PharmaChk: a decade of research and development towards the first quantitative, field-based medicine quality screening instrument.

Biomedical and clinical scientists play a major role in translating observations into interventions - therapeutics, diagnostics, and medical devices including screening instruments - that improve the health of individuals and the public. This path from observation to intervention is often long and beset with obstacles, many unanticipated. We believe that sharing concrete, real-word examples of scientists in academia moving along this path will highlight some of the types of challenges one may face; here we focus on an intervention being developed by the Zaman lab at Boston University - PharmaChk, the first quantitative, field-based instrument for medicine quality screening. Specifically, this paper describes the first ten years of scientific and engineering work towards the development of this instrument. Launched from a need observed by medicine quality scientists, the development of PharmaChk has required the integration of multiple technologies enabled by knowledge and expertise across diverse fields of science and engineering, including chemistry, ultrasonics, fluid dynamics, optics, computer science, and automation. These efforts have been shaped and driven by the many challenges we have faced and the technical, commercial, and financial support that we have received from many collaborators. By sharing this example, we hope to inspire our colleagues to pursue their own paths to new healthcare solutions.

Corneal Stromal Filler Injection as a Novel Approach to Correct Presbyopia-An Ex Vivo Pilot Study.

Purpose: To evaluate the ex vivo feasibility of corneal stromal filler injection to create bifocality to correct presbyopia by flattening the central posterior corneal surface and thus increase refractive power. Methods: Femtosecond laser-assisted corneal stromal pockets of varying diameters close to the posterior corneal curvature were cut into rabbit eyes ex vivo. Subsequently, hyaluronic acid was injected to flatten the central posterior curvature. Refractive parameters were determined using perioperatively acquired three-dimensional optical coherence tomography (OCT) scans. Using micrometer-resolution OCT, corneal endothelial cell morphology and density were evaluated. Results: Following filler injection into the corneal stromal pockets, a fair volume-dependent increase of central refractive power up to 4 diopters (dpt) was observed. Unremarkable refractive changes of the peripheral posterior (3 mm, 0.20 ± 0.11 dpt; 2 mm, 0.11 ± 0.10 dpt) and the anterior corneal curvature (3 mm, 0.20 ± 0.34 dpt; 2 mm, 0.33 ± 0.31 dpt) occurred. Only negligible changes in astigmatism were observed. Different sizes of optical zones could be established. Furthermore, no alterations of corneal endothelial morphology or endothelial cell density (2831 ± 356 cells/mm2 vs. 2734 ± 292 cells/mm2; P = 0.552) due to the adjacent laser treatment were observed. Conclusions: The ex vivo investigations proved the principle of injecting a filler material into femtosecond laser-created corneal stromal pockets close to the posterior corneal curvature as an efficacious, individually adjustable, and novel approach to correct presbyopia without ablating corneal tissue. Translational Relevance: Due to the aging population worldwide, presbyopia is an increasing problem; thus, our study may encourage further exploration to extend the treatment spectrum of clinically used femtosecond laser systems to correct presbyopia.

Sensing, monitoring, and release of therapeutics: the translational journey of next generation bandages (Erratum).

This erratum corrects an error in "Sensing, monitoring, and release of therapeutics: the translational journey of next generation bandages," by Z. Li et al.

Special Section Guest Editorial: Translational Biophotonics.

This guest editorial introduces the special section on Translational Biophotonics.

Sensing, monitoring, and release of therapeutics: the translational journey of next generation bandages.

This article aims to be a progress report on the Sensing, Monitoring And Release of Therapeutics (SMART) bandage-one of the three technologies that received the inaugural SPIE Photonics West Translational Research Symposium Award in 2015. Invented and developed by Dr. Conor L. Evans and his research team at the Wellman Center for Photomedicine, Massachusetts General Hospital, the SMART bandage is a tool aiming to provide measurements of physiological parameters in the skin alongside the administration of therapeutics on-demand. Since the project began in 2012, the chemists, physicists, and biomedical engineers in the team have worked closely with partners from academia and industry to develop oxygen-sensing SMART bandage prototypes that are now in first-in-human clinical studies. This report gives perspectives on the genesis and translational journey of the technology with an emphasis on the challenges encountered, and the solutions innovated at each stage of development.

Special Section Guest Editorial: Translational Biophotonics.

This guest editorial introduces the Special Section on Translational Biophotonics.

Bridging medicine and biomedical technology: enhance translation of fundamental research to patient care.

