Clinical pathway development to standardize pharmacological medication management of agitation in pediatric inpatient settings.

Objective: Acute agitation in pediatrics is commonly encountered in hospital settings, can contribute to significant physical and psychological distress, and management is highly varied in practice. As such, the development of a standardized pharmacologic guideline is paramount. We aimed to develop a novel clinical pathway (CP) for management of acute agitation for all hospitalized pediatric patients in Canada. Methods: Healthcare professionals in Canada with expertise in treating and managing pediatric agitation formed a working group and developed a CP through conducting a literature review, engaging key partners, and obtaining interdisciplinary consensus (iterative real-time discussions with content experts). Once developed, the preliminary CP was presented to additional internal and external partners via multiple grand rounds and a webinar; feedback from participants guided final CP revisions. Results: The working group created a pediatric inpatient CP to guide pharmacologic management of agitation and serve as an easy-to-use clinical and educational resource with three complementary sections including: 1) a treatment algorithm, 2) a quick reference medication chart, and 3) two supporting documents, which provide a general overview of non-pharmacologic strategies prior to CP implementation and an illustrative scenario to accompany the medication chart to ensure effective utilization. Conclusions: This is the first CP to standardize pharmacological treatment and management of acute agitation in children in inpatient settings in Canada. Although further research is warranted to assess implementation and support process improvement, the CP can be adapted by individual institutions to assist in prompt pharmacological management of pediatric agitation to potentially improve outcomes for patients, families, and healthcare professionals.

Objectif: L'agitation aiguë en pédiatrie survient couramment en milieu hospitalier, elle peut contribuer à une détresse physique et psychologique significative, et la prise en charge en est très variée dans la pratique. Ainsi, l'élaboration de lignes directrices pharmacologiques standardisées est essentielle. Nous cherchions à développer un nouveau parcours clinique (PC) de la prise en charge de l'agitation aiguë pour tous les patients pédiatriques hospitalisés au Canada. Méthodes: Les professionnels de la santé au Canada qui ont l'expertise du traitement et de la prise en charge de l'agitation pédiatrique ont formé un groupe de travail et développé un PC en menant une revue littéraire, en embauchant des partenaires cibles, et en obtenant un consensus interdisciplinaire (discussions itératives en temps réel avec des experts en contenu). Une fois développé, le PC préliminaire a été présenté à des partenaires internes et externes additionnels lors de multiples grandes rondes et à un webinaire; les commentaires des participants ont guidé les révisions finales du PC. Résultats: Le groupe de travail a créé un PC pour patient psychiatrique hospitalisé afin de guider la prise en charge pharmacologique de l'agitation et de servir de ressource clinique et éducative facile à utiliser munie de trois sections complémentaires notamment : 1) un algorithme de traitement, 2) un tableau des médicaments de référence, et 3) deux documents de soutien, qui offrent un aperçu général de stratégies non-pharmacologiques avant la mise en œuvre du PC et un scénario illustré pour accompagner le tableau des médicaments afin d'assurer une utilisation efficace. Conclusions: C'est le premier PC qui normalise le traitement pharmacologique et la prise en charge de l'agitation aiguë chez les enfants en milieu hospitalier au Canada. Bien que plus de recherche soit justifiée afin d'évaluer la mise en œuvre et de soutenir l'amélioration du processus, le PC peut être adapté par les institutions individuelles afin d'aider à une gestion pharmacologique rapide de l'agitation pédiatrique et de potentiellement aider à la gestion pharmacologique de l'agitation pédiatrique pour les patients, les familles et les professionnels de la santé.

Integrated care models for youth mental health: A systematic review and meta-analysis.

