ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Jiali Wang,Chong Wang,Qiao Wang,Zhuohao Zhang,Hui Wang,Shengyi Wang,Zhangcai Chi,Luoran Shang,Wuqing Wang,Yilai Shu
Local drug delivery has become an effective method for disease therapy in fine organs including ears, eyes, and noses. However, the multiple anatomical and physiological barriers, unique clearance pathways, and sensitive perceptions characterizing these organs have led to suboptimal drug delivery efficiency. Here, we developed dexamethasone sodium phosphate-encapsulated gelatin methacryloyl (Dexsp@GelMA) microgel particles, with finely tunable size through well-designed microfluidics, as otic drug delivery vehicles for hearing loss therapy. The release kinetics, encapsulation efficiency, drug loading efficiency, and cytotoxicity of the GelMA microgels with different degrees of methacryloyl substitution were comprehensively studied to optimize the microgel formulation. Compared to bulk hydrogels, Dexsp@GelMA microgels of certain sizes hardly cause air-conducted hearing loss in vivo. Besides, strong adhesion of the microgels on the round window membrane was demonstrated. Moreover, the Dexsp@GelMA microgels, via intratympanic administration, could ameliorate acoustic noise-induced hearing loss and attenuate hair cell loss and synaptic ribbons damage more effectively than Dexsp alone. Our results strongly support the adhesive and intricate microfluidic-derived GelMA microgels as ideal intratympanic delivery vehicles for inner ear disease therapies, which provides new inspiration for microfluidics in drug delivery to the fine organs.
研究领域:
生物医学工程
·
药剂学
·
听力学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Yuanwei He,Ziyu Chen,Qinglang Liu,Zhiyang Li,Dingsheng Wen,Hong Zhang,Ming Zhang,Di Jiang,Huaan Li,Lu Wen,Gang Chen
Systemic drug administration provides convenience and non-invasive benefits for preventing and treating inner ear diseases . However, the blood-labyrinth barrier (BLB) restricts the transport of drugs to inner ear tissues. Ultrasound can stimulate specific areas and penetrate tissues, with the potential to overcome physiological barriers. We present a novel strategy based on low-pressure pulsed ultrasound assisted by microbubbles (USMB) to transiently open the BLB and deliver therapeutics into the inner ear. A pulsed ultrasound device with adjustable pressure was established; the generated ultrasound was transmitted through the external auditory canal into the guinea pig's inner ear. We observed that the application of microbubbles allowed the use of safe and efficient ultrasound conditions to penetrate the BLB. We found that USMB-mediated BLB opening seemed to be associated with a reduced expression of the tight junction proteins zonula occludens-1 and occludin . Following intravenous administration, hydrophilic dexamethasone sodium phosphate (DSP), hydrophobic curcumin (CUR), as well as drug-loaded nanoparticles (Fe 3 O 4 @CUR NPs) could be efficiently delivered into the inner ear. We observed better drug accumulation in the perilymph of the inner ear, resulting in less drug (cisplatin)-induced ototoxicity . Furthermore, physiological, hematological, and histological studies showed that the modulation of the BLB by low-pressure USMB was a safe process without significant adverse effects . We conclude that USMB could become a promising strategy for the systematic delivery of therapeutics in the treatment of inner ear diseases.
研究领域:
医学
·
药理学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
·
2025
·Vol. 113
·期 3
·e37892
·
IF 3.9
Yingjie Wang,Haobo Li,Junming Zhang,Mengyu Chen,Yiyin Pan,Xiangxin Lou
Hearing loss is often regarded as “invisible disability” which seriously affects the quality of life. The majority of hearing loss cases are caused by the damage to inner ear hair cells or connected spiral ganglion cells, and there is a lack of effective treatment measures. In recent years, significant progress has been made in the use of two-dimensional (2D) culture systems to induce the regeneration of auditory cells. However, the regenerated hair cells cannot form effective functional ciliary bundles under the 2D system, let alone establish synaptic contact with spiral ganglion cells, so they cannot truly achieve physiological repair of hearing. In this study, our aim is to construct a three-dimensional (3D) organ of Corti organoid through 3D bioprinting, which combines “3D culture scaffold + multiple induction signals + inner ear stem cells.” Then we evaluate the effects of the organoids on the differentiation of inner ear stem cells into auditory cells. We found that the organoids promoted adhesion and growth of inner ear stem cells, as well as the production of hair cells and nerve cells. The research may develop a novel approach for studying auditory cell regeneration and hearing loss repair.
