CXCL12 defines lung endothelial heterogeneity and promotes distal vascular growth.

There is a growing amount of data uncovering the cellular diversity of the pulmonary circulation and mechanisms governing vascular repair after injury. However, the molecular and cellular mechanisms contributing to the morphogenesis and growth of the pulmonary vasculature during embryonic development are less clear. Importantly, deficits in vascular development lead to significant pediatric lung diseases, indicating a need to uncover fetal programs promoting vascular growth. To address this, we used a transgenic mouse reporter for expression of Cxcl12, an arterial endothelial hallmark gene, and performed single-cell RNA sequencing on isolated Cxcl12-DsRed+ endothelium to assess cellular heterogeneity within pulmonary endothelium. Combining cell annotation with gene ontology and histological analysis allowed us to segregate the developing artery endothelium into functionally and spatially distinct subpopulations. Expression of Cxcl12 is highest in the distal arterial endothelial subpopulation, a compartment enriched in genes for vascular development. Accordingly, disruption of CXCL12 signaling led to, not only abnormal branching, but also distal vascular hypoplasia. These data provide evidence for arterial endothelial functional heterogeneity and reveal conserved signaling mechanisms essential for pulmonary vascular development.

Insights into the Pathogenesis of Pulmonary Fibrosis from Genetic Diseases.

Pulmonary fibrosis is a disease process associated with significant morbidity and mortality, with limited therapeutic options owing to an incomplete understanding of the underlying pathophysiology. Mechanisms driving the fibrotic cascade have been elucidated through studies of rare and common variants in surfactant-related and telomere-related genes in familial and sporadic forms of pulmonary fibrosis, as well as in multisystem Mendelian genetic disorders that present with pulmonary fibrosis. In this translational review, we outline insights into the pathophysiology of pulmonary fibrosis derived from genetic forms of the disease, with a focus on model systems, shared cellular and molecular mechanisms, and potential targets for therapy.

Engineering of magnetic nanoparticles as magnetic particle imaging tracers.

Magnetic particle imaging (MPI) has recently emerged as a promising non-invasive imaging technique because of its signal linearly propotional to the tracer mass, ability to generate positive contrast, low tissue background, unlimited tissue penetration depth, and lack of ionizing radiation. The sensitivity and resolution of MPI are highly dependent on the properties of magnetic nanoparticles (MNPs), and extensive research efforts have been focused on the design and synthesis of tracers. This review examines parameters that dictate the performance of MNPs, including size, shape, composition, surface property, crystallinity, the surrounding environment, and aggregation state to provide guidance for engineering MPI tracers with better performance. Finally, we discuss applications of MPI imaging and its challenges and perspectives in clinical translation.

A systematic review of trends in all-cause mortality among people with diabetes.

AIMS/HYPOTHESIS: We examined all-cause mortality trends in people with diabetes and compared them with trends among people without diabetes. METHODS: MEDLINE, EMBASE and CINAHL databases were searched for observational studies published from 1980 to 2019 reporting all-cause mortality rates across ≥2 time periods in people with diabetes. Mortality trends were examined by ethnicity, age and sex within comparable calendar periods. RESULTS: Of 30,295 abstracts screened, 35 studies were included, providing data on 69 separate ethnic-specific or sex-specific populations with diabetes since 1970. Overall, 43% (3/7), 53% (10/19) and 74% (32/43) of the populations studied had decreasing trends in all-cause mortality rates in people with diabetes in 1970-1989, 1990-1999 and 2000-2016, respectively. In 1990-1999 and 2000-2016, mortality rates declined in 75% (9/12) and 78% (28/36) of predominantly Europid populations, and in 14% (1/7) and 57% (4/7) of non-Europid populations, respectively. In 2000-2016, mortality rates declined in 33% (4/12), 65% (11/17), 88% (7/8) and 76% (16/21) of populations aged <40, 40-54, 55-69 and ≥70 years, respectively. Among the 33 populations with separate mortality data for those with and without diabetes, 60% (6/10) of the populations with diabetes in 1990-1999 and 58% (11/19) in 2000-2016 had an annual reduction in mortality rates that was similar to or greater than in those without diabetes. CONCLUSIONS/INTERPRETATION: All-cause mortality has declined in the majority of predominantly Europid populations with diabetes since 2000, and the magnitude of annual mortality reduction matched or exceeded that observed in people without diabetes in nearly 60% of populations. Patterns of diabetes mortality remain uncertain in younger age groups and non-Europid populations. REGISTRATION: PROSPERO registration ID CRD42019095974. Graphical abstract.