OBJECTIVES: To evaluate the effectiveness of integrated models of mental healthcare in enhancing clinical outcomes, quality of life, satisfaction with care and health service delivery outcomes in young people aged 12-25 years. A secondary objective was to identify common components of integrated mental health interventions. METHODS: A systematic review and meta-analysis of studies published 2001-2023 that assessed clinical or health service use outcomes of integrated care, relative to treatment as usual, for any mental health condition in 12-25 years old accessing community-based care. RESULTS: Of 11,444 titles identified, 15 studies met inclusion criteria and 6 studies were entered in the meta-analysis. Pooled effect size found integrated care was associated with a greater reduction in depressive symptoms relative to treatment as usual at 4-6 months (standardised mean difference = -0.260, 95% confidence interval = [-0.39, -0.13], p = 0.001). Of the seven studies reporting access or engagement, all reported higher rates of both in the intervention arm. The most frequent components of integration were use of a multidisciplinary team (13/15 studies), shared treatment planning (11/15) and workforce training in the model (14/15). CONCLUSIONS: Integrated models of mental healthcare are associated with a small, but significant, increase in effectiveness for depressive symptoms relative to treatment as usual. Given integrated care may increase access and engagement, future research should focus on assessing the impact of integrated care in a wider range of settings and outcomes, including clinical and functional recovery, satisfaction with care and system-level outcomes such as cost-effectiveness.

Characterizing the Use of Nabiximols (Δ9-Tetrahydrocannabinol-Cannabidiol) Buccal Spray in Pediatric Patients.

Background: Nabiximols is a commercially available cannabinoid buccal spray containing 2.7 mg Δ9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD) per spray. It is approved by Health Canada for adults with cancer pain or spasticity/neuropathic pain related to multiple sclerosis. Despite a lack of published studies regarding the use of nabiximols in children, it is being used in clinical practice for indications of pain, nausea/vomiting, and spasticity. Objective: To describe the use of nabiximols in children. Methods: This retrospective single-cohort study involved hospitalized pediatric patients who received at least 1 dose of nabiximols between January 2005 and August 2018. Descriptive statistical analyses were performed. Results: A total of 34 patients were included. The median age was 14 (range 0.6-18) years, and 11 patients (32%) were admitted under the oncology service. The median dose of nabiximols was 1.9 (range 0.3-10.8) sprays per day, and the median duration was 3.8 (range 1-213) days. Nabiximols was most commonly used to treat pain and nausea/vomiting and was most frequently prescribed by pain specialists. Perceived effectiveness was documented in 17 (50%) of the cases, with variable results being reported. The most commonly reported adverse effects were drowsiness and tachycardia (3/34, 9%, for each). Conclusion: In this study, nabiximols was prescribed for children in all age groups, for a variety of conditions, but most commonly for pain and nausea/vomiting. Further study, in the form of a large, prospective randomized controlled trial with clearly defined efficacy and safety end points for nausea/vomiting and/or pain, is needed to determine whether nabiximols is effective and safe in children.

Contexte: Le nabiximols est un vaporisateur buccal cannabinoïde disponible dans le commerce qui contient 2,7 mg de Δ9-tetrahydrocannabinol [THC] et 2,5 mg de cannabidiol [CBD] par vaporisation. Il est approuvé par Santé Canada pour les adultes souffrant de douleur cancéreuse ou de spasticité/douleur neuropathique liée à la sclérose en plaques. Malgré le manque d'études publiées concernant l'utilisation du nabiximols chez les enfants, il est utilisé en pratique clinique pour des indications de douleur, de nausées/vomissements et de spasticité. Objectif: Décrire l'utilisation du nabiximols chez les enfants. Méthodes: Cette étude rétrospective à cohorte unique comprenait des patients pédiatriques hospitalisés ayant reçu au moins 1 dose de nabiximols entre janvier 2005 et août 2018. Des analyses statistiques descriptives ont été réalisées. Résultats: Au total, 34 patients ont été inclus. L'âge médian était de 14 ans [intervalle de 0,6 à 18 ans] et 11 enfants (32 %) étaient des patients en oncologie. La dose médiane de nabiximols était de 1,9 [intervalle de 0,3 à 10,8] vaporisation par jour et la durée médiane était de 3,8 [intervalle de 1 à 213] jours. Le nabiximols était le plus couramment utilisé pour traiter la douleur et les nausées/vomissements et était le plus souvent prescrit par des spécialistes de la douleur. L'efficacité perçue a été documentée dans 17 (50 %) des cas, avec des résultats variables rapportés. Les effets indésirables le plus fréquemment rapportés étaient la somnolence et la tachycardie (3/34, 9 % chacun). Conclusion: Dans cette étude, le nabiximols a été prescrit à des enfants de toutes les tranches d'âge, pour diverses pathologies, mais le plus souvent pour des douleurs et des nausées/vomissements. Une étude plus approfondie, sous la forme d'un vaste essai contrôlé randomisé prospectif avec des paramètres d'efficacité et d'innocuité clairement définis pour les nausées/vomissements et/ou la douleur, est nécessaire pour déterminer si le nabiximols est efficace et sûr chez les enfants.

