Chitosan is a natural polymer with acceptable biocompatibility, biodegradability, and mechanical stability; hence, it has been widely appraised for drug and gene delivery applications. However, there has been no comprehensive assessment to tailor-make chitosan cross-linkers of various types and functionalities as well as complex chitosan-based semi- and full-interpenetrating networks for drug delivery systems (DDSs). Herein, various fabrication methods developed for chitosan hydrogels are deliberated, including chitosan crosslinking with and without diverse cross-linkers. Tripolyphosphate, genipin and multi-functional aldehydes, carboxylic acids, and epoxides are common cross-linkers used in developing biomedical chitosan for DDSs. Methods deployed for modifying the properties and performance of chitosan hydrogels, via their composite production (semi- and full-interpenetrating networks), are also cogitated here. In addition, recent advances in the fabrication of advanced chitosan hydrogels for drug delivery applications such as oral drug delivery, transdermal drug delivery, and cancer therapy are discussed. Lastly, thoughts on what is needed for the chitosan field to continue to grow is also debated in this comprehensive review article.

Biomaterial Groups Department of Biomedical Engineering Amirkabir University of Technology Tehran Iran

Department of Biomedical Engineering Faculty of Engineering and Natural Sciences Istinye University Istanbul 34396 Turkey

Department of Medical Biotechnology School of Advanced Technologies in Medicine Shahid Beheshti University of Medical Sciences Tehran Iran; Cellular and Molecular Biology Research Center Shahid Beheshti University of Medical Sciences Tehran Iran

Department of Physics Sharif University of Technology P O Box 11155 9161 Tehran Iran

Department of Polymer Technology Faculty of Chemistry Gdańsk University of Technology G Narutowicza 11 12 80 233 Gdańsk Poland

Department of Tissue Engineering and Biomaterials School of Advanced Medical Sciences and Technologies Hamadan University of Medical Sciences 6517838736 Hamadan Iran

Provincial Key Lab of Pulp and Paper Science and Technology and Joint International Research Lab of Lignocellulosic Functional Materials Nanjing Forestry University Nanjing 210037 China

Regional Centre of Advanced Technologies and Materials Czech Advanced Technology and Research Institute Palacký University in Olomouc Šlechtitelů 27 783 71 Olomouc Czech Republic

School of Chemical Petroleum and Gas Engineering Iran University of Science and Technology Narmak P O Box 16846 Tehran Iran

School of Engineering Macquarie University Sydney New South Wales 2109 Australia

School of Engineering Macquarie University Sydney New South Wales 2109 Australia; Department of Physics Sharif University of Technology P O Box 11155 9161 Tehran Iran; Department of Materials Science and Engineering Pohang University of Science and Technology 77 Cheongam ro Nam gu Pohang Gyeongbuk 37673 South Korea

School of Health Sciences and Biomedical Engineering Hebei University of Technology Tianjin China; School of Engineering Saveetha University Chennai India; Department of Materials Engineering UFPI Teresina Brazil

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