The 'Bridging medicine and biomedical technology' special all-congress session took place for the first time at the OSA Biophotonics Congress: Optics in Life Sciences in 2017 (http://www.osa.org/enus/meetings/osa_meetings/optics_in_the_life_sciences/bridging_medicine_and_biomedical_technology_specia/). The purpose was to identify key challenges the biomedical scientists in academia have to overcome to translate their discoveries into clinical practice through robust collaborations with industry and discuss best practices to facilitate and accelerate the process. Our paper is intended to complement the session by providing a deeper insight into the concept behind the structure and the content we developed.

Biomedical optics centers: forty years of multidisciplinary clinical translation for improving human health.

Despite widespread government and public interest, there are significant barriers to translating basic science discoveries into clinical practice. Biophotonics and biomedical optics technologies can be used to overcome many of these hurdles, due, in part, to offering new portable, bedside, and accessible devices. The current JBO special issue highlights promising activities and examples of translational biophotonics from leading laboratories around the world. We identify common essential features of successful clinical translation by examining the origins and activities of three major international academic affiliated centers with beginnings traceable to the mid-late 1970s: The Wellman Center for Photomedicine (Mass General Hospital, USA), the Beckman Laser Institute and Medical Clinic (University of California, Irvine, USA), and the Medical Laser Center Lübeck at the University of Lübeck, Germany. Major factors driving the success of these programs include visionary founders and leadership, multidisciplinary research and training activities in light-based therapies and diagnostics, diverse funding portfolios, and a thriving entrepreneurial culture that tolerates risk. We provide a brief review of how these three programs emerged and highlight critical phases and lessons learned. Based on these observations, we identify pathways for encouraging the growth and formation of similar programs in order to more rapidly and effectively expand the impact of biophotonics and biomedical optics on human health.

Aerosol therapy in intensive and intermediate care units: prospective observation of 2808 critically ill patients.

PURPOSE: Unlike in the outpatient setting, delivery of aerosols to critically ill patients may be considered complex, particularly in ventilated patients, and benefits remain to be proven. Many factors influence aerosol delivery and recommendations exist, but little is known about knowledge translation into clinical practice. METHODS: Two-week cross-sectional study to assess the prevalence of aerosol therapy in 81 intensive and intermediate care units in 22 countries. All aerosols delivered to patients breathing spontaneously, ventilated invasively or noninvasively (NIV) were recorded, and drugs, devices, ventilator settings, circuit set-up, humidification and side effects were noted. RESULTS: A total of 9714 aerosols were administered to 678 of the 2808 admitted patients (24 %, CI95 22-26 %), whereas only 271 patients (10 %) were taking inhaled medication before admission. There were large variations among centers, from 0 to 57 %. Among intubated patients 22 % (n = 262) received aerosols, and 50 % (n = 149) of patients undergoing NIV, predominantly (75 %) inbetween NIV sessions. Bronchodilators (n = 7960) and corticosteroids (n = 1233) were the most frequently delivered drugs (88 % overall), predominantly but not exclusively (49 %) administered to patients with chronic airway disease. An anti-infectious drug was aerosolized 509 times (5 % of all aerosols) for nosocomial infections. Jet-nebulizers were the most frequently used device (56 %), followed by metered dose inhalers (23 %). Only 106 (<1 %) mild side effects were observed, despite frequent suboptimal set-ups such as an external gas supply of jet nebulizers for intubated patients. CONCLUSIONS: Aerosol therapy concerns every fourth critically ill patient and one-fifth of ventilated patients.

Non-invasive transdermal two-dimensional mapping of cutaneous oxygenation with a rapid-drying liquid bandage.

Oxygen plays an important role in wound healing, as it is essential to biological functions such as cell proliferation, immune responses and collagen synthesis. Poor oxygenation is directly associated with the development of chronic ischemic wounds, which affect more than 6 million people each year in the United States alone at an estimated cost of $25 billion. Knowledge of oxygenation status is also important in the management of burns and skin grafts, as well as in a wide range of skin conditions. Despite the importance of the clinical determination of tissue oxygenation, there is a lack of rapid, user-friendly and quantitative diagnostic tools that allow for non-disruptive, continuous monitoring of oxygen content across large areas of skin and wounds to guide care and therapeutic decisions. In this work, we describe a sensitive, colorimetric, oxygen-sensing paint-on bandage for two-dimensional mapping of tissue oxygenation in skin, burns, and skin grafts. By embedding both an oxygen-sensing porphyrin-dendrimer phosphor and a reference dye in a liquid bandage matrix, we have created a liquid bandage that can be painted onto the skin surface and dries into a thin film that adheres tightly to the skin or wound topology. When captured by a camera-based imaging device, the oxygen-dependent phosphorescence emission of the bandage can be used to quantify and map both the pO2 and oxygen consumption of the underlying tissue. In this proof-of-principle study, we first demonstrate our system on a rat ischemic limb model to show its capabilities in sensing tissue ischemia. It is then tested on both ex vivo and in vivo porcine burn models to monitor the progression of burn injuries. Lastly, the bandage is applied to an in vivo porcine graft model for monitoring the integration of full- and partial-thickness skin grafts.