Porous Silicon Nanoparticles Embedded in Poly(lactic-co-glycolic acid) Nanofiber Scaffolds Deliver Neurotrophic Payloads to Enhance Neuronal Growth.

Scaffolds made from biocompatible polymers provide physical cues to direct the extension of neurites and to encourage repair of damaged nerves. The inclusion of neurotrophic payloads in these scaffolds can substantially enhance regrowth and repair processes. However, many promising neurotrophic candidates are excluded from this approach due to incompatibilities with the polymer or with the polymer processing conditions. This work provides one solution to this problem by incorporating porous silicon nanoparticles (pSiNPs) that are pre-loaded with the therapeutic into a polymer scaffold during fabrication. The nanoparticle-drug-polymer hybrids are prepared in the form of oriented poly(lactic-co-glycolic acid) nanofiber scaffolds. We test three different therapeutic payloads: bpV(HOpic), a small molecule inhibitor of phosphatase and tensin homolog (PTEN); an RNA aptamer specific to tropomyosin-related kinase receptor type B (TrkB); and the protein nerve growth factor (NGF). Each therapeutic is loaded using a loading chemistry that is optimized to slow the rate of release of these water-soluble payloads. The drug-loaded pSiNP-nanofiber hybrids release approximately half of their TrkB aptamer, bpV(HOpic), or NGF payload in 2, 10, and >40 days, respectively. The nanofiber hybrids increase neurite extension relative to drug-free control nanofibers in a dorsal root ganglion explant assay.

Moldless Printing of Silicone Lenses With Embedded Nanostructured Optical Filters.

Optical lenses are among the oldest technological innovations (3000 years ago) and they have enabled a multitude of applications in healthcare and in our daily lives. The primary function of optical lenses has changed little over time; they serve mainly as a light-collection (e.g. reflected, transmitted, diffracted) element, and the wavelength and/or intensity of the collected light is usually manipulated by coupling with various external optical filter elements or coatings. This generally results in losses associated with multiple interfacial reflections, and increases the complexity of design and construction. In this work we introduce a change in this paradigm, by integrating both light-shaping and image magnification into a single lens element using a moldless procedure that takes advantage of the physical and optical properties of mesoporous silicon (PSi) photonic crystal nanostructures. Casting of a liquid poly(dimethyl) siloxane (PDMS) pre-polymer solution onto a PSi film generates a droplet with contact angle that is readily controlled by the silicon nanostructure, and adhesion of the cured polymer to the PSi photonic crystal allows preparation of lightweight (10 mg) freestanding lenses (4.7 mm focal length) with an embedded optical component (e.g. optical rugate filter, resonant cavity, distributed Bragg reflector). Our fabrication process shows excellent reliability (yield 95%) and low cost and we expect our lens to have implications in a wide range of applications. As a proof-of-concept, using a single monolithic lens/filter element we demonstrate: fluorescence imaging of isolated human cancer cells with rejection of the blue excitation light, through a lens that is self-adhered to a commercial smartphone; shaping the emission spectrum of a white light emitting diode (LED) to tune the color from red through blue; and selection of a narrow wavelength band (bandwidth 5 nm) from a fluorescent molecular probe.

A transcriptomic signature of tertiary Gleason 5 predicts worse clinicopathological outcome.

OBJECTIVE: To investigate the genomic features of tertiary pattern 5 (TP5) on radical prostatectomy specimens in an effort to explain the poor clinical outcomes associated with this disease subtype. PATIENTS AND METHODS: Data from 159 men with Gleason Grade Group (GGG) 3 or 4 were considered. All patients had Decipher diagnostic testing with transcript profiles and single-channel array normalisation (SCAN)-normalised expression of coding genes. The relationship between Decipher and TP5 was investigated by linear and binary logistic regressions. A differential transcriptomic analysis between patients with and without TP5 was performed. The prognostic role of these genes on progression-free survival (PFS) and overall survival (OS) was evaluated using The Cancer Genome Atlas. RESULTS: In all, 52/159 (33%) patients had GGG 3-4 with TP5 disease. TP5 was associated with a higher Decipher score (ß 0.07, 95% confidence interval [CI] 0.02-0.13; P = 0.04) and higher likelihood of falling within the intermediate- or high-risk categories (odds ratio 3.34, 95% CI 1.34-8.35; P = 0.01). Analysis of microarray data revealed an 18-gene signature that was differentially expressed in patients with TP5; 13 genes were over- and five under-expressed in the TP5 cohort. The overexpression of cyclin dependent kinase inhibitor 2B (CDKN2B), polo-like kinase 1 (PLK1), or cell division cycle 20 (CDC20) was associated with worse PFS. The group harbouring overexpression of at least one gene had a 5-year PFS rate of 50% vs 74% in the group without overexpression (P < 0.001). CONCLUSIONS: Our studies have elucidated unique genomic features of TP5, whilst confirming previous clinical findings that patients harbouring TP5 tend to have worse prognosis. This is the first RNA-based study to investigate the molecular diversity of TP5 and the first correlating CDKN2B to poorer prognosis in patients with prostate cancer.

