Hydrogel-Based Dental Biomaterials and Artificial Neural Network (ANN)Based Modeling for Precision Head and Neck Immunotherapy: AComprehensive Review of Solutions and Translational Advances
Copyright (c) 2025 K. S. Kadam, V. S. Gadakh, S. Ponnapureddy (Author)

This work is licensed under a Creative Commons Attribution 4.0 International License.
Abstract
Cancer immunotherapy has emerged as a transformative approach in oncology, harnessing the body’s immune system to target and eradicate malignant cells. However, clinical efficacy remains limited by systemic toxicity, inadequate drug availability, and poor tumor targeting. Hydrogels have gained significant attention as biomaterial platforms capable of addressing these limitations through localized and controlled delivery of immunotherapeutic agents, owing to their biocompatibility, biodegradability, and tunable properties. This article discusses recent advancements in hydrogel-based drug delivery systems for cancer immunotherapy, encompassing fundamental materials, fabrication methods, and applications in immune modulation, cell-based therapies, cancer vaccines, and tumor microenvironment remodeling. While preclinical studies demonstrate that hydrogels enhance localized delivery, improve immune responses, and reduce systemic side effects, challenges remain in large-scale production, immunogenicity concerns, and precise control over drug release kinetics. This study used an artificial neural network (ANN) to establish quantitative relationships between hydrogel formulation parameters and performance characteristics. A feedforward shallow neural network with one hidden layer containing 5 neurons was developed and trained using experimental data from five hydrogel samples, with polymer concentration (wt%) and swelling ratio (g/g) as inputs, and elastic modulus (kPa), burst release (%), and total release (%) as outputs. Predictive results revealed that increasing polymer concentration enhanced elastic modulus, while swelling ratio predominantly influenced release characteristics, with both parameters exhibiting antagonistic interactions when combined. Linear regression analysis confirmed exceptional prediction accuracy with error margins below 1%, validating the reliability of this computational approach. These results show that ANN serve as powerful tools for predicting hydrogel behavior, enabling rational design of delivery systems with optimized mechanical properties and controlled release kinetics. The integration of advanced biomaterials with computational modeling represents a promising pathway toward safer, more effective, and personalized cancer immunotherapies.
Keywords
- Hydrogels,
- Cancer immunotherapy,
- Drug delivery,
- Tumor microenvironment,
- Immunomodulators,
- Smart hydrogels
References
- Pennock GK and Chow LQ. The evolving role of immune checkpoint inhibitors in cancer treatment. The Oncologist 2015; 20:812–22
- Zhang Y and Zhang Z. The history and advances in cancer immunotherapy: Understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cellular & Molecu-lar Immunology 2020; 17:807–21
- Zafar S, Hanif M, Azeem M, Mahmood K, and Gondal SA. Role of crosslinkers for synthesizing biocompatible, biodegradable and mechanically strong hydrogels with desired release profile. Poly-mer Bulletin 2022; 79:9199–219
- Kciuk M, Yahya EB, Mohamed Ibrahim Mohamed M, Rashid S, Iqbal MO, Kontek R, et al. Recent advances in molecular mechanisms of cancer immunotherapy. Cancers 2023; 15:2721
- Yan MJ, Wongvibulsin S, McKenzie S, Smart CN, and Nguyen MO. Cutaneous metastases of alveolar rhabdomyosarcoma in a young adult. JAAD Case Reports 2025
