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Principal Investigator: P. Worth Longest
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
Fiscal Year: 2024
Award: $733,241
Funding agency: National Heart Lung and Blood Institute
Hypoxemia and acute respiratory distress syndrome (ARDS) arising from direct lung injury are associated
with a dysfunctional lung surfactant system; however, large clinical trials of surfactant replacement therapy have
been unsuccessful in this population. The method employed for surfactant delivery in these unsuccessful trials
was liquid bolus instillation, which often requires intubation, use of large liquid volumes (~500 ml) and subsequent
mechanical ventilation often late in the progression of ARDS. A successful dry powder aerosol synthetic lung
surfactant product would provide the advantages of early surfactant administration, potentially before the need
for invasive mechanical ventilation (IMV), rapid and high dose delivery to the alveolar region, and improved
efficacy compared with instillation based on preliminary animal model findings.
The goal of this study is the preclinical development of a synthetic lung surfactant dry powder aerosol product
(including delivery strategies, formulations and devices) for administration to adults experiencing hypoxemia or
ARDS from direct lung injury in a rapid, efficient and safe manner while receiving different modes of ventilation
support. Aerosol delivery strategies and devices will be developed and optimized for high efficiency aerosol
administration during high flow nasal cannula (HFNC) therapy, noninvasive positive pressure ventilation (NPPV)
and IMV. High efficiency aerosol administration will be enabled by a combination of a highly dispersible spray-
dried powder formulation, a new positive-pressure dry powder inhaler (DPI), and an excipient enhanced growth
(EEG) aerosol delivery strategy. Aerosolization performance and lung delivery efficiency will be established and
optimized using a concurrent approach of realistic in vitro experiments and computational fluid dynamics (CFD)
modeling. Animal experiments (in rats) will be implemented to determine appropriate levels of the surfactant
protein analog and assess in vivo efficacy of the lead synthetic surfactant dry powder formulation in different
models of direct lung injury. Specific aims of the project are as follows:
Specific Aim 1. Develop a synthetic surfactant dry powder aerosol formulation that can be easily dispersed into
a small particle aerosol with low air volume, exhibit hygroscopic growth, and enable stable product storage.
Specific Aim 2. Develop and optimize surfactant delivery strategies and devices that enable safe, efficient and
rapid aerosol administration to adults receiving HFNC, NPPV or IMV.
Specific Aim 3. Test the efficacy of the lead synthetic surfactant formulations administered with an animal-
version of the air-jet DPI using in vivo rat models of acute lung injury (ALI) mimicking bacterial infection, viral
infection, and ventilator-induced lung injury.
Outcomes and Impact. The proposed advances directly address multiple previous failure mechanisms related
to instilled and aerosolized (liquid and powder) surfactants and are necessary to make aerosolized surfactant
therapy for hypoxemia or ARDS with the option of early treatment a viable option in adults.
Terms: <0-11 years old><21+ years old><ARDS><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adolescent><Adolescent Youth><Adult><Adult ARDS><Adult Human><Adult RDS><Adult Respiratory Distress Syndrome><Aerosols><Affect><Air><Air Pressure><Alveolar><Alveolus><Animal Experiments><Animal Model><Animal Models and Related Studies><Animals><Area><Bacterial Infections><Bacterial Pneumonia><Blood leukocyte><Bolus><Bolus Infusion><Bronchial Alveolus><Bruise><COVID-19><CV-19><Cannulas><Chemical Surfactants><Chest><Child><Child Youth><Childhood><Children (0-21)><Clinical><Clinical Trials><Common Rat Strains><Contusions><Coronavirus Infectious Disease 2019><Cyclicity><Da Nang Lung><Development><Device or Instrument Development><Devices><Dose><Dropsy><Dryness><Early treatment><Edema><Epithelial Cells><Excipients><Exhalation><Exhaling><Exhibits><Failure><Formulation><Gases><Generalized Growth><Goals><Growth><Hour><Human><Hydrops><Hygroscopicity><Hypoxemia><In Vitro><Infant><Inflammation><Inhalation><Inhalators><Inhaler><Inhaling><Intubation><Lead><Leukocytes><Leukocytes Reticuloendothelial System><Liquid substance><Lung><Lung Alveolar Epithelia><Lung Respiratory System><Lung Surfactant><Lung damage><Marrow leukocyte><Mechanical ventilation><Methods><Modeling><Modern Man><Nasal><Nasal Passages Nose><Near Drowning><Nebulizer><Nose><Outcome><Patients><Pb element><Performance><Periodicity><Phosphatides><Phospholipids><Population><Powder dose form><Powders><Procedures><Production><Proteins><Pulmonary Surfactant-Associated Protein B><Pulmonary Surfactant-Associated Protein SP-B><Pulmonary Surfactants><Radiation Injuries><Rat><Rats Mammals><Rattus><Respiratory Expiration><Respiratory System, Nose, Nasal Passages><Rhythmicity><SP-B Protein><SP-B peptide><Shock Lung><Social Support System><Source><Stiff lung><Stress><Support System><Surfactant Protein SP-B><Surfactant protein B><Surfactant therapy><System><Technology><Thorace><Thoracic><Thorax><Tissue Growth><Treatment Cost><Ventilator-induced lung injury><Viral Diseases><Viral Pneumonia><Virus Diseases><Wettability><White Blood Cells><White Cell><adulthood><aerosolized><alveolar epithelium><analog><animal experiment><aspirate><bacteria infection><bacteria pneumonia><bacterial disease><comparable efficacy><comparative efficacy><compare efficacy><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cost><cytokine><design><designing><developmental><device development><early therapy><efficacy testing><experience><experiment><experimental animal><experimental animals><experimental research><experimental study><experiments><fluid><fungal pneumonia><heavy metal Pb><heavy metal lead><hypoxemic><improved><in vivo><instrument development><irradiation injury><juvenile><juvenile human><kids><liquid><lung injury><mechanical respiratory assist><mechanically ventilated><meter><model of animal><mortality><nebulization><nebulize><ontogeny><particle><pediatric><peptide analog><pharmacologic><pre-clinical development><preclinical development><pressure><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><surfactant><surfactant deficiency><surfactant production><surfactant replacement therapy><synthetic surfactant><therapeutic surfactants><ventilation><ventilation induced lung injury><ventilator associated lung injury><viral infection><virus infection><virus-induced disease><wet lung><white blood cell><white blood corpuscle><youngster>