研究领域:
再生医学
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听力科学
·
组织工程学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2022
·Vol. 18
·期 36
·2106591
·
IF 15.153
Kaili Chen,Fei Wang,Rui Ding,Zhengwei Cai,Tianyuan Zou,Andi Zhang,Dongye Guo,Bin Ye,Wenguo Cui,Mingliang Xiang
The least damaging and most economical method to deliver drugs or carriers into the inner ear for treatment of disease is through the middle ear. However, the retention of drug in the middle ear is an obstacle. Here, inspired by the adhesion of mussels, a methacrylate gelatin microspheres (GM) coupling polydopamine (PDA) layer (GM@PDA) with excellent adhesive ability is constructed, and Ebselen liposomes are further loaded into the GM@PDA (GM@PDA@Lipo-Ebselen). The loading capacity of GM@PDA for Ebselen liposomes is 25 ± 1 µg mg −1 microspheres. GM@PDA@Lipo-Ebselen could be injected on round windows membrane (RWM) and tightly adheres to the surface of RWM by PDA, and the microspheres are even still attached to the RWM after 360° rotation and inverted shaking. The in vivo imaging system shows that the adhesive microspheres can prolong the retention of the middle ear cavity for more than 7 days. The hearing of mice in the GM@PDA@Lipo-Ebselen group is significantly recovered, especially on day 14 after noise exposure, and the hearing of each frequency is restored to baseline level. At 32 kHz frequency, the survival of outer hair cells recovers from 48 0± 6% to 93 ± 2%. Therefore, the adhesive and injectable hydrogel microspheres provide a promising strategy for the treatment of hearing loss.
研究领域:
生物材料学
·
药剂学
·
耳科学
✓ 已验证
DOI
PubMed
高影响因子
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
·
2018
·
IF 1.883
Juan Dai,Wei Long,Zhongping Liang,Lu Wen,Fan Yang,Gang Chen
Delivery of biomacromolecular drugs into the inner ear is challenging, mainly because of their inherent instability as well as physiological and anatomical barriers. Therefore, protein-friendly, hydrogel-based delivery systems following local administration are being developed for inner ear therapy. Herein, biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing interferon α-2 b (IFN α-2 b) were loaded in chitosan/glycerophosphate (CS/GP)-based thermosensitive hydrogel for IFN delivery by intratympanic injection. The injectable hydrogel possessed a physiological pH and formed semi-solid gel at 37 °C, with good swelling and deswelling properties. The CS/GP hydrogel could slowly degrade as visualized by scanning electron microscopy (SEM). The presence of NPs in CS/GP gel largely influenced in vitro drug release. In the guinea pig cochlea, a 1.5- to 3-fold increase in the drug exposure time of NPs-CS/GP was found than those of the solution, NPs and IFN-loaded hydrogel. Most importantly, a prolonged residence time was attained without obvious histological changes in the inner ear. This biodegradable, injectable, and thermosensitive NPs-CS/GP system may allow longer delivery of protein drugs to the inner ear, thus may be a potential novel vehicle for inner ear therapy.
