Key Takeaways & Executive Findings
- •• Oral natural hydrogels offer superior biocompatibility, biodegradability, and low toxicity, making them ideal for safe and effective drug delivery. • They enable precise drug targeting and controlled release, overcoming gastrointestinal barriers and improving bioavailability. • Emerging smart hydrogels, such as pH-responsive and ROS-responsive systems, are advancing personalized and intelligent drug delivery. • Challenges remain in mechanical strength and potential immunogenicity, necessitating further optimization for clinical translation.
Abstract
BACKGROUND: Oral drug delivery has consistently been the most preferred route of administration due to its high patient compliance, significantly enhancing the overall treatment experience compared to injectables. However, the gastrointestinal environment severely limits drug bioavailability. As the demand for biocompatibility and biodegradability in the medical field continues to grow, natural hydrogels have emerged as ideal drug delivery carriers, attracting widespread attention. OBJECTIVE: To explore the development and application of oral hydrogels made from various natural materials, from material selection to synthesis methods. METHODS: A comprehensive literature search was conducted in the PubMed and Web of Science databases using the English search terms “oral hydrogels, physical crosslinking, chemical crosslinking, natural material, therapy, drug delivery, application of disease research” to identify the most recent relevant articles published from 2009 to 2024. A total of 83 articles were selected for review. RESULTS AND CONCLUSION: Hydrogels, as a promising new drug delivery system, exhibit significant advantages in achieving precise drug delivery and controlled release. Oral natural hydrogels stand out in the field of drug delivery due to their excellent biocompatibility, good degradability, and extremely low potential toxicity. They not only enable precise drug delivery but also effectively avoid irritation caused by direct contact between drugs and the gastrointestinal tract, providing a safer and more effective route for drug administration. With the continuous exploration of researchers, novel intelligent hydrogel delivery systems based on natural materials are emerging, such as pectin-based pH-responsive hydrogels and hyaluronic acid-based reactive oxygen species-responsive hydrogels. These new materials open new avenues for intelligent and precise drug delivery. However, natural material hydrogels also expose some issues to be solved during application: on one hand, natural materials generally suffer from insufficient mechanical properties and tensile strength, making it difficult to meet complex drug delivery needs; on the other hand, although natural materials originate from nature, they may still trigger immune responses in the human body.
1. Introduction
Natural hydrogels, as environmentally friendly hydrogels, possess superior biocompatibility and biodegradability compared to synthetic hydrogels, allowing them to degrade safely in vivo and greatly reduce irritation and potential toxicity to organisms [1]. With these advantages, natural hydrogels have been widely applied in frontier fields such as controlled drug release, targeted delivery, and tissue engineering [2], becoming a research hotspot.
Oral administration has consistently been the most preferred route of drug delivery due to its high patient compliance, significantly enhancing the treatment experience compared to injectables. However, the extreme environment of the gastrointestinal tract, slow drug absorption, and biological barriers severely limit the bioavailability of oral drugs, posing major challenges to oral drug delivery. The development of oral natural hydrogels has overcome this dilemma [3]. Most oral natural hydrogels are composed of natural polysaccharides, which exhibit high stability against enzymatic degradation in the gastrointestinal tract [4-5]. Therefore, natural hydrogels can efficiently deliver drugs to the lesion site, ensure full drug utilization, and demonstrate good sustained-release effects [6]. More notably, some natural molecules possess disease-targeting capabilities, providing strong support for precise drug release [7-8]. Additionally, with the rising popularity of traditional Chinese medicine, many small-molecule components of Chinese herbs are being applied in novel material research. Most of these small molecules are poorly water-soluble and have extremely poor stability in the gastrointestinal tract, limiting their absorption and utilization. Research on oral hydrogels for traditional Chinese medicine small molecules offers new insights for the modernization of traditional medicine. Using natural hydrogels to deliver probiotics, proteins, and other bioactive agents provides new possibilities for conventional drug administration routes, such as oral insulin and oral vaccines, offering patients more convenient dosing methods [9]. Currently, oral natural hydrogels have achieved significant progress in the treatment of various diseases.
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YANG Qi, XIANG Xi, WANG Han, ZOU Zhen, ZHANG Lunci, Mireadeli·Abulimiti, LIAO Yue, LI Xinzhi (2026). Development and application of natural oral hydrogels in drug delivery systems. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21470
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Frequently Asked Questions
What are natural oral hydrogels?
Natural oral hydrogels are three-dimensional networks of hydrophilic polymers derived from natural sources, such as polysaccharides and proteins. They can absorb large amounts of water and are designed for oral administration to deliver drugs, offering high biocompatibility and biodegradability.
What are the advantages of using natural oral hydrogels for drug delivery?
They provide excellent biocompatibility, biodegradability, and low toxicity, enabling safe degradation in the body. They can protect drugs from the harsh gastrointestinal environment, achieve targeted and controlled release, and improve bioavailability, thus enhancing therapeutic efficacy and patient compliance.
What are the main challenges in developing natural oral hydrogels?
Key challenges include insufficient mechanical strength and tensile properties, which limit their use in complex delivery scenarios, and potential immunogenicity despite their natural origin. Researchers are addressing these issues through chemical modifications and hybrid crosslinking strategies.
How are natural oral hydrogels synthesized?
They are synthesized via physical crosslinking (non-covalent interactions like hydrogen bonding and ionic interactions), chemical crosslinking (covalent bond formation), or a combination of both (physical-chemical dual crosslinking) to achieve desired properties such as mechanical strength and responsiveness.
What are the future directions for natural oral hydrogels?
Future research focuses on developing smart hydrogels with stimuli-responsive properties (e.g., pH, ROS), improving mechanical performance, minimizing immune responses, and expanding applications to personalized medicine and combination therapies.
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