Establishing obstetrics-specific metrics and interventions for antimicrobial stewardship.

Background: To describe baseline antimicrobial stewardship (AMS) metrics and apply AMS interventions in an inpatient obstetrical population. Methods: From October 2018 to October 2019, our tertiary-care obstetrical center reviewed components of our AMS program, which included: (1) antimicrobial consumption data, (2) point prevalence surveys (PPS), and (3) prospective audit and feedback. We reviewed institutional data for antimicrobial consumption from the pharmacy database. Detailed point prevalence surveys were conducted for all antimicrobial prescriptions on two predefined dates each month. Daily audits and feedback assessed the appropriateness of all non-protocolized antimicrobials. Results: Our average antimicrobial length of therapy (LOT) was 12 days per 100 patient-days, where erythromycin (2.33), amoxicillin (2.28), and ampicillin (1.81) were the greatest contributors. Point prevalence surveys revealed that 28.8% of obstetrical inpatients were on antimicrobials, of which 11.2% were inappropriate. Protocolized antimicrobials were 62% less likely (p = 0.027) to be inappropriate. From 565 audited prescriptions, 110 (19.5%) resulted in feedback, where 90% of recommendations were accepted and implemented. The most common reasons for interventions include incorrect dosage, recommending a diagnostic test before continuing antimicrobials, and changing antimicrobials based on specific culture and sensitivity. Conclusions: Antimicrobial use in obstetrics is unique compared to general inpatients. We provide a baseline set of metrics for AMS at our obstetrical center intending to lay the groundwork for AMS programming in our discipline. Antimicrobial protocolization, as well as audit and feedback, are feasible interventions to improve antimicrobial prescribing patterns.

Historique: Décrire les mesures de gouvernance antimicrobienne (GAM) fondamentales et utiliser les interventions de GAM dans une population obstétricale hospitalisée. Méthodologie: D'octobre 2018 à octobre 2019, le centre obstétrical de soins tertiaires a révisé les éléments du programme de GAM, qui incluait : 1) les données sur la consommation d'antimicrobiens, 2) les enquêtes de prévalence ponctuelles (EPP) et 3) la vérification et la rétroaction prospectives. Les chercheurs ont examiné les données institutionnelles relatives à la consommation d'antimicrobiens dans la base de données de la pharmacie. Ils ont effectué des enquêtes de prévalence ponctuelles détaillées sur toutes les prescriptions d'antimicrobiens à deux dates déterminées chaque mois. Les vérifications et les rétroactions quotidiennes ont permis d'évaluer la pertinence de tous les antimicrobiens non protocolisés. Résultats: La durée du traitement antimicrobien moyen était de 12 jours sur 100 jours-patients, et l'érythromycine (2,33), l'amoxicilline (2,28) et l'ampicilline (1,81) étaient les plus utilisées. Les enquêtes de prévalence ponctuelles ont révélé que 28,8 % des patientes obstétricales hospitalisées prenaient des antimicrobiens, dont 11,2 % étaient inappropriés. Les antimicrobiens protocolisés étaient 62 % moins susceptibles d'être inappropriés (p = 0,027). Des 565 prescriptions vérifiées, 110 (19,5 %) ont donné lieu à des rétroactions, et 90 % des recommandations ont été acceptées et mises en œuvre. Les principales raisons d'intervenir incluaient une posologie inexacte, la recommandation d'un test diagnostique avant de poursuivre l'antimicrobien, ainsi que le changement d'antimicrobien d'après la culture et sensibilité spécifiques. Conclusions: L'utilisation d'antimicrobiens est unique en obstétrique par rapport aux autres patients hospitalisés. Les chercheurs fournissent la série de mesures de GAM de référence utilisée à leur centre obstétrical pour jeter les bases de la programmation de la GAM dans la discipline. La protocolisation des antimicrobiens, de même que la vérification et la rétroaction, est une intervention faisable pour améliorer les profils de prescription d'antimicrobiens.

