Noninvasive Ocular Nanoparticle Delivery: 20-Year Analysis

May 14, 2025 Author Summary 0

Understanding the Challenge: Ocular Drug Delivery

Ocular diseases such as dry eye, infections, glaucoma, myopia, and fundus disease are often treated with topical medications like eye drops, ointments, and tablets. However, these traditional methods face several limitations: short drug retention due to tear drainage, limited permeability, poor patient adherence, and potential side effects from frequent dosing.

These barriers hinder the long-term effectiveness and patient-friendliness of treatments. To address this, researchers have turned to noninvasive transocular drug delivery systems. These technologies have demonstrated practical value by overcoming anatomical challenges like the corneal barrier and tear washout, enhancing drug targeting and bioavailability, and reducing systemic drug loss.

Thanks to rapid progress in biomaterials, nanotechnology, and drug formulation sciences, these advanced systems are gaining traction for their ability to improve drug stability, prolong therapeutic effects, and reduce administration frequency.

A Bibliometric Overview of the Field

A recent study published in Biomolecules and Biomedicine analyzed global research output on noninvasive nanoparticle-based ocular drug delivery from 2004 to 2023. Using bibliometric tools (VOSviewer and CiteSpace), the study evaluated 695 English-language articles sourced from the Web of Science Core Collection.

The analysis covered publication trends, institutional and national contributions, author productivity, journal impact, and thematic keyword developments. Results showed a steady increase in publications over the past 20 years, with a notable rise after 2012 and a peak of 109 papers in 2023.

Who’s Contributing to the Research?

Countries and Institutions

Four countries accounted for the majority of publications:

  • China (220 documents)

  • USA (112)

  • India (80)

  • Spain (65)

While China led in publication volume, the USA and Spain had higher average citations per paper, indicating broader impact. Other active countries included Canada, Egypt, Italy, Portugal, and Saudi Arabia.

Top contributing institutions were:

  • University of Santiago de Compostela (29 publications, 64.10 average citations)

  • University of Florida (24 publications, 93.88 average citations)

  • Shenyang Pharmaceutical University (20 publications)
    These institutions have played pivotal roles in shaping the research landscape in this field.

Key Journals Publishing in the Field

Research appeared in 198 journals. The most active journals were:

  • International Journal of Pharmaceutics (57 publications)

  • Pharmaceutics (36)

  • Journal of Drug Delivery Science and Technology (30)

  • International Journal of Nanomedicine (22)

  • Journal of Controlled Release (21; highest average citations per article)

These journals primarily focus on drug delivery, nanomedicine, biopharmaceutics, and controlled release technologies, reflecting the interdisciplinary nature of ocular drug delivery research.

Research Themes and Evolving Focus

Keyword Analysis

Analysis of 321 keywords revealed high-frequency terms such as:

  • Drug delivery

  • Nanoparticle

  • Controlled release

  • Hydrogel

  • Contact lens

  • Solid lipid nanoparticles (LNPs)

Terms with high betweenness centrality included “controlled release,” “cell,” “dry eye,” “mechanism,” “expression,” and “ocular drug delivery”—highlighting their significance in shaping research directions.

Keyword Clustering and Timeline

The clustering of keywords identified 14 thematic modules, with 11 core areas:

  1. Chitosan

  2. Contact lenses

  3. Glaucoma

  4. Bioavailability

  5. Cornea

  6. Drug delivery

  7. Corneal wound healing

  8. Ocular

  9. Solid lipid nanoparticles

  10. Nanostructured lipid carriers

  11. Dexamethasone

Some research themes such as chitosan and corneal wound healing have been active since the early 2000s, while others like lipid nanoparticles and nanostructured lipid carriers emerged more recently and continue to gain traction.

Technological Innovations in Delivery Systems

The study outlines the practical applications of several noninvasive delivery systems:

  • Contact lenses have been developed to release drugs like timolol and vancomycin over extended periods, improving retention and reducing dosing frequency.

  • Hydrogels composed of materials such as chitosan and silk fibroin have shown promise in corneal regeneration and keratitis treatment.