- Jamnezhad S, Asefnejad A, Motififard M, Yazdekhasti H, Kolooshani A, Saber-Samandari S, and Khandan A. Development and investigation of novel alginate-hyaluronic acid bone fillers us-ing freeze drying technique for orthopedic field. Nanomedicine Research Journal 2020; 5:306–15
- Stephen B, Kwiatkowski E, Anderson MR, Derbala MH, Salih I, Castillo L, et al. Abstract A114: Impact of liver metastases and systemic biomarkers on immunotherapy response and survival outcomes in patients with solid tumors. Cancer Immunology Research 2025; 13:A114–A
- Schubert ML, Schmitt M, Wang L, Ramos C, Jordan K, Muller-Tidow C, et al. Side-effect management of chimeric antigen receptor (CAR) T-cell therapy. Annals of Oncology 2021; 32:34–48
- Liu C, Yang M, Zhang D, Chen M, and Zhu D. Clinical cancer immunotherapy: Current progress and prospects. Frontiers in Immunology 2022; 13:961805
- Seo HS, Wang CPJ, Park W, and Park CG. Short review on advances in hydrogel-based drug delivery strategies for cancer immunotherapy. Tissue Engineering and Regenerative Medicine 2022 :1–18
- Fan T, Zhang M, Yang J, Zhu Z, Cao W, and Dong C. Therapeutic cancer vaccines: Advancements, challenges and prospects. Signal Transduction and Targeted Therapy 2023; 8:450
- Vergati M, Intrivici C, Huen NY, Schlom J, and Tsang KY. Strategies for cancer vaccine development. BioMed Research International 2010; 2010:596432
- Abdou P, Wang Z, Chen Q, Chan A, Zhou DR, Gunadhi V, et al. Advances in engineering local drug delivery systems for cancer immunotherapy. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 2020; 12:e1632
- Mukherjee AG, Wanjari UR, Namachivayam A, Murali R, Prabakaran D, Ganesan R, et al. Role of immune cells and receptors in cancer treatment: An immunotherapeutic approach. Vaccines 2023; 10:1493
- Dahri M, Beheshtizadeh N, Seyedpour N, Nakhostin-Ansari A, Aghajani F, Seyedpour S, et al. Biomaterial-based delivery platforms for transdermal immunotherapy. Biomedicine & Phar-macotherapy 2023; 165:115048
- Asefnejad A and Shadman-Manesh V. Exploring the Impact of Ceramic Reinforcements on the Mechanical Properties of Wound Dressings and their Influence on Wound Healing and Drug Release. Scientific Hypotheses 2024; 1:73–85
- Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology 2018; 36:1714–68
- Han L, Peng K, Qiu LY, Li M, Ruan JH, He LL, et al. Hitchhiking on controlled-release drug delivery systems: Opportunities and challenges for cancer vaccines. Frontiers in Pharmacology 2021; 12:679602
- Gupta S and Shukla S. Limitations of immunotherapy in cancer. Cureus 2022; 14
- Emens LA, Romero PJ, Anderson AC, Bruno TC, Capitini CM, Collyar D, et al. Challenges and opportunities in cancer immunotherapy: A Society for Immunotherapy of Cancer (SITC) strategic vi-sion. Journal for ImmunoTherapy of Cancer 2024; 12:e009063
- Moghadas BK, Ghanbari N, and Nasri P. Advancements in nanoparticle biosensors: Applications, properties, and considerations for improving performance and detection capabilities. Scientific Hypotheses 2024; 1:53–71
- Soleimani M, Asgharzadeh Salmasi A, Asghari S, Joneidi Yekta H, Kamyab Moghadas B, Shahriari S, et al. Optimization and fabrication of alginate scaffold for alveolar bone regeneration with sufficient drug release. International Nano Letters 2021; 11:295–305
- Mikhail AS, Morhard R, Mauda-Havakuk M, Kassin M, Arrichiello A, and Wood BJ. Hydrogel drug delivery systems for minimally invasive local immunotherapy of cancer. Advanced Drug Delivery Reviews 2023; 202:115083
