Maternal exposure to airborne particulate matter during pregnancy and lactation induces kidney injury in rat dams and their male offspring: the role of vitamin D in pregnancy and beyond.

BACKGROUND: Little is known about the transgenerational effects of maternal exposure to fine particulate matter (PM2.5) on offspring kidney health. This study investigated the effect of maternal administration of PM2.5 or PM2.5 with vitamin D during pregnancy and lactation on renal injury in rat dams and their offspring. METHODS: Nine pregnant Sprague-Dawley rats received oral administration of normal saline, airborne PM2.5, or PM2.5 with vitamin D from gestational day 11 to postpartum day 21. Kidneys of rat dams (n = 3 for each group) and their male offspring (n = 5 for each group) were taken for analysis on postpartum or postnatal day 21. RESULTS: Maternal PM2.5 exposure increased glomerular damage, tubulointerstitial injury, and cortical macrophage infiltration in both dams and pups; all increases were attenuated by vitamin D administration. In dam kidneys, PM2.5 increased the protein expression of vitamin D receptor (VDR), klotho, and tumor necrosis factor-α; vitamin D lessened these changes. The expressions of renin, nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor-kappa B (NF-κB) p50 decreased in rat dams exposed to PM2.5. In offspring kidneys, exposure to maternal PM2.5 reduced the expression of VDR, renin, angiotensin-converting enzyme (ACE), Nrf2, and NF-κB p50, but increased cytochrome P450 24A1 expression. Maternal vitamin D administration with PM2.5 enhanced VDR, ACE, and NF-κB p50 activities in pup kidneys. CONCLUSION: PM2.5 exposure during nephrogenesis may exert transgenerational renal impairment, and maternal vitamin D intake could attenuate PM2.5-induced kidney damage in mothers and their offspring.

Subchronic particulate matter exposure underlying polyhexamethylene guanidine phosphate-induced lung injury: Quantitative and qualitative evaluation with chest computed tomography.

Our study was to explore the effects of subchronic particulate matter (PM) exposure on lung injury induced by polyhexamethylene guanidine phosphate (PHMG-p) in a rat model. Specifically, we investigated pulmonary inflammation, fibrosis, and tumor formation using chest computed tomography (CT), and histopathologic examination. PHMG-p was administered intratracheally to 20 male rats. After an initial week of PHMG-p treatment, the experimental group (PM group) received intratracheal administration of PM suspension, while the control group received normal saline. This regimen was continued for 10 weeks to induce subchronic PM exposure. Chest CT scans were conducted on all rats, followed by the extraction of both lungs for histopathological analysis. All CT images underwent comprehensive quantitative and qualitative analyses. Pulmonary inflammation was markedly intensified in rats subjected to subchronic PM exposure in the PM group compared to those in the control. Similarly, lung fibrosis was more severe in the PM group as observed on both chest CT and histopathologic examination. Quantitative chest CT analysis revealed that the mean lesion volume was significantly greater in the PM group than in the control group. Although the incidence of bronchiolo-alveolar hyperplasia was higher in the PM group compared to the control group, this difference was not statistically significant. In summary, subchronic PM exposure exacerbated pulmonary inflammation and fibrosis underlying lung injury induced by PHMG-p.

Longitudinal long term follow up investigation on the carcinogenic impact of polyhexamethylene guanidine phosphate in rat models.