Late-life suicide in Asian people living in New Zealand: a qualitative study of coronial records.

BACKGROUND: There has been no previous study examining the phenomenon of suicide in older Asians in New Zealand. The aim of this study was to identify common factors and gain a better understanding of late-life suicide in Asian people living in New Zealand. METHODS: New Zealand Coronial Services provided records of all closed cases of late-life suicides (age ≥ 65 years) between July 2007 and December 2012. Out of the total of 225 cases, 15 were recorded as being of Asian ethnicity. These cases were reviewed in their entirety using a qualitative thematic analysis approach. RESULTS: Eight Asian men and seven Asian women completed suicide during this period. The majority (93%) lived with their families, and 80% were found by family after having completed suicide at home. Three main themes emerged from the thematic analysis: (i) suicide occurring in the context of a family; (ii) declining physical health; and (iii) a violent method of suicide. The role of the family has not been previously identified in other studies of late-life suicide in New Zealand. CONCLUSIONS: Further research is needed to identify ways Asian families can access culturally appropriate and accessible support and mental health services for their older members at risk of suicide. There is also a need for developing post-suicide interventions specifically for Asian families. The findings of this study have added to the growing evidence of declining physical health acting as a drive for late-life suicide.

Non-ignorable missingness in logistic regression.

Nonresponses and missing data are common in observational studies. Ignoring or inadequately handling missing data may lead to biased parameter estimation, incorrect standard errors and, as a consequence, incorrect statistical inference and conclusions. We present a strategy for modelling non-ignorable missingness where the probability of nonresponse depends on the outcome. Using a simple case of logistic regression, we quantify the bias in regression estimates and show the observed likelihood is non-identifiable under non-ignorable missing data mechanism. We then adopt a selection model factorisation of the joint distribution as the basis for a sensitivity analysis to study changes in estimated parameters and the robustness of study conclusions against different assumptions. A Bayesian framework for model estimation is used as it provides a flexible approach for incorporating different missing data assumptions and conducting sensitivity analysis. Using simulated data, we explore the performance of the Bayesian selection model in correcting for bias in a logistic regression. We then implement our strategy using survey data from the 45 and Up Study to investigate factors associated with worsening health from the baseline to follow-up survey. Our findings have practical implications for the use of the 45 and Up Study data to answer important research questions relating to health and quality-of-life. Copyright © 2017 John Wiley & Sons, Ltd.

On the impact of nonresponse in logistic regression: application to the 45 and Up study.

BACKGROUND: In longitudinal studies, nonresponse to follow-up surveys poses a major threat to validity, interpretability and generalisation of results. The problem of nonresponse is further complicated by the possibility that nonresponse may depend on the outcome of interest. We identified sociodemographic, general health and wellbeing characteristics associated with nonresponse to the follow-up questionnaire and assessed the extent and effect of nonresponse on statistical inference in a large-scale population cohort study. METHODS: We obtained the data from the baseline and first wave of the follow-up survey of the 45 and Up Study. Of those who were invited to participate in the follow-up survey, 65.2% responded. Logistic regression model was used to identify baseline characteristics associated with follow-up response. A Bayesian selection model approach with sensitivity analysis was implemented to model nonignorable nonresponse. RESULTS: Characteristics associated with a higher likelihood of responding to the follow-up survey include female gender, age categories 55-74, high educational qualification, married/de facto, worked part or partially or fully retired and higher household income. Parameter estimates and conclusions are generally consistent across different assumptions on the missing data mechanism. However, we observed some sensitivity for variables that are strong predictors for both the outcome and nonresponse. CONCLUSIONS: Results indicated in the context of the binary outcome under study, nonresponse did not result in substantial bias and did not alter the interpretation of results in general. Conclusions were still largely robust under nonignorable missing data mechanism. Use of a Bayesian selection model is recommended as a useful strategy for assessing potential sensitivity of results to missing data.