- Farazin A, Torkpour Z, Dehghani S, Mohammadi R, Fahmy MD, Saber SS, and orhers. A review on polymeric wound dress for the treatment of burns and diabetic wounds. 2021
- Lei L, Huang D, Gao H, He B, Cao J, and Pep-pas NA. Hydrogel-guided strategies to stimulate an effective immune response for vaccine-based cancer immunotherapy. Science Advances 2022; 8:eadc8738
- Zheng H, Li M, Wu L, Liu W, Liu Y, Gao J, et al. Progress in the application of hydrogels in immunotherapy of gastrointestinal tumors. Drug Delivery 2023; 30:2161670
- Li X, Xu X, Xu M, Geng Z, Ji P, and Liu Y. Hydrogel systems for targeted cancer therapy. Frontiers in Bioengineering and Biotechnology 2023; 11:1140436
- Liu C, Liao Y, Liu L, Xie L, Liu J, Zhang Y, et al. Application of injectable hydrogels in cancer immunotherapy. Frontiers in Bioengineering and Biotechnology 2023; 11:1121887
- Huang H, Cong HT, Lin Z, Liao L, Shuai CX, Qu N, et al. Manipulation of conducting polymer hydrogels with different shapes and related multi-functionality. Small 2024; 20:2309575
- Rezaei H, Asefnejad A, Daliri-Joupari M, and Joughehdoust S. In-vitro cellular and in-vivo investigation of ascorbic acid and β-glycerophosphate loaded gelatin/sodium alginate injectable hydro-gels for urinary incontinence treatment. Progress in Biomaterials 2021; 10:161–71
- Rezaei H, Asefnejad A, Joupari MD, and Joughe-hdoust S. The physicochemical and mechanical investigation of siloxane modified gelatin/sodium alginate injectable hydrogels loaded by ascorbic acid and β-glycerophosphate. Materials Today Communications 2021; 26:101914
- Haririan Y and Asefnejad A. Biopolymer hydrogels and synergistic blends for tailored wound healing. International Journal of Biological Macromolecules 2024:135519
- Satchanska G, Davidova S, and Petrov PD. Natural and synthetic polymers for biomedical and environmental applications. Polymers 2024; 16:1159
- Wang Z, Wei H, Huang Y, Wei Y, and Chen J. Naturally sourced hydrogels: Emerging fundamental materials for next-generation healthcare sensing. Chemical Society Reviews 2023; 52:2992–3034
- Raisi A, Asefnejad A, Shahali M, Doozandeh Z, Kamyab Moghadas B, Saber-Samandari S, and Khandan A. A soft tissue fabricated using a freeze-drying technique with carboxymethyl chitosan and nanoparticles for promoting effects on wound healing. Journal of Nanoanalysis 2020; 7:262–74
- Wei Y, Wang K, Luo S, Li F, Zuo X, Fan C, et al. Programmable DNA hydrogels as artificial extracellular matrix. Small 2022; 18:2107640
- Terzopoulou Z, Zamboulis A, Koumentakou I, Michailidou G, Noordam MJ, and Bikiaris DN. Biocompatible synthetic polymers for tissue engineering purposes. Biomacromolecules 2022; 23:1841–63
- Dirauf M, Muljajew I, Weber C, and Schubert US. Recent advances in degradable synthetic polymers for biomedical applications-Beyond polyesters. Progress in Polymer Science 2022; 129:101547
- Hwang J, An EK, Zhang W, Kim HJ, Eom Y, and Jin JO. Dual-functional alginate and collagen-based injectable hydrogel for the treatment of cancer and its metastasis. Journal of Nanobiotechnology 2022; 20:245
- Laomeephol C, Areecheewakul S, Tawinwung S, Suppipat K, Chunhacha P, Neves NM, et al. Potential roles of hyaluronic acid in in vivo CAR T cell reprogramming for cancer immunotherapy. Nanoscale 2022; 14:17821–40
- Yuan CS, Teng Z, Yang S, He Z, Meng LY, Chen XG, et al. Reshaping hypoxia and silencing CD73 via biomimetic gelatin nanotherapeutics to boost immunotherapy. Journal of Controlled Release 2022; 351:255–71
- Wang Z, Ye Q, Yu S, and Akhavan B. Polyethylene glycol (PEG)-based hydrogels for drug delivery in cancer therapy: A comprehensive review. Advanced Healthcare Materials 2023; 12:2300105