Polyhexamethylene guanidine phosphate (PHMG-p) is a major component in humidifier disinfectants, which cause life-threatening lung injuries. However, to our knowledge, no published studies have investigated associations between PHMG-p dose and lung damage severity with long-term follow-up. Therefore, we evaluated longitudinal dose-dependent changes in lung injuries using repeated chest computed tomography (CT). Rats were exposed to low (0.2 mg/kg, n = 10), intermediate (1.0 mg/kg, n = 10), and high (5.0 mg/kg, n = 10) doses of PHMG-p. All rats underwent repeated CT scans after 10 and 40 weeks following the first exposure. All CT images were quantitatively analyzed using commercial software. Inflammation/fibrosis and tumor counts underwent histopathological evaluation. In both radiological and histopathologic results, the lung damage severity increased as the PHMG-p dose increased. Moreover, the number, size, and malignancy of the lung tumors increased as the dose increased. Bronchiolar-alveolar hyperplasia developed in all groups. During follow-up, there was intergroup variation in bronchiolar-alveolar hyperplasia progression, although bronchiolar-alveolar adenomas or carcinomas usually increase in size over time. Thirty-three carcinomas were detected in the high-dose group in two rats. Overall, lung damage from PHMG-p and the number and malignancy of lung tumors were shown to be dose-dependent in a rat model using repeated chest CT scans during a long-term follow-up.

Multifunctional Intelligent Wearable Devices Using Logical Circuits of Monolithic Gold Nanowires.

Although multifunctional wearable devices have been widely investigated for healthcare systems, augmented/virtual realities, and telemedicines, there are few reports on multiple signal monitoring and logical signal processing by using one single nanomaterial without additional algorithms or rigid application-specific integrated circuit chips. Here, multifunctional intelligent wearable devices are developed using monolithically patterned gold nanowires for both signal monitoring and processing. Gold bulk and hollow nanowires show distinctive electrical properties with high chemical stability and high stretchability. In accordance, the monolithically patterned gold nanowires can be used to fabricate the robust interfaces, programmable sensors, on-demand heating systems, and strain-gated logical circuits. The stretchable sensors show high sensitivity for strain and temperature changes on the skin. Furthermore, the micro-wrinkle structures of gold nanowires exhibit the negative gauge factor, which can be used for strain-gated logical circuits. Taken together, this multifunctional intelligent wearable device would be harnessed as a promising platform for futuristic electronic and biomedical applications.

Particulate matter induces arrhythmia-like cardiotoxicity in zebrafish embryos by altering the expression levels of cardiac development- and ion channel-related genes.

Air pollution is a risk factor that increases cardiovascular morbidity and mortality. In this study, we investigated the cardiotoxicity of particulate matter (PM) exposure using a zebrafish embryo model. We found that PM exposure induced cardiotoxicity, such as arrhythmia, during cardiac development. PM exposure caused cardiotoxicity by altering the expression levels of cardiac development (T-box transcription factor 20, natriuretic peptide A, and GATA-binding protein 4)- and ion-channel (scn5lab, kcnq1, kcnh2a/b, and kcnh6a/b)-related genes. In conclusion, this study showed that PM induces the aberrant expression of cardiac development- and ion channel-related genes, leading to arrhythmia-like cardiotoxicity in zebrafish embryos. Our study provides a foundation for further research on the molecular and genetic mechanisms of cardiotoxicity induced by PM exposure.

Supramolecular Hydrogels for Precisely Controlled Antimicrobial Peptide Delivery for Diabetic Wound Healing.

Diabetic wound patients are often exposed to bacterial infections with delayed healing process due to hyperglycemia in the damaged skin tissue. Antimicrobial peptides (AMPs) have been investigated for the treatment of infection-induced diabetic wounds, but their low stability and toxicity have limited their further applications to diabetic chronic wound healing. Here, we developed a precisely controlled AMP-releasing injectable hydrogel platform, which could respond to infection-related materials of matrix metalloproteinases (MMPs) and reactive oxygen species (ROS). The injectable supramolecular hydrogel was prepared by the simple mixing of hyaluronic acid modified with cyclodextrin (HA-CD) and adamantane (Ad-HA). Ad-HA was conjugated with AMP via the cyclic peptide linker composed of MMP and ROS cleavable sequence (Ad-HA-AMP). Remarkably, only when the AMP-tethered hydrogel was exposed to both MMP and ROS simultaneously, AMP was released from the hydrogel, enabling the controlled release of AMP without causing cytotoxicity. In addition, we confirmed the enhanced serum stability of the Ad-HA-AMP conjugate. The antimicrobial activity of Ad-HA-AMP was maintained much longer than that of the native AMP. Finally, we could demonstrate the greatly improved wound-healing effect of AMP-tethered hydrogels with enhanced safety for the treatment of infection-induced diabetic chronic wounds. Taken together, we successfully demonstrated the feasibility of sHG-AMP for diabetic chronic wound healing.