Sodium-glucose cotransporter 2 inhibitors for treatment of diabetes mellitus after kidney transplantation.

INTRODUCTION: Diabetes mellitus in kidney transplant recipients is a risk factor for cardiovascular events and premature death. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are increasingly used in nontransplant populations to improve diabetes control and cardiovascular and renal benefits. Limited literature exists regarding the safety and efficacy of these agents in renal transplant recipients. METHODS: We retrospectively reviewed all kidney transplant recipients within our health system who were prescribed a SGLT2i after transplantation for diabetes. The safety, tolerability, and effectiveness of SGLT2i were analyzed. RESULTS: Thirty-nine kidney transplant recipients were initiated on SGLT2i therapy, twenty-seven of which remained on therapy for at least 1 year. Ten (25%) patients experienced an adverse event while on a SGLT2i, with urinary tract infections (UTI) being the most common. Seventeen patients (43%) discontinued the SGLT2i at the time of chart review, most commonly due to cost and kidney function decline. The median [IQR] hemoglobin A1c (HbA1c) at SGLT2i initiation of 8.4% [7.8-9.2] decreased to 7.5% [6.8-8.0%] after 3 months and 7.5% [6.5-7.9] after 12 months. No meaningful change in kidney function or tacrolimus exposure was observed. CONCLUSION: SGLT2i may be a safe and effective treatment for diabetes in kidney transplant recipients. Cost is a barrier to SGLT2i therapy, and UTIs were the most frequently encountered adverse events in this cohort. More studies are needed to understand the safety profile and determine the effect of SGLT2i on diabetes-related comorbidities among kidney transplant recipients.

Incidence and Predictive Factors Associated with Beta-Lactam Neurotoxicity in the Critically Ill: A Retrospective Cohort Study.

BACKGROUND: Beta-lactam neurotoxicity is a relatively uncommon yet clinically significant adverse effect in critically ill patients. This study sought to define the incidence of neurotoxicity, derive a prediction model for beta-lactam neurotoxicity, and then validate the model in an independent cohort of critically ill adults. METHODS: This retrospective cohort study evaluated critically ill patients treated with ≥ 48 h of cefepime, piperacillin/tazobactam, or meropenem. Two separate cohorts were created: a derivation cohort and a validation cohort. Patients were screened for beta-lactam neurotoxicity by using search terms and diagnosis codes, followed by clinical adjudication using a standardized adverse event scoring tool. Multivariable regression models and least absolute shrinkage and selection operator were used to identify surrogates for neurotoxicity and develop a multivariable prediction model. RESULTS: The overall incidence of beta-lactam neurotoxicity was 2.6% (n/N = 34/1323) in the derivation cohort and 2.1% in the validation cohort (n/N = 16/767). The final multivariable neurotoxicity assessment tool included weight, Charlson comorbidity score, age, and estimated creatinine clearance as predictors of neurotoxicity. Incidence of neurotoxicity reached 4% in those with a body mass index more than 30 kg/m2. Use of the candidate variables in the neurotoxicity assessment tool suggested that a score more than 35 would identify a patient at high risk for neurotoxicity with 75% sensitivity and 54% specificity. CONCLUSIONS: In this single center cohort of critically ill patients, beta-lactam neurotoxicity was demonstrated less frequently than previously reported. We identified obesity as a novel risk factor for the development of neurotoxicity. The prediction model needs to be further refined before it can be used in clinical practice as a tool to avoid drug-related harm.

Assessment of gender differences in letters of recommendation for pharmacy residency applicants.