研究领域:
药学
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生物医学工程
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药物递送系统
·
内耳治疗
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2020
·
IF 5.186
Zhang Yan,Wang Yanfei,Yao Xuebo,Wang Changquan,Chen Fangyi,Liu Dong,Shao Ming,Xu Zhigang
Hair cells in the inner ear and lateral lines are mechanosensitive receptor cells whose development and function are tightly regulated. Several transcription factors as well as splicing factors have been identified to play important roles in hair cell development, whereas the role of RNA stability in this process is poorly understood. In the present work, we report that RNA-binding motif protein 24a (Rbm24a) is indispensable for hair cell development in zebrafish. Rbm24a expression is detected in the inner ear as well as lateral line neuromasts. Albeit rbm24a deficient zebrafish do not survive beyond 9 days post fertilization (dpf) due to effects outside of the inner ear, rbm24a deficiency does not affect the early development of inner ear except for delayed otolith formation and semicircular canal fusion. However, hair cell development is severely affected and hair bundle is disorganized in rbm24a mutants. As a result, the auditory and vestibular function of rbm24a mutants are compromised. RNAseq analyses identified several Rbm24a-target mRNAs that are directly bound by Rbm24a and are dysregulated in rbm24a mutants. Among the identified Rbm24a-target genes, lrrc23, dfna5b, and smpx are particularly interesting as their dysregulation might contribute to the inner ear phenotypes in rbm24a mutants. In conclusion, our data suggest that Rbm24a affects hair cell development in zebrafish through regulating mRNA stability.
研究领域:
发育生物学
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分子生物学
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神经科学
·
遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2021
·
IF 5.268
Mingyue Ai,Chuanjia Guo,Liwei Wang,Ming Hu,Kaixu Xu,Chen Li,Zhimin Zhou
It is important to achieve precise surface charge manipulation of non-spherical drug microcrystals using facile and time-efficient methods for local drug delivery. In this study, silk-coated dexamethasone (DEX) non-spherical microcrystals were synthesized by precipitation technique followed by alternate deposition of poly(allylamine hydrochloride) (PAH) (or PAH-coated Fe 3 O 4 ) and silk fibroin (SF) via layer-by-layer assembly. EDC and glutaraldehyde were employed to manipulate positive or negative charge of particles by simple chemical cross-linking reactions, respectively. In vivo assessment was carried out by intratympanic (IT) injection of DEX non-spherical microcrystals in guinea pigs. In vivo pharmacokinetic results demonstrate that negatively charged DEX microcrystals appeared to improve outcomes of inner ear delivery in comparison to positively-charged counterparts. This is partly because of the adhesive features of the SF. The present study may provide new ideas to construct surface charge-tunable drug delivery vehicles that are capable of crossing biological barriers, especially for inner ear delivery due to the simple and practical strategy.
研究领域:
药学
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2013
·
IF 2.987
Xiao Zhang,Gang Chen,Lu Wen,Fan Yang,A-li Shao,Xia Li,Wei Long,Lei Mu
The aim of this study was to develop novel multiple agents loaded poly ( d , l -lactide-co-glycolide acid) (PLGA) nanoparticles (NPs) and evaluate their potential for brain delivery via inner ear administration. PLGA NPs loaded with salvianolic acid B (Sal B), tanshinone IIA (TS IIA) and panax notoginsenoside (PNS) were prepared by double emulsion/solvent evaporation method. It was observed that optimized NPs displayed satisfactory encapsulation efficiency and desired sustained-release characteristics. NPs following intratympanic administration (IT) in guinea pigs greatly improved drug distribution within the inner ear, cerebrospinal fluid (CSF) and brain tissues compared with intravenous administration (IV). Pharmacodynamic studies demonstrated that NPs following IT markedly inhibited oxidizing reactions and protected the brain from cerebral ischemia reperfusion (I/R) injury by upregulating superoxide dismutase (SOD) activity both in serum and brain tissues, simultaneously significantly reducing the levels of malondialdehyde (MDA) and nitric oxide synthase (NOS). Moreover intratympanic delivery did not cause injury of cochlear function by preliminary study on the toxicity. These findings suggested that PLGA NPs-based delivery system via inner ear administration was a promising candidate to brain delivery for the treatment of brain diseases.