Health Status and Activity Discomfort among Elderly Drivers: Reality of Health Awareness.

As the number of elderly drivers rapidly increases worldwide, interest in the dangers of driving is growing as accidents rise. The purpose of this study was to conduct a statistical analysis of the driving risk factors of elderly drivers. In this analysis, data from the government organization's open data were used for the secondary processing of 10,097 people. Of the 9990 respondents, 2168 were current drivers, 1552 were past drivers but were not driving presently, and 6270 did not have a driver's license; the participants were divided into groups accordingly. The elderly drivers who were current drivers had a better subjective health status than those who were not. Visual and hearing aids were used in the current driving group, and their depression symptoms reduced as they drove. The elderly who were current drivers experienced difficulties while driving in terms of decreased vision, hearing loss, reduced arm/leg reaction speed, decreased judgment of the road conditions such as signals and intersections, and a decreased sense of speed. The results suggest that elderly drivers are unaware of the medical conditions that can negatively affect their driving. This study contributes to the safety management of elderly drivers by understanding their mental and physical status.

Microalgae-Based Biohybrid Microrobot for Accelerated Diabetic Wound Healing.

A variety of wound healing platforms have been proposed to alleviate the hypoxic condition and/or to modulate the immune responses for the treatment of chronic wounds in diabetes. However, these platforms with the passive diffusion of therapeutic agents through the blood clot result in the relatively low delivery efficiency into the deep wound site. Here, a microalgae-based biohybrid microrobot for accelerated diabetic wound healing is developed. The biohybrid microrobot autonomously moves at velocity of 33.3 µm s-1 and generates oxygen for the alleviation of hypoxic condition. In addition, the microrobot efficiently bound with inflammatory chemokines of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) for modulating the immune responses. The enhanced penetration of microrobot is corroborated by measuring fibrin clots in biomimetic wound using microfluidic devices and the enhanced retention of microrobot is confirmed in the real wounded mouse skin tissue. After deposition on the chronic wound in diabetic mice without wound dressing, the wounds treated with microrobots are completely healed after 9 days with the significant decrease of inflammatory cytokines below 31% of the control level and the upregulated angiogenesis above 20 times of CD31+ cells. These results confirm the feasibility of microrobots as a next-generation platform for diabetic wound healing.

Hematotoxic Effect of Respiratory Exposure to PHMG-p and Its Integrated Genetic Analysis.

Polyhexamethylene guanidine phosphate (PHMG-p), the main ingredient of humidifier disinfectants, circulates systemically through the lungs; however, its toxicological assessment has been primarily limited to pulmonary disease. Herein, we investigated the possible abnormalities in hematopoietic function 20 weeks after intratracheal instillation of PHMG-p in a rat model. Notable abnormalities were found out in the peripheral blood cell count and bone marrow (BM) biopsy, while RNA sequencing of BM tissue revealed markedly altered gene expression. Furthermore, signaling involved in hematopoietic dysfunction was predicted by analyzing candidate genes through Ingenuity Pathway Analysis (IPA) program. Respiratory PHMG-p exposure significantly decreased monocyte and platelet (PLT) counts and total protein, while significantly increasing hemoglobin and hematocrit levels in peripheral blood. Histopathological analysis of the BM revealed a reduced number of megakaryocytes, with no significant differences in spleen and liver weight to body weight. Moreover, PHMG-p exposure significantly activated estrogen receptor signaling and RHOA signaling, and inhibited RHOGDI signaling. In IPA analysis, candidate genes were found to be strongly related to 'hematological system development and function' and 'hematological disease.' Accordingly, our results suggest that PHMG-p could affect hematopoiesis, which participates in monocyte differentiation and PLT production, and may induce hematologic diseases via the respiratory tract.