PURPOSE: Letters of recommendation (LORs) are highly regarded components of pharmacy residency applications, as they provide insight into an applicant's character and capabilities. In other medical fields, differences in language have been reported for letters written for female and male applicants; however, data on gender differences in LORs for pharmacy residency applications are currently lacking. METHODS: LORs for applicants to our institution's postgraduate year 1 pharmacy residency program for the 2019-2020 academic year were extracted and processed by a natural language processing service. Words within 18 categories were identified and counted for each LOR. Total word count was also compared. RESULTS: Of the 473 LORs included for analysis, 320 (67.7%) were written for female applicants and 153 (32.3%) were written for male applicants. Approximately two-thirds of all writers were women for both female and male applicants. In comparing letters for women and men, there was a statistically significant difference in the percentage of LORs that contained terms in categories described as gendered, solitary/reserved, and desire. There was no statistically significant difference in total word count or in the presence of words in other categories such as grindstone, standout, agentic, or communal. When controlling for grade point average, writer gender, duration that the writer knew the applicant, and the writer's professional position, there were no changes to the statistical findings. CONCLUSION: Letters written for female and male applicants were largely similar with regard to length and word categories utilized. While no clear gender bias was found when evaluating pharmacy residency LORs, writers must continue to assess their implicit biases and how those biases might affect a candidate's application.

Unsupervised Deep Visual-Inertial Odometry with Online Error Correction for RGB-D Imagery.

While numerous deep approaches to the problem of vision-aided localization have been recently proposed, systems operating in the real world will undoubtedly experience novel sensory states previously unseen even under the most prodigious training regimens. We address the localization problem with online error correction (OEC) modules that are trained to correct a vision-aided localization network's mistakes. We demonstrate the generalizability of the OEC modules and describe our unsupervised deep neural network approach to the fusion of RGB-D imagery with inertial measurements for absolute trajectory estimation. Our network, dubbed the Visual-Inertial-Odometry Learner (VIOLearner), learns to perform visual-inertial odometry (VIO) without inertial measurement unit (IMU) intrinsic parameters or the extrinsic calibration between an IMU and camera. The network learns to integrate IMU measurements and generate hypothesis trajectories which are then corrected online according to the Jacobians of scaled image projection errors with respect to spatial grids of pixel coordinates. We evaluate our network against state-of-the-art (SoA) VIO, visual odometry (VO), and visual simultaneous localization and mapping (VSLAM) approaches on the KITTI Odometry dataset as well as a micro aerial vehicle (MAV) dataset that we collected in the AirSim simulation environment. We demonstrate better than SoA translational localization performance against comparable SoA approaches on our evaluation sequences.

Using Contact Forces and Robot Arm Accelerations to Automatically Rate Surgeon Skill at Peg Transfer.

OBJECTIVE: Most trainees begin learning robotic minimally invasive surgery by performing inanimate practice tasks with clinical robots such as the Intuitive Surgical da Vinci. Expert surgeons are commonly asked to evaluate these performances using standardized five-point rating scales, but doing such ratings is time consuming, tedious, and somewhat subjective. This paper presents an automatic skill evaluation system that analyzes only the contact force with the task materials, the broad-bandwidth accelerations of the robotic instruments and camera, and the task completion time. METHODS: We recruited N = 38 participants of varying skill in robotic surgery to perform three trials of peg transfer with a da Vinci Standard robot instrumented with our Smart Task Board. After calibration, three individuals rated these trials on five domains of the Global Evaluative Assessment of Robotic Skill (GEARS) structured assessment tool, providing ground-truth labels for regression and classification machine learning algorithms that predict GEARS scores based on the recorded force, acceleration, and time signals. RESULTS: Both machine learning approaches produced scores on the reserved testing sets that were in good to excellent agreement with the human raters, even when the force information was not considered. Furthermore, regression predicted GEARS scores more accurately and efficiently than classification. CONCLUSION: A surgeon's skill at robotic peg transfer can be reliably rated via regression using features gathered from force, acceleration, and time sensors external to the robot. SIGNIFICANCE: We expect improved trainee learning as a result of providing these automatic skill ratings during inanimate task practice on a surgical robot.

Imaging colon cancer development in mice: IL-6 deficiency prevents adenoma in azoxymethane-treated Smad3 knockouts.