Two-Dimensional Nanoparticle Cluster Formation in Supercritical Fluid CO2.

Supercritical fluid carbon dioxide (sc-CO2) is capable of depositing nanoparticles in small structures of silicon substrates because of its gas-like penetration, liquid-like solvation abilities, and near-zero surface tension. In nanometer-sized shallow wells on silicon surface, formation of two-dimensional (2D) monolayer metal nanoparticle (NP) clusters can be achieved using the sc-CO2 deposition method. Nanoparticles tend to fill nanostructured holes first, and then, if sufficient nanoparticles are available, they will continue to cover the flat areas nearby, unless defects or other surface imperfections are available. In addition, SEM images of two-dimensional gold (Au) nanoparticle clusters formed on a flat silicon surface with two to a dozen or more of the nanoparticles are provided to illustrate the patterns of nanoparticle cluster formation in sc-CO2.

Genetics and immunotherapy: using the genetic landscape of gliomas to inform management strategies.

Recent work in genetics has identified essential driver mutations in gliomas and has profoundly changed our understanding of tumorigenesis. New insights into the molecular basis of glioma has informed the development of therapies demonstrating considerable potential, including immunotherapeutic approaches such as peptide and dendritic cell vaccines against EGFRvIII. However, the selective targeting of one component of a dysregulated pathway may be inadequate for a durable clinical response, given the intratumoral heterogeneity of glioblastoma (GBM) and hypermutated profiles displayed by tumor recurrences. Immune checkpoint blockade with anti-cytotoxic T lymphocyte antigen-4 (CTLA) and anti-programmed cell death 1 (PD-1) have demonstrated encouraging results in clinical trials with other solid tumors, and recent data suggest that this type of therapy may be particularly useful for tumors with high mutational burdens. Although the survival for patients with GBM has remains grim, the use of immunotherapy may finally change patient outcomes.

Transient liver function abnormality following treatment with rabbit antithymocyte globulin for nonmyeloablative hematopoetic stem cell transplant: two case reports.

Rabbit antithymocyte globulin (rATG) is increasingly used in nonmyeloablative hematopoetic stem cell transplant (HSCT). Elevated liver function tests (LFTs) have been reported for antithymocyte globulin in the treatment of aplastic anemia, but not when used in a conditioning regimen for HSCT. We describe two cases of patients receiving a conditioning regimen for HSCT containing rATG who developed a transient, severe transaminase elevation. In the first case, a 66-year-old woman with a history of acute myeloid leukemia received the first dose of rATG and the patient's transaminases were found to be extremely elevated within a few hours. The aspartate transaminase (AST) peaked at 1286 U/L and alanine transaminase (ALT) peaked at 991 U/L and both resolved within a week. In the second case, a 72-year-old woman with a history of non-Hodgkin lymphoma received the first dose of rATG and the AST and ALT were found to be 1212 U/L and 689 U/L, respectively, 1 h after finishing the infusion. Like the previous case, the transaminase elevation resolved within a week. LFT abnormalities induced by rATG during conditioning therapy for HSCT may be transient and have a rapid onset after the first dose, but quickly subside without any complications or sequelae. It is important to follow the LFTs closely, as well as monitor for any signs and symptoms of acute liver failure.

Shunt revision requirements after posthemorrhagic hydrocephalus of prematurity: insight into the time course of shunt dependency.

PURPOSE: Intraventricular hemorrhage (IVH) is a common affliction of preterm infants and often results in posthemorrhagic hydrocephalus (PHH). These patients typically eventually require permanent CSF diversion and are presumed to be indefinitely shunt-dependent. To date, however, there has been no study of long-term shunt revision requirements in patients with PHH. METHODS: We analyzed retrospectively collected data for 89 preterm patients diagnosed with grades III and IV IVH and PHH at our institution from 1998 to 2011. RESULTS: Sixty-nine out of 89 patients (77.5%) underwent ventriculoperitoneal (VP) shunt placement, and 33 (47.8%) required at least one shunt revision and 18 (26.1%) required multiple revisions. The mean ± standard deviation follow-up time for shunted patients was 5.0 ± 3.3 years. The majority of early failures were due to proximal catheter malfunction, while later failures were mostly due to distal catheter problems. There was a significant difference in the number of patients requiring revisions in the first 3 years following initial VP shunt insertion compared after 3 years, with 28 revisions versus 10 (p < 0.004). In 8 out of 10 patients who underwent shunt revisions after 3 years, evidence of obstructive hydrocephalus was found on imaging either in the form of an isolated fourth ventricular cyst or aqueductal stenosis. CONCLUSIONS: Our results suggest that in a distinct subset of patients with PHH, obstructive hydrocephalus may develop, resulting in long-term dependence on CSF diversion. Further study on the factors associated with long-term shunt dependence and revision requirements within the PHH group is warranted.