Wireless theranostic smart contact lens for monitoring and control of intraocular pressure in glaucoma.

Glaucoma is one of the irreversible ocular diseases that can cause vision loss in some serious cases. Although Triggerfish has been commercialized for monitoring intraocular pressure in glaucoma, there is no smart contact lens to monitor intraocular pressure and take appropriate drug treatment in response to the intraocular pressure levels. Here, we report a precisely integrated theranostic smart contact lens with a sensitive gold hollow nanowire based intraocular pressure sensor, a flexible drug delivery system, wireless power and communication systems and an application specific integrated circuit chip for both monitoring and control of intraocular pressure in glaucoma. The gold hollow nanowire based intraocular pressure sensor shows high ocular strain sensitivity, chemical stability and biocompatibility. Furthermore, the flexible drug delivery system can be used for on-demand delivery of timolol for intraocular pressure control. Taken together, the intraocular pressure levels can be successfully monitored and controlled by the theranostic smart contact lens in glaucoma induced rabbits. This theranostic smart contact lens would be harnessed as a futuristic personal healthcare platform for glaucoma and other ocular diseases.

Exposure to airborne particulate matter induces renal tubular cell injury in vitro: the role of vitamin D signaling and renin-angiotensin system.

Background: Exposure to air pollution can interfere with the vitamin D endocrine system. This study investigated the effects of airborne particulate matter (PM) on renal tubular cell injury in vitro and explored the underlying mechanisms. Methods: HK-2 human renal proximal tubule cells were treated with PM with or without 1,25(OH)2D3 analog, 19-Nor-1,25(OH)2D2 (paricalcitol, 10 nM) for 48 h. The dose- and time-dependent cytotoxicity of PM with or without paricalcitol was determined via cell counting kit-8 assay. Cellular oxidative stress was assessed using commercially available enzyme-linked immunosorbent assay kits. The protein expression of vitamin D receptor (VDR), cytochrome P450(CYP)27B1, CYP24A1, renin, angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AT1), nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor-kB (NF-kB), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 was determined. Results: PM exposure decreased HK-2 cell viability in a dose- and time-dependent manner. The activities of superoxide dismutase and malondialdehyde in HK-2 cells increased significantly in the group exposed to PM. PM exposure decreased VDR and Nrf2, while increasing CYP27B1, renin, ACE, AT1, NF-kB, TNF-α, and IL-6. The expression of VDR, CYP27B1, renin, ACE, AT1, and TNF-α was reversed by paricalcitol treatment. Paricalcitol also restored the cell viability of PM-exposed HK-2 cells. Conclusion: Our findings indicate that exposure to PM induces renal proximal tubular cell injury, concomitant with alteration of vitamin D endocrine system and renin angiotensin system. Vitamin D could attenuate renal tubular cell damage following PM exposure by suppressing the renin-angiotensin system and by partially inhibiting the inflammatory response.

Analysis of lung cancer-related genetic changes in long-term and low-dose polyhexamethylene guanidine phosphate (PHMG-p) treated human pulmonary alveolar epithelial cells.