The development of colorectal cancer in the azoxymethane-induced mouse model can be observed by using a miniaturized optical coherence tomography (OCT) imaging system. This system is uniquely capable of tracking disease development over time, allowing for the monitoring of morphological changes in the distal colon due to tumor development and the presence of lymphoid aggregates. By using genetically engineered mouse models deficient in Interleukin 6 (IL-6) and Smad family member 3 (Smad3), the role of inflammation on tumor development and the immune system can be elucidated. Smad3 knockout mice develop inflammatory response, wasting, and colitis associated cancer while deficiency of proinflammatory cytokine IL-6 confers resistance to tumorigenesis. We present pilot data showing that the Smad3 knockout group had the highest tumor burden, highest spleen weight, and lowest thymus weight. The IL-6 deficiency in Smad3 knockout mice prevented tumor development, splenomegaly, and thymic atrophy. This finding suggests that agents that inhibit IL-6 (e.g. anti-IL-6 antibody, non-steroidal anti-inflammatory drugs [NSAIDs], etc.) could be used as novel therapeutic agents to prevent disease progression and increase the efficacy of anti-cancer agents. OCT can also be useful for initiating early therapy and assessing the benefit of combination therapy targeting inflammation.

Dual optical modality endoscopic imaging of cancer development in the mouse colon.

BACKGROUND AND OBJECTIVE: We utilize a miniature, dual-modality endoscope that combines fluorescence-based surface magnifying chromoendoscopy (SMC) and optical coherence tomography (OCT) to follow the anatomical changes that occur during adenoma development in the mouse colon. MATERIALS AND METHODS: Twenty-five mice were treated with the carcinogen azoxymethane (AOM) to induce tumor development in the distal colon, or were treated with saline as control, and were imaged over six months. OCT detects adenoma number with high sensitivity and specificity and can measure lesion size. In methylene blue-lavaged colons, SMC detects changes in the colonic crypts. SMC images of control mouse colons exhibit reticulated patterns of crypts of equal size, forming either a dot or honeycomb pattern. RESULTS: Images of AOM-treated colons show mild crypt irregularities even in grossly normal tissue. Images of small to medium adenoma exhibit larger crypts, more intense signal, and irregular spacing whereas those of large adenoma have heterogeneous, intense signal and loss of crypt structure. CONCLUSIONS: The combination of OCT and SMC permits the detection of neoplastic events from the earliest stages of crypt irregularities before gross tissue changes are noted, through to measuring the growth of protruding adenoma.

In vivo molecular mapping of the tumor microenvironment in an azoxymethane-treated mouse model of colon carcinogenesis.

BACKGROUND AND OBJECTIVE: Development of miniaturized imaging systems with molecular probes enables examination of molecular changes leading to initiation and progression of colorectal cancer in an azoxymethane (AOM)-induced mouse model of the disease. Through improved and novel studies of animal disease models, more effective diagnostic and treatment strategies may be developed for clinical translation. We introduce use of a miniaturized multimodal endoscope with lavage-delivered fluorescent probes to examine dynamic microenvironment changes in an AOM-treated mouse model. STUDY DESIGN/MATERIALS AND METHODS: The endoscope is equipped with optical coherence tomography (OCT) and laser induced fluorescence (LIF) imaging modalities. It is used with Cy5.5-conjugated antibodies to create time-resolved molecular maps of colon carcinogenesis. We monitored in vivo changes in molecular expression over a five month period for four biomarkers: epithelial growth factor receptor (EGFR), transferrin receptor (TfR), transforming growth factor beta 1 (TGFß1), and chemokine (C-X-C motif) receptor 2 (CXCR2). In vivo OCT and LIF images were compared over multiple time points to correlate increases in biomarker expression with adenoma development. RESULTS: This system is uniquely capable of tracking in vivo changes in molecular expression over time. Increased expression of the biomarker panel corresponded to sites of disease and offered predictive utility in highlighting sites of disease prior to detectable structural changes. Biomarker expression also tended to increase with higher tumor burden and growth rate in the colon. CONCLUSION: We can use miniaturized dual modality endoscopes with fluorescent probes to study the tumor microenvironment in developmental animal models of cancer and supplement findings from biopsy and tissue harvesting.

Investigating trends in discharge destinations and impact on allied health service utilization in an Australian hospice.

Australia's population is aging and increasing. The palliative care needs of the population are also increasing in parallel, with more patients being referred to services for a broad range of reasons including symptom management, psychosocial support, and end-of-life care. Our study looks at how this manifests at on inpatient hospice in Melbourne, Australia, in terms of discharge destinations and allied health service utilization. We noted a trend in more discharges to residential care facilities, which appeared more likely for those patients who were admitted for assessment or had longer length of stay. Patients who were admitted for assessment also appeared in overall to utilize allied health services more than those admitted for end-of-life care. This information will help tailor resource allocation according to the current trends.