Contralateral approach for clipping of bilateral anterior circulation aneurysms.

Patients with bilateral anterior circulation aneurysms present a management challenge. These lesions may be treated in a staged manner or alternatively, for select patients, a contralateral approach may be utilized to treat bilateral aneurysms with a single surgery. In this narrated video illustration, we present the case of a 57-year-old woman with incidentally discovered bilateral aneurysms (left middle cerebral artery [MCA], left anterior choroidal artery and right MCA). A contralateral approach through a left pterional craniotomy was performed formicrosurgical clipping of all three aneurysms. The techniques of pterional craniotomy, contralateral approach, microsurgical clipping and intraoperative angiography are reviewed. The authors are grateful to Wuyang Yang, M.D. for his assistance. The video can be found here: http://youtu.be/MlPIu3hQZkg.

Association Between First-time Neurologic Events and Metronidazole Treatment: A Case-time Control Study.

PURPOSE: Metronidazole, a widely used antimicrobial medication, has been linked to neurologic adverse drug reactions. This study investigates the association between metronidazole use and first-time neurologic events. METHODS: We conducted a case-time-control study using data from the Danish National Patient Register and the National Prescription Register in years 2013 to 2021. Patients with a first-time diagnosis of encephalopathy, cerebellar dysfunction, or peripheral neuropathy were included. Conditional logistic regression analyses were performed to estimate the risk of neurologic events associated with metronidazole use. FINDINGS: Out of 476,066 first-time metronidazole prescriptions, the 100-day cumulative incidence of peripheral neuropathy was 0.016%, and 0.002% for cerebellar dysfunction or encephalopathy. In the case-time control study, we identified 17,667 persons with a first-time neurologic event and were included for the analysis. The estimated odds ratio for the combined neurologic events was 0.98 (95% CI, 0.59-1.64, P = 0.95) with no statistically significant association across different subgroups and time windows. IMPLICATIONS: Our findings suggest that metronidazole-induced neurologic events may be rarer than previously described, and we did not find any consistent or statistically significant association between metronidazole exposure. Nonetheless, clinicians should remain vigilant to potential neurologic risks in patients receiving metronidazole, to ensure its safe and effective use.

Identifying people living with cystic fibrosis in the Danish National Patient Registry: A validation study.

BACKGROUND: The Danish National Patient Registry (DNPR) serves as a valuable resource for scientific research. However, to ensure accurate results in cystic fibrosis (CF) studies that rely on DNPR data, a robust case-identification algorithm is essential. This study aimed to develop and validate algorithms for the reliable identification of CF patients in the DNPR. METHODS: Using the Danish Cystic Fibrosis Registry (DCFR) as a reference, accuracy measures including sensitivity and positive predictive value (PPV) for case-finding algorithms deployed in the DNPR were calculated. Algorithms were based on minimum number of hospital contacts with CF as the main diagnosis and minimum number of days between first and last contact. RESULTS: An algorithm requiring a minimum of one hospital contact with CF as the main diagnosis yielded a sensitivity of 96.1 % (95 % CI: 94.2 %; 97.4 %) and a PPV of 84.9 % (82.0 %; 87.4 %). The highest-performing algorithm required minimum 2 hospital visits and a minimum of 182 days between the first and the last contact and yielded a sensitivity of 95.9 % (95 % CI: 94.1 %; 97.2 %), PPV of 91.0 % (95 % CI: 88.6 %; 93.0 %) and a cohort entry delay of 3.2 months at the 75th percentile (95th percentile: 38.7 months). CONCLUSIONS: The DNPR captures individuals with CF with high sensitivity and is a valuable resource for CF-research. PPV was improved at a minimal cost of sensitivity by increasing requirements of minimum number of hospital contacts and days between first and last contact. Cohort entry delay increased with number of required hospital contacts.

Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome pulmonary fibrosis.

Hermansky-Pudlak syndrome (HPS) is a genetic disorder of endosomal protein trafficking associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. We utilized HPS mouse models and human lung tissue to investigate mechanisms of AT2 cell dysfunction driving fibrotic remodeling in HPS. Starting at 8 weeks of age, HPS mice exhibited progressive loss of AT2 cell numbers. HPS AT2 cell was impaired ex vivo and in vivo. Incorporating AT2 cell lineage tracing in HPS mice, we observed aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and p53 activation. Lineage tracing and modeling studies demonstrated that HPS AT2 cells were primed to persist in a Krt8+ reprogrammed transitional state, mediated by p53 activity. Intrinsic AT2 progenitor cell dysfunction and p53 pathway dysregulation are novel mechanisms of disease in HPS-related pulmonary fibrosis, with the potential for early targeted intervention before the onset of fibrotic lung disease.

Education, employment, and income among people living with cystic fibrosis across three decades - A matched cohort study using Danish health registries.

BACKGROUND: Past and ongoing advancements in cystic fibrosis (CF) care warrant long-term analysis of the societal impact of the condition. This study aims to evaluate changes in key socioeconomic factors across three decades among people living with CF (pwCF), compared with both the general population and an early-onset chronic disease population. METHODS: This nationwide, registry-based, matched cohort study included all pwCF ≥ 18 years in Denmark in the years 1990, 2000, 2010, and 2018. Each person living with CF was matched to five individuals in the general population and five individuals living with type 1 diabetes or juvenile arthritis based on age, sex, and municipality. RESULTS: The Danish adult CF population increased nearly fourfold from 88 in 1990 to 331 in 2018, and mean age increased by ten years. The educational level of pwCF was similar to the two comparator cohorts, while pwCF were less often in employment and more often permanently outside the labor force. Personal and household income levels of the CF cohort were higher than those of the comparator cohorts. CONCLUSIONS: The disadvantage in employment for pwCF remained, but, over time, the societal profiles of the one-year CF cohorts increasingly converged with those of the comparator cohorts, indicative of improved clinical management, extended life expectancy, and the supportive role of the Danish welfare system in reducing health inequalities. Further research should be done to evaluate the effects of the newly introduced modulator therapies on employment, considering the broader societal impact and impact on quality of life.

Porous silicon embedded in a thermoresponsive hydrogel for intranasal delivery of lipophilic drugs to treat rhinosinusitis.

Intranasal delivery is the most preferred route of drug administration for treatment of a range of nasal conditions including chronic rhinosinusitis (CRS), caused by an infection and inflammation of the nasal mucosa. However, localised delivery of lipophilic drugs for persistent nasal inflammation is a challenge especially with traditional topical nasal sprays. In this study, a composite thermoresponsive hydrogel is developed and tuned to obtain desired rheological and physiochemical properties suitable for intranasal administration of lipophilic drugs. The composite is comprised of drug-loaded porous silicon (pSi) particles embedded in a poloxamer 407 (P407) hydrogel matrix. Mometasone Furoate (MF), a lipophilic corticosteroid (log P of 4.11), is used as the drug, which is loaded onto pSi particles at a loading capacity of 28 wt%. The MF-loaded pSi particles (MF@pSi) are incorporated into the P407-based thermoresponsive hydrogel (HG) matrix to form the composite hydrogel (MF@pSi-HG) with a final drug content ranging between 0.1 wt% to 0.5 wt%. Rheomechanical studies indicate that the MF@pSi component exerts a minimal impact on gelation temperature or strength of the hydrogel host. The in-vitro release of the MF payload from MF@pSi-HG shows a pronounced increase in the amount of drug released over 8 h (4.5 to 21-fold) in comparison to controls consisting of pure MF incorporated in hydrogel (MF@HG), indicating an improvement in kinetic solubility of MF upon loading into pSi. Ex-vivo toxicity studies conducted on human nasal mucosal tissue show no adverse effect from exposure to either pure HG or the MF@pSi-HG formulation, even at the highest drug content of 0.5 wt%. Experiments on human nasal mucosal tissue show the MF@pSi-HG formulation deposits a quantity of MF into the tissues within 8 h that is >19 times greater than the MF@HG control (194 ± 7 µg of MF/g of tissue vs. <10 µg of MF/g of tissue, respectively).