Ventilator-integrated jet nebulization systems: tidal volume control and efficiency of synchronization.

BACKGROUND: Jet nebulizers constitute the aerosolization devices most frequently used during mechanical ventilation. Continuous nebulization can influence the delivered tidal volume (V(T)) and lead to significant medication loss during expiration. Ventilators thus provide integrated jet nebulization systems that are synchronized during inspiration and ostensibly keep VT constant. METHODS: This was a bench study of systems integrated in the Evita XL, Avea, Galileo, and G5 ventilators. The VT delivered with and without nebulization, the inspiratory synchronization of nebulization, and the aerosol deposition were measured with 2 locations of the nebulizer. RESULTS: Changes in V(T) with the nebulizer were below 20 mL and below 10% of set V(T) for all ventilators. Synchronization was good at the beginning of insufflation, but prolonged nebulization was observed with all ventilators at the end of insufflation, until up to 1 s during expiration: 5-80% of nebulization occurred during expiration with significant aerosol loss in the expiratory limb. Synchrony could be improved by (1) reducing gas compression/decompression phenomena proximal to the jet nebulizer and (2) increasing inspiratory time, which reduced the amount of nebulization occurring during expiration. Placing the nebulizer upstream in the inspiratory limb did not affect inspiratory synchrony but allowed reduction of the amount of aerosol lost in the expiratory limb. CONCLUSIONS: Jet nebulizer systems integrated in the tested ventilators are reliable in terms of V(T) control. Gas compression in tubing driving gas to the nebulizer delays synchronization and reduces nebulization yield if the nebulizer is placed close to the Y-piece. Increasing inspiratory time with no end-inspiratory pause reduces the expiratory loss of medication if placement of the nebulizer upstream in the inspiratory limb is not feasible.

Aerosol therapy during mechanical ventilation: an international survey.

PURPOSE: To describe the practice, knowledge and beliefs about aerosol therapy during mechanical ventilation in an international sample of physicians working in intensive care units (ICU). METHODS: A self-administered survey was emailed to physicians who worked regularly in ICUs. The physicians were identified from the databases of the European and French societies of intensive care medicine and the REVA network. RESULTS: Of the 1,192 responses (15 % response rate), 854 were analyzed. Of the respondents, who represented 611 departments in 70 countries, 99 % reported using aerosol therapy during mechanical ventilation (including non-invasive), 43 % exclusively used nebulizers and 55 % also used metered dose inhalers. Nebulization relied on jet, ultrasonic and vibrating mesh nebulizers (55 %, 44 % and 14 % of respondents, respectively). Bronchodilators and steroids were the most frequently delivered drugs, and 80 % of respondents had a positive opinion concerning nebulized colistin and 30 % reported the use of nebulized antibiotics at least every other month. During nebulization, ventilator settings were never changed by 77 % of respondents, 65 % reported placing a filter on the expiratory limb, and of these 28 % never changed it. Only 22 % of respondents using heated humidifiers reported turning them off during nebulization. Specific knowledge about droplet size and nebulization yield was poor. A majority of respondents (87 %) thought that ultrasonic nebulizers outperform jet nebulizers, while 69 % had no opinion concerning mesh nebulizers. CONCLUSIONS: Aerosol therapy during mechanical ventilation is used by over 95 % of intensivists, mostly for bronchodilator and steroid administration, but also frequently for antibiotics. The current scientific knowledge about optimal implementation seemed infrequently applied, suggesting the need for educational programs and research focusing on a better bench-to-bedside transfer of knowledge.

Bioequivalence of inhaled drugs: fundamentals, challenges and perspectives.

Interest in bioequivalence (BE) of inhaled drugs derives largely from the desire to offer generic substitutes to successful drug products. The complexity of aerosol dosage forms renders them difficult to mimic and raises questions regarding definitions of similarities and those properties that must be controlled to guarantee both the quality and the efficacy of the product. Despite a high level of enthusiasm to identify and control desirable properties there is no clear guidance, regulatory or scientific, for the variety of aerosol dosage forms, on practical measures of BE from which products can be developed. As more data on the pharmaceutical and clinical relevance of various techniques, as described in this review, become available, it is likely that a path to the demonstration of BE will become evident. In the meantime, debate on this topic will continue.

Delivery of helium­oxygen mixture during spontaneous breathing: evaluation of three high-concentration face masks.