Light-activated content release from liposomes.

Successful integration of diagnostic and therapeutic actions at the level of individual cells requires new materials that combine biological compatibility with functional versatility. This review focuses on the development of liposome-based functional materials, where payload release is activated by light. Methods of sensitizing liposomes to light have progressed from the use of organic molecular moieties to the use of metallic plasmon resonant structures. This development has facilitated application of near infrared light for activation, which is preferred for its deep penetration and low phototoxicity in biological tissues. Presented mechanisms of light-activated liposomal content release enable precise in vitro manipulation of minute amounts of reagents, but their use in clinical diagnostic and therapeutic applications will require demonstration of safety and efficacy.

NIR-activated content release from plasmon resonant liposomes for probing single-cell responses.

Technological limitations have prevented the interrogation and manipulation of cellular activity in response to bioactive molecules within model and living systems that is required for the development of diagnostic and treatment modalities for diseases, such as cancer. In this work, we demonstrate that gold-coated liposomes are capable of encapsulation and on-demand release of signaling molecules with a spatial and temporal resolution leading to activation of individual cells. As a model system, we used cells modified to overexpress a certain G-protein coupled receptor, the CCK2 receptor, and achieved its activation in a single cell via the localized release of its agonist. This content release was triggered by illumination of the liposomes at wavelengths corresponding to the plasmon resonance of the gold coating. The use of plasmon resonant liposomes may enable on-demand release of a broad range of molecules using biologically safe near-infrared light and without molecule chemical modification. In combination with the spectral tunability of plasmon resonant coating, this technology may allow for multiplexed interrogation of complex and diverse signaling pathways in model or living tissues with unprecedented spatial and temporal control.

Molecular catch and release: controlled delivery using optical trapping with light-responsive liposomes.

Gold-coated liposomes are maneuvered using an optical trap to achieve precise delivery of encapsulated molecular cargo. Movement and payload release from these plasmon resonant nanocapsules are independently controlled using a pulsed trapping beam. This technology enables in vitro delivery of a payload to a selected cell and may be applied to the interrogation of individual cells within their biological microenvironment.

Wavelength-Selective Light-Induced Release from Plasmon Resonant Liposomes.

Biodegradable, spectrally tunable plasmon resonant nanocapsules are created via the deposition of gold onto the surface of 100 nm diameter thermosensitive liposomes. These nanocapsules demonstrate selective release of encapsulated contents upon illumination with light of a wavelength matching their distinct resonance bands, which correspond to 760 and 1210 nm in this study. Spectrally selective release is accomplished through the use of multiple, low intensity laser pulses delivered over a period of less than four minutes, ensuring that illumination affects only the gold-coated liposomes and avoids heating the surrounding media. The result of this illumination scheme for selective release using multiple wavelengths of light is a biologically safe mechanism for realizing drug delivery, microfluidic, and sensor applications.

Plasmon resonant gold-coated liposomes for spectrally controlled content release.

We recently demonstrated that liposome-supported plasmon resonant gold nanoshells are degradable into components of a size compatible with renal clearance, potentially enabling their use as multifunctional agents in applications in nanomedicine, including imaging, diagnostics, therapy, and drug delivery (Troutman et al., Adv. Mater. 2008, 20, 2604-2608). When illuminated with laser light at the wavelength matching their plasmon resonance band, gold-coated liposomes rapidly release their encapsulated substances, which can include therapeutic and diagnostic agents. The present research demonstrates that release of encapsulated agents from gold-coated liposomes can be spectrally controlled by varying the location of the plasmon resonance band; this spectral tuning is accomplished by varying the concentration of gold deposited on the surface of liposomes. Furthermore, the amount of laser energy required for release is qualitatively explained using the concept of thermal confinement (Jacques, Appl. Opt. 1993, 32(3), 2447-2454). Overlapping thermal confinement zones can be avoided by minimizing the laser pulse width, resulting in lower energy requirements for liposomal content release and less global heating of the sample. Control of heating is especially important in drug delivery applications, where it enables spatial and spectral control of delivery and prevents thermal damage to tissue.