研究领域:
药剂学
·
神经科学
·
药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
Small
·
2024
·
IF 13
Ke Xu,Yiwei Du,Baoying Xu,Yuqi Huang,Wei Feng,Dehong Yu,Yu Chen,Xueling Wang
Nanoparticle-based drug delivery strategies have emerged as a crucial avenue for comprehensive sensorineural hearing loss treatment. Nevertheless, developing therapy vectors crossing both biological and cellular barriers has encountered significant challenges deriving from various external factors. Herein, the rational integration of gelatin nanoparticles (GNPs) with tetrahedral DNA nanostructures (TDNs) to engineer a distinct drug-delivery nanosystem (designed as TDN@GNP) efficiently enhances the biological permeability and cellular internalization, further resolving the dilemma of noise-induced hearing loss via loading epigallocatechin gallate (EGCG) with anti-lipid peroxidation property. Rationally engineering of TDN@GNP demonstrates dramatic alterations in the physicochemical key parameters of TDNs that are pivotal in cell-particle interactions and promote cellular uptake through multiple endocytic pathways. Furthermore, the EGCG-loaded nanosystem (TDN-EGCG@GNP) facilitates efficient inner ear drug delivery by superior permeability through the biological barrier (round window membrane), maintaining high drug concentration within the inner ear. The TDN-EGCG@GNP actively overcomes the cell membrane, exhibiting hearing protection from noise insults via reduced lipid peroxidation in outer hair cells and spiral ganglion neurons. This work exemplifies how integrating diverse vector functionalities can overcome biological and cellular barriers in the inner ear, offering promising applications for inner ear disorders.
研究领域:
药学
·
生物医学工程
·
纳米技术
·
耳鼻喉科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Liping Zhang,Yuan Xu,Wenjuan Cao,Shibao Xie,Lu Wen,Gang Chen
Background The round window membrane (RWM) functions as the primary biological barrier for therapeutic agents in the inner ear via local application. Previous studies on inner ear nano-drug delivery systems mostly focused on their pharmacokinetics and distribution in the inner ear, but seldom on the interaction with the RWM. Clarifying the transport mechanism of nanoparticulate carriers across RWM will shed more light on the optimum design of nano-drug delivery systems intended for meeting demands for their clinical application.Methods The poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) encapsulating coumarin-6 were prepared by emulsifying solvent evaporation method. We utilized confocal laser scanning microscope (CLSM) in combination with transmission electron microscope to investigate the transport pathway of PLGA NPs in the RWM. Simultaneously, the concentration and time dependence of NPs across the RWM were also determined. The endocytic mechanism of NPs through this membrane interface was classically analyzed by means of various endocytic inhibitors. The intracellular location of NPs into lysosomes was evaluated using CLSM scanning microscope colocalization analysis. The Golgi-related inhibitors were employed to probe into the function of Golgi and endoplasmic reticulum (ER) in the discharge of NPs out of cells.Results PLGA NPs were herein transported through the RWM of a sandwich-like structure into the perilymph via the transcellular pathway. NPs were internalized predominantly via macropinocytosis and caveolin-mediated endocytic pathways. After being internalized, the endocytosed cargos were entrapped within the lysosomal compartments and/or the endoplasmic reticulum/Golgi apparatus which mediated the exocytotic release of NPs.Conclusion For the first time, we showed the translocation itinerary of NPs in RWM, providing a guideline for the rational fabrication of inner ear nanoparticulate carriers with better therapeutic effects.
研究领域:
药学
·
纳米技术
·
生物医学工程
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Stem Cells International
·
2015
·
IF 2.813
Quanwen Liu,Yi Shen,Jiarong Chen,Jie Ding,Zihua Tang,Cui Zhang,Jianling Chen,Liang Li,Ping Chen,Jinfu Wang
In this paper, we developed a two-step-induction method of generating functional hair cells from inner ear multipotent cells. Multipotent cells from the inner ear were established and induced initially into progenitor cells committed to the inner ear cell lineage on the poly-L-lysine substratum. Subsequently, the committed progenitor cells were cultured on the mitotically inactivated chicken utricle stromal cells and induced into hair-cell-like cells containing characteristic stereocilia bundles. The hair-cell-like cells exhibited rapid permeation of FM1-43FX. The whole-cell patch-clamp technique was used to measure the membrane currents of cells differentiated for 7 days on chicken utricle stromal cells and analyze the biophysical properties of the hair-cell-like cells by recording membrane properties of cells. The results suggested that the hair-cell-like cells derived from inner ear multipotent cells were functional following differentiation in an enabling environment.
研究领域:
发育生物学
·
神经科学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）