  • Microneedles (MNs) offer minimally invasive drug delivery to ocular tissues. Innovations include dissolvable needles and localized delivery of iron-based nanoparticles and riboflavin for bacterial keratitis and corneal crosslinking.

These systems aim to overcome limitations of conventional formulations by enhancing stability, targeting precision, and patient comfort.

Transition in Material Preferences

The article highlights a shift from earlier reliance on chitosan-based systems to the growing use of cationic liposomes and lipid nanoparticles (LNPs). LNPs have demonstrated improved biocompatibility, stability, and potential for gene therapy and RNA delivery.

Recent studies cited in the paper describe successful LNP-mediated delivery of siRNA and CRISPR/Cas9 for treating anterior segment diseases and genetic disorders of the cornea.

Clinical Implications and Future Outlook

The research emphasizes that noninvasive nanoparticle drug delivery systems provide a promising strategy for managing chronic eye conditions like:

  • Glaucoma: by lowering intraocular pressure through improved drug penetration

  • Age-related macular degeneration (AMD): via anti-VEGF therapies delivered through the ocular surface

Looking forward, the study suggests that future efforts should focus on developing intelligent drug delivery systems that can respond to environmental changes in the eye, such as pH or temperature. This could allow for more precise, personalized treatments.

Recommendations

The authors advise:

  • Researchers to explore new nanomaterials to enhance stability, bioavailability, and targeting.

  • Clinicians to monitor ocular responses closely, considering potential toxicity.

  • Industry stakeholders to evaluate the cost-effectiveness and market viability of new delivery platforms.

Conclusion

This 20-year bibliometric analysis offers a comprehensive overview of global research trends in noninvasive ocular nanoparticle drug delivery. The findings highlight key contributors, emerging technologies, and evolving research priorities—informing both academic inquiry and clinical development.

By focusing on practical challenges and potential solutions, this work supports the advancement of more effective, safer, and patient-friendly ocular therapies.

 

The translation of the preceding English text in Chinese:

 

认识挑战：眼部药物递送

干眼症、感染、青光眼、近视和眼底病等眼病常通过局部药物治疗，如滴眼液、眼膏和口服片剂。然而，这些传统治疗方法面临诸多限制：由于泪液排出导致药物停留时间短、渗透性有限、患者依从性差，以及频繁用药可能带来的副作用。

这些障碍限制了治疗的长期效果和患者的接受程度。为了解决这些问题，研究人员转向了非侵入性的经眼药物递送系统。这些技术通过克服角膜屏障和泪液冲洗等解剖学难题，增强了药物的靶向性和生物利用度，并减少了药物的系统性流失，展现出实际应用价值。

随着生物材料、纳米技术和药物制剂科学的快速进展，这些先进系统越来越受到重视，它们有望提高药物稳定性、延长治疗效果并减少给药频率。

该领域的文献计量综述

《Biomolecules and Biomedicine》最近发表的一项研究分析了2004年至2023年间关于非侵入性纳米颗粒眼部药物递送的全球研究成果。研究采用了VOSviewer和CiteSpace等文献计量工具，评估了Web of Science核心合集中的695篇英文文献。

分析内容涵盖了发表趋势、国家和机构的贡献、作者产出、期刊影响力以及关键词主题发展。结果显示，在过去20年中，相关发表数量稳步增长，尤其在2012年后明显上升，2023年达到109篇的高峰。