- Jafaripour N, Omidvar H, Saber-Samandari S, Mohammadi R, Shokrani Foroushani R, Kamyab Moghadas B, et al. Synthesize and Characteriza-tion of a Novel Cadmium Selenide Nanoparticle with Iron Precursor Applicable in Hyperthermia of Cancer Cells. International Journal of Nanoscience and Nanotechnology 2021; 17:77–90
- Gao Y, Peng K, and Mitragotri S. Covalently crosslinked hydrogels via step-growth reactions: Crosslinking chemistries, polymers, and clinical impact. Advanced Materials 2021; 33:2006362
- Foroutan S, Hashemian M, Khosravi M, Nejad MG, Asefnejad A, Saber-Samandari S, and Khandan A porous sodium alginate-CaSiO3 polymer reinforced with graphene nanosheet: fabrication and optimality analysis. Fibers and Polymers 2021; 22:540–9
- Karimi M, Asefnejad A, Aflaki D, Surendar A, Baharifar H, Saber-Samandari S, et al. Fabrication of shapeless scaffolds reinforced with baghdadite-magnetite nanoparticles using a 3D printer and freeze-drying technique. Journal of Materials Research and Technology 2021; 14:3070–9
- Li Z, Lu F, and Liu Y. A review of the mechanism, properties, and applications of hydrogels prepared by enzymatic cross-linking. Journal of Agricultural and Food Chemistry 2023; 71:10238–49
- Song YE, Eckman N, Sen S, Jons CK, Saouaf OM, and Appel EA. Highly extensible physi-cally crosslinked hydrogels for high-speed 3D bio-printing. Advanced Healthcare Materials 2025:2404988
- Khandan A, Jazayeri H, Fahmy MD, and Razavi M. Hydrogels: Types, structure, properties, and applications. Biomaterials for Tissue Engineering 2017:143–69
- Liu B and Chen K. Advances in hydrogel-based drug delivery systems. Gels 2024; 10:262
- Cao J, Wu B, Yuan P, Liu Y, and Hu C. Research progress of sodium alginate-based hydrogels in biomedical engineering. Gels 2025; 11:758
- Zhou Y, Chen K, Cheng H, and Zhang S. Recent advances in polysaccharide-based hydrogels for tumor immunotherapy. Gels 2025; 11:152
- Zhang X, Guo X, Wu Y, and Gao J. Locally injectable hydrogels for tumor immunotherapy. Gels 2021; 7:224
- Ren X, Wang N, Zhou Y, Song A, Jin G, Li Z, et al. An injectable hydrogel using an immunomodulating gelator for amplified tumor immunotherapy by blocking the arginase pathway. Acta Biomaterialia 2021; 124:179–90
- Kim J, Choi Y, Kim DH, Yoon HY, and Kim K. Injectable hydrogel-based combination cancer immunotherapy for overcoming localized therapeutic efficacy. Pharmaceutics 2022; 14:1908
- Li J, Luo G, Zhang C, Long S, Guo L, Yang G, et al. In situ injectable hydrogel-loaded drugs induce anti-tumor immune responses in melanoma immunochemotherapy. Materials Today Bio 2022; 14:100238
- Flores-Torres S, Dimitriou NM, Pardo LA, Kort-Mascort J, Pal S, Peza-Chavez O, et al. Bio-printed multicomponent hydrogel co-culture tumor-immune model for assessing and simulating tumor-infiltrated lymphocyte migration and functional activation. ACS Applied Materials & Interfaces 2023; 15:33250–62
- Wang Z, Zhai B, Sun J, Zhang X, Zou J, Shi Y, et al. Recent advances of injectable in situ-forming hydrogels for preventing postoperative tumor recurrence. Drug Delivery 2024; 31:2400476
- Zhang Z, Chen X, Gao S, Fang X, and Ren S. 3D bioprinted tumor model: A prompt and convenient platform for overcoming immunotherapy resistance by recapitulating the tumor microenvironment. Cel-lular Oncology 2024; 47:1113–26
- Khodami N, Asefnejad A, Ghanbari N, and Agh-dam HA. Advanced 3D Printing Techniques for Scaffold Fabrication in Bone Tissue Engineering. Scientific Hypotheses 2025; 2:1–35
- Liang H, Mirinejad MS, Asefnejad A, Bahari-far H, Li X, Saber-Samandari S, et al. Fabrication of tragacanthