtACP) of mitochondrial fatty acid synthase (mtFAS). This catalytic capability of the purified mtPPT protein (encoded by AT3G11470) was directly demonstrated in an in vitro assay that phosphopantetheinylated mature Arabidopsis apo-mtACP isoforms. The mitochondrial localization of the AT3G11470-encoded proteins was validated by the ability of their N-terminal 80-residue leader sequence to guide a chimeric GFP protein to this organelle. A T-DNA-tagged null mutant mtppt-1 allele shows an embryo-lethal phenotype, illustrating a crucial role of mtPPT for embryogenesis. Arabidopsis RNAi transgenic lines with reduced mtPPT expression display typical phenotypes associated with a deficiency in the mtFAS system, namely miniaturized plant morphology, slow growth, reduced lipoylation of mitochondrial proteins, and the hyperaccumulation of photorespiratory intermediates, glycine and glycolate. These morphological and metabolic alterations are reversed when these plants are grown in a non-photorespiratory condition (i.e. 1% CO2 atmosphere), demonstrating that they are a consequence of a deficiency in photorespiration due to the reduced lipoylation of the photorespiratory glycine decarboxylase.

Pro-oxidative synergic bactericidal effect of NO: kinetics and inhibition by nitroxides.

NO plays diverse roles in physiological and pathological processes, occasionally resulting in opposing effects, particularly in cells subjected to oxidative stress. NO mostly protects eukaryotes against oxidative injury, but was demonstrated to kill prokaryotes synergistically with H2O2. This could be a promising therapeutic avenue. However, recent conflicting findings were reported describing dramatic protective activity of NO. The previous studies of NO effects on prokaryotes applied a transient oxidative stress while arbitrarily checking the residual bacterial viability after 30 or 60min and ignoring the process kinetics. If NO-induced synergy and the oxidative stress are time-dependent, the elucidation of the cell killing kinetics is essential, particularly for survival curves exhibiting a "shoulder" sometimes reflecting sublethal damage as in the linear-quadratic survival models. We studied the kinetics of NO synergic effects on H2O2-induced killing of microbial pathogens. A synergic pro-oxidative activity toward gram-negative and gram-positive cells is demonstrated even at sub-µM/min flux of NO. For certain strains, the synergic effect progressively increased with the duration of cell exposure, and the linear-quadratic survival model best fit the observed survival data. In contrast to the failure of SOD to affect the bactericidal process, nitroxide SOD mimics abrogated the pro-oxidative synergy of NO/H2O2. These cell-permeative antioxidants, which hardly react with diamagnetic species and react neither with NO nor with H2O2, can detoxify redox-active transition metals and catalytically remove intracellular superoxide and nitrogen-derived reactive species such as (•)NO2 or peroxynitrite. The possible mechanism underlying the bactericidal NO synergy under oxidative stress and the potential therapeutic gain are discussed.