PURPOSE: To evaluate the efficacy of delivering a mixture of helium and oxygen gas (He­O2) in spontaneous ventilation. Three high oxygen flow reservoir masks were tested: the Heliox21, specifically designed for helium; the Hi-Ox80 mask, with an inspiratory and an expiratory valve; and a standard high-concentration face mask. METHODS: This prospective randomized crossover study was performed in six healthy volunteers in a laboratory setting. Volunteers breathed a mixture of 78% He/22% O2 through each of the masks under two different breathing conditions (rest and hyperventilation: minute ventilation of 14.9 ± 6.1 and 26.7 ± 8.7 L min(−1), respectively) and four different He­O2 flow rates (7, 10, 12, and 15 L min(−1)). RESULTS: A nasopharyngeal catheter was used to estimate He pharyngeal concentration (Fp [He]) in the airways in order to determine the percentage of contamination with room air (% air cont) at end-expiration. Under all testing conditions, the Hi-Ox80 mask presented a significantly lower % air cont. During resting breathing pattern, a Fp [He] higher than 50% was achieved in 54% of the tests performed with the Hi-Ox80 mask compared to 29% for the Heliox21 mask and only 17% for the standard mask. At hyperventilation, a Fp [He] higher than 50% was achieved in 17% of the tests performed with the Hi-Ox mask compared to 4% for the other two masks. CONCLUSION: He­O2 administration via the usual high-concentration reservoir masks results in significant dilution by room air. The Hi-Ox80 mask minimized room air contamination and much more frequently achieved a pharyngeal He concentration higher than 50%.

The use of combined single photon emission computed tomography and X-ray computed tomography to assess the fate of inhaled aerosol.

BACKGROUND: Gamma camera imaging is widely used to assess pulmonary aerosol deposition. Conventional planar imaging provides limited information on its regional distribution. In this study, single photon emission computed tomography (SPECT) was used to describe deposition in three dimensions (3D) and combined with X-ray computed tomography (CT) to relate this to lung anatomy. Its performance was compared to planar imaging. METHODS: Ten SPECT/CT studies were performed on five healthy subjects following carefully controlled inhalation of radioaerosol from a nebulizer, using a variety of inhalation regimes. The 3D spatial distribution was assessed using a central-to-peripheral ratio (C/P) normalized to lung volume and for the right lung was compared to planar C/P analysis. The deposition by airway generation was calculated for each lung and the conducting airways deposition fraction compared to 24-h clearance. RESULTS: The 3D normalized C/P ratio correlated more closely with 24-h clearance than the 2D ratio for the right lung [coefficient of variation (COV), 9% compared to 15% p < 0.05]. Analysis of regional distribution was possible for both lungs in 3D but not in 2D due to overlap of the stomach on the left lung. The mean conducting airways deposition fraction from SPECT for both lungs was not significantly different from 24-h clearance (COV 18%). Both spatial and generational measures of central deposition were significantly higher for the left than for the right lung. CONCLUSIONS: Combined SPECT/CT enabled improved analysis of aerosol deposition from gamma camera imaging compared to planar imaging. 3D radionuclide imaging combined with anatomical information from CT and computer analysis is a useful approach for applications requiring regional information on deposition.

The effects of simulated airway diseases and affected flow distributions on aerosol deposition.

BACKGROUND: Experimental and theoretical aspects of targeted drug delivery have been addressed several times in this journal. Herein, a computational study of particle deposition patterns within healthy and diseased lungs has been performed, using a validated aerosol dosimetry model and a flow-resistance model. OBJECTIVE: To evaluate to what extent the uneven flow distributions produced by the physical manifestations of respiratory diseases affect the deposition patterns of inhaled aerosolized drugs. METHODS: Diseases were simulated by constrictions and blockages, which caused uneven flow distributions. Respiratory conditions of sedentary and pronounced activities, and of particle sizes ranging from 0.1 microm to 10 microm, were used as the basis for the calculated deposition patterns. RESULTS: Findings are presented that describe flow as a function of airway disease state (eg, flow redistribution). Data on the effects of lung morphologies, healthy and diseased, on compartmental (tracheobronchial and pulmonary) and local (airway generation) aerosol deposition are also given. By formulating these related factors, modeling results show that aerosolized drugs can be effectively targeted to appropriate sites within lungs to elicit positive therapeutic effects. CONCLUSIONS: We have addressed the complexities involved when taking into account interactive effects between diseased airway morphologies and redistributed air flows on the transport and deposition of inhaled particles. Our results demonstrate that respiratory diseases may influence the deposition of inhaled drugs used in their treatment in a systematic and predictable manner. We submit this work as a first step in establishing the use of mathematical modeling techniques as a sound scientific basis to relate airway diseases and aerosolized drug delivery protocols.