BACKGROUND: Lung injury elicited by respiratory exposure to humidifier disinfectants (HDs) is known as HD-associated lung injury (HDLI). Current elucidation of the molecular mechanisms related to HDLI is mostly restricted to fibrotic and inflammatory lung diseases. In our previous report, we found that lung tumors were caused by intratracheal instillation of polyhexamethylene guanidine phosphate (PHMG-p) in a rat model. However, the lung cancer-related genetic changes concomitant with the development of these lung tumors have not yet been fully defined. We aimed to discover the effect of long-term exposure of PHMG-p on normal human lung alveolar cells. METHODS: We investigated whether PHMG-p could increase distorted homeostasis of oncogenes and tumor-suppressor genes, with long-term and low-dose treatment, in human pulmonary alveolar epithelial cells (HPAEpiCs). Total RNA sequencing was performed with cells continuously treated with PHMG-p and harvested after 35 days. RESULTS: After PHMG-p treatment, genes with transcriptional expression changes of more than 2.0-fold or less than 0.5-fold were identified. Within 10 days of exposure, 2 protein-coding and 5 non-coding genes were selected, whereas in the group treated for 27-35 days, 24 protein-coding and 5 non-coding genes were identified. Furthermore, in the long-term treatment group, 11 of the 15 upregulated genes and 9 of the 14 downregulated genes were reported as oncogenes and tumor suppressor genes in lung cancer, respectively. We also found that 10 genes of the selected 24 protein-coding genes were clinically significant in lung adenocarcinoma patients. CONCLUSIONS: Our findings demonstrate that long-term exposure of human pulmonary normal alveolar cells to low-dose PHMG-p caused genetic changes, mainly in lung cancer-associated genes, in a time-dependent manner.

Pulmonary fibrosis model using micro-CT analyzable human PSC-derived alveolar organoids containing alveolar macrophage-like cells.

Human lung organoids (hLOs) are useful for disease modelling and drug screening. However, a lack of immune cells in hLOs limits the recapitulation of in vivo cellular physiology. Here, we generated hLOs containing alveolar macrophage (AMφ)-like cells derived from pluripotent stem cells (PSC). To bridge hLOs with advanced human lung high-resolution X-ray computed tomography (CT), we acquired quantitative micro-CT images. Three hLO types were observed during differentiation. Among them, alveolar hLOs highly expressed not only lung epithelial cell markers but also AMφ-specific markers. Furthermore, CD68+ AMφ-like cells were spatially organized on the luminal epithelial surface of alveolar hLOs. Bleomycin-treated alveolar hLOs showed upregulated expression of fibrosis-related markers and extracellular matrix deposits in the alveolar sacs. Alveolar hLOs also showed structural alterations such as excessive tissue fraction under bleomycin treatment. Therefore, we suggest that micro-CT analyzable PSC-derived alveolar hLOs are a promising in vitro model to predict lung toxicity manifestations, including fibrosis.

Bioinspired urease-powered micromotor as an active oral drug delivery carrier in stomach.

Self-propelling micro- and nano-motors (MNMs) have been extensively investigated as an emerging oral drug delivery carrier for gastrointestinal (GI) tract diseases. However, the propulsion of current MNMs reported so far is mostly based on the redox reaction of metals (such as Zn and Mg) with severe propulsion gas generation, remaining non-degradable residue in the GI tract. Here, we develop a bioinspired enzyme-powered biopolymer micromotor mimicking the mucin penetrating behavior of Helicobacter pylori in the stomach. It converts urea to ammonia and the subsequent increase of pH induces local gel-sol transition of the mucin layer facilitating the penetration into the stomach tissue layer. The successful fabrication of micromotors is confirmed by high-resolution transmission electron microscopy, electron energy loss spectroscopy, dynamic light scattering analysis, zeta-potential analysis. In acidic condition, the immobilized urease can efficiently converted urea to ammonia, comparable with that of neutral condition because of the increase of surrounding pH during propulsion. After administration into the stomach, the micromotors show enhanced penetration and prolonged retention in the stomach for 24 h. Furthermore, histological analysis shows that the micromotors are cleared within 3 days without causing any toxicity in the GI tract. The enhanced penetration and retention of the micromotors as an active oral delivery carrier in the stomach would be successfully harnessed for the treatment of various GI tract diseases.

Supramolecular host-guest hyaluronic acid hydrogels enhance corneal wound healing through dynamic spatiotemporal effects.

Severe corneal wounds can lead to ulceration and scarring if not promptly and adequately treated. Hyaluronic acid (HA) has been investigated for the treatment of corneal wounds due to its remarkable biocompatibility, transparency and mucoadhesive properties. However, linear HA has low retention time on the cornea while many chemical moieties used to crosslink HA can cause toxicity, which limits their clinical ocular applications. Here, we used supramolecular non-covalent host-guest interactions between HA-cyclodextrin and HA-adamantane to form shear-thinning HA hydrogels and evaluated their impact on corneal wound healing. Supramolecular HA hydrogels facilitated adhesion and spreading of encapsulated human corneal epithelial cells ex vivo and improved corneal wound healing in vivo as an in situ-formed, acellular therapeutic membrane. The HA hydrogels were absorbed within the corneal stroma over time, modulated mesenchymal cornea stromal cell secretome production, reduced cellularity and inflammation of the anterior stroma, and significantly mitigated corneal edema compared to treatment with linear HA and untreated control eyes. Taken together, our results demonstrate supramolecular HA hydrogels as a promising and versatile biomaterial platform for corneal wound healing.

STAT3 maintains skin barrier integrity by modulating SPINK5 and KLK5 expression in keratinocytes.

Skin barrier dysfunction induces skin inflammation. Signal transducer and activator of transcription 3 (STAT3) is known to be involved in Th17-mediated immune responses and barrier integrity in the cornea and intestine; however, its role in the skin barrier remains largely unknown. In this study, we elucidated the potential role of STAT3 in the skin barrier and its effect on kallikrein-related peptidase 5 (KLK5) and serine protease inhibitor Kazal-type 5 (SPINK5) expression using a mouse model with keratinocyte-specific ablation of STAT3. Keratinocyte-specific loss of STAT3 induced a cutaneous inflammatory phenotype with pruritus and intense scratching behaviour in mice. Transcriptomic analysis revealed that the genes associated with impaired skin barrier function, including KLK5, were upregulated. The effect of STAT3 on KLK5 expression in keratinocytes was not only substantiated by the increase in KLK5 expression following treatment with STAT3 siRNA but also by its decreased expression following STAT3 overexpression. Overexpression and IL-17A-mediated stimulation of STAT3 increased the expression of SPINK5, which was blocked by STAT3 siRNA. These results suggest that the expression of SPINK5 and KLK5 in keratinocytes could be dependent on STAT3 and that STAT3 might play an essential role in the maintenance of skin barrier homeostasis.

Evaluation of the effect of filtered ultrafine particulate matter on bleomycin-induced lung fibrosis in a rat model using computed tomography, histopathologic analysis, and RNA sequencing.

We aimed to investigate the effect of chronic particulate matter (PM) exposure on bleomycin-induced lung fibrosis in a rat model using chest CT, histopathologic evaluation, and RNA-sequencing. A bleomycin solution was intratracheally administrated to 20 male rats. For chronic PM exposure, after four weeks of bleomycin treatment to induce lung fibrosis, PM suspension (experimental group) or normal saline (control group) was intratracheally administrated for 10 weeks. Chest CT was carried out in all rats, and then both lungs were extracted for histopathologic evaluation. One lobe from three rats in each group underwent RNA sequencing, and one lobe from five rats in each group was evaluated by western blotting. Inflammation and fibrosis scores in both chest CT and pathologic analysis were significantly more aggravated in rats with chronic PM exposure than in the control group. Several genes associated with inflammation and immunity were also upregulated with chronic PM exposure. Our study revealed that chronic PM exposure in a bleomycin-induced lung fibrosis rat model aggravated pulmonary fibrosis and inflammation, proven by chest CT, pathologic analysis, and RNA sequencing.

MTF1 Is Essential for the Expression of MT1B, MT1F, MT1G, and MT1H Induced by PHMG, but Not CMIT, in the Human Pulmonary Alveolar Epithelial Cells.