谁在推动研究？

国家和机构

四个国家贡献了大部分研究文献：

  • 中国（220篇）

  • 美国（112篇）

  • 印度（80篇）

  • 西班牙（65篇）

尽管中国在发表数量上领先，美国和西班牙的平均引用次数更高，表明其研究影响力更大。其他积极参与的国家还包括加拿大、埃及、意大利、葡萄牙和沙特阿拉伯。

主要贡献机构包括：

  • 圣地亚哥德孔波斯特拉大学（29篇，平均引用64.10次）

  • 佛罗里达大学（24篇，平均引用93.88次）

  • 沈阳药科大学（20篇）

这些机构在该研究领域的发展中发挥了关键作用。

主要发表期刊

研究成果分布在198本期刊中，最活跃的包括：

  • International Journal of Pharmaceutics（57篇）

  • Pharmaceutics（36篇）

  • Journal of Drug Delivery Science and Technology（30篇）

  • International Journal of Nanomedicine（22篇）

  • Journal of Controlled Release（21篇，平均每篇引用次数最高）

这些期刊主要聚焦于药物递送、纳米医学、生物药剂学及控释技术，反映出眼部药物递送研究的跨学科特征。

研究主题与发展重点

关键词分析

对321个关键词的分析显示高频术语包括：

  • 药物递送

  • 纳米颗粒

  • 控释

  • 水凝胶

  • 隐形眼镜

  • 固体脂质纳米颗粒（LNPs）

具有较高中介中心性的关键词包括：“控释”、“细胞”、“干眼”、“机制”、“表达”和“眼部药物递送”，凸显其在研究方向中的核心地位。

关键词聚类与时间线

关键词聚类揭示了14个主题模块，其中11个核心研究方向包括：

  • 壳聚糖

  • 隐形眼镜

  • 青光眼

  • 生物利用度

  • 角膜

  • 药物递送

  • 角膜创伤愈合

  • 眼部

  • 固体脂质纳米颗粒

  • 纳米结构脂质载体

  • 地塞米松

某些研究主题如壳聚糖和角膜愈合自2000年代初已活跃，而脂质纳米颗粒和纳米结构脂质载体等较新主题则近年来快速发展。

递送系统的技术创新

研究列举了几种非侵入性递送系统的实际应用：

  • 隐形眼镜：被开发用于缓释药物，如噻吗洛尔和万古霉素，延长药效时间，减少给药频率。

  • 水凝胶：由壳聚糖和丝素等材料制成，显示出在角膜再生和角膜炎治疗中的潜力。

  • 微针（MNs）：提供微创的眼部给药方式。创新形式包括可溶性微针和局部递送铁基纳米颗粒及核黄素，应用于细菌性角膜炎和角膜交联。

这些系统旨在克服传统配方的局限，提升药物稳定性、靶向精度和患者舒适性。

材料使用偏好的转变

文章指出，研究重点已从早期主要依赖壳聚糖系统转向阳离子脂质体和脂质纳米颗粒（LNPs）的应用。LNPs表现出更好的生物相容性和稳定性，并具备基因治疗和RNA递送的潜力。

文中引用的近期研究报道了LNP介导的siRNA和CRISPR/Cas9递送，用于治疗眼前节疾病和角膜的遗传性病变。

临床意义与未来展望

研究强调，非侵入性纳米药物递送系统为慢性眼病（如青光眼和年龄相关性黄斑变性）提供了有前景的管理策略：

  • 青光眼：通过改善药物渗透性来降低眼压

  • AMD：通过眼表递送抗VEGF治疗

未来，研究建议重点发展“智能药物递送系统”，能够对眼部环境变化（如pH或温度）做出响应，从而实现更精准、个体化的治疗。

建议

研究作者建议：

  • 研究人员：探索新型纳米材料以增强稳定性、生物利用度及靶向性；

  • 临床医生：密切监测眼部反应，警惕潜在毒性；

  • 产业界：评估新型递送平台的成本效益和市场可行性。

结语

这项为期20年的文献计量分析全面展现了全球在非侵入性眼部纳米颗粒药物递送领域的研究趋势。研究揭示了关键贡献者、新兴技术和不断演进的研究重点，为学术探索和临床开发提供了方向。

通过聚焦实际挑战与可行解决方案，本研究有助于推动更有效、安全且更易被患者接受的眼科治疗方案的发展。

Reference:

Dan Li, Qing Ye, Chao Li

Trends in noninvasive ocular nanoparticle drug delivery: A bibliometric analysis (2004–2023).

Biomol Biomed [Internet]. 2025 Mar. 4 [cited 2025 May 12];

Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/11772

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