The inhalation of humidifier disinfectants (HDs) is linked to HD-associated lung injury (HDLI). Polyhexamethylene guanidine (PHMG) is significantly involved in HDLI, but the correlation between chloromethylisothiazolinone (CMIT) and HDLI remains ambiguous. Additionally, the differences in the molecular responses to PHMG and CMIT are poorly understood. In this study, RNA sequencing (RNA-seq) data showed that the expression levels of metallothionein-1 (MT1) isoforms, including MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X, were increased in human pulmonary alveolar epithelial cells (HPAEpiCs) that were treated with PHMG but not in those treated with CMIT. Moreover, upregulation of MT1B, MT1F, MT1G, and MT1H was observed only in PHMG-treated HPAEpiCs. The protein expression level of metal regulatory transcription factor 1 (MTF1), which binds to the promoters of MT1 isoforms, was increased in PHMG-treated HPAEpiCs but not in CMIT-treated HPAEpiCs. However, the expression of early growth response 1 (EGR1) and nuclear receptor superfamily 3, group C, member 1 (NR3C1), other transcriptional regulators involved in MT1 isomers, were increased regardless of treatment with PHMG or CMIT. These results suggest that MTF1 is an essential transcription factor for the induction of MT1B, MT1F, MT1G, and MT1H by PHMG but not by CMIT.

Evaluation of the long-term effect of polyhexamethylene guanidine phosphate in a rat lung model using conventional chest computed tomography with histopathologic analysis.

There have been no studies on the effects of polyhexamethylene guanidine phosphate (PHMG) after a long period of exposure in the rodent model. We aimed to evaluate long-term lung damage after PHMG exposure using conventional chest computed tomography (CT) and histopathologic analysis in a rat model. A PHMG solution was intratracheally administrated to 24 male rats. At 8, 26, and 52 weeks after PHMG instillation, conventional chest CT was performed in all rats and both lungs were extracted for histopathologic evaluation. At 52 weeks after PHMG instillation, four carcinomas had developed in three of the eight rats (37.5%). Bronchiolo-alveolar hyperplasia and adenoma were found in rats at 8, 26, and 52 weeks post-instillation. The number of bronchiolo-alveolar hyperplasia significantly increased over time (P-value for trend< 0.001). The severity of lung fibrosis and fibrosis scores significantly increased over time (P-values for trend = 0.002 and 0.023, respectively). Conventional chest CT analysis showed that bronchiectasis and linear density scores suggestive of fibrosis significantly increased over time (P-value for trend < 0.001). Our study revealed that one instillation of PHMG in a rat model resulted in lung carcinomas and progressive and irreversible fibrosis one year later based on conventional chest CT and histopathologic analysis. PHMG may be a lung carcinogen in the rat model.

Biomimetic Supramolecular Drug Delivery Hydrogels for Accelerated Skin Tissue Regeneration.

Skin tissue is regenerated by the combinational function of skin cells, extracellular matrix (ECM), and bioactive molecules. As an artificial ECM, supramolecular hydrogels exhibited outstanding capability to mimic the physical properties of ECM. However, the lack of biochemical function in supramolecular hydrogels has limited further tissue engineering applications. Here, we developed self-assembling supramolecular drug delivery hydrogels to mimic the skin tissue regeneration process. The supramolecular hydrogels were prepared to encapsulate fibroblasts by the host-guest interaction of cyclodextrin-modified gelatin (GE-CD) and adamantane-modified hyaluronate (Ad-HA) in conjugation with human growth hormone (hGH) for accelerated skin tissue regeneration. In vitro, GE-CD/Ad-HA-hGH hydrogels showed highly facilitated cell growth by the controlled hGH delivery. After a subcutaneous injection into the back of mice, IVIS imaging of bioengineered fibroblasts to express red fluorescence protein (RFP) revealed prolonged cell survival and proliferation in the supramolecular hydrogels for more than 21 days. We could also observe the improved skin tissue regeneration by the facilitated fibroblast proliferation with angiogenesis. Taken together, we could confirm the feasibility of biomimetic supramolecular drug delivery GE-CD/Ad-HA-hGH hydrogels for various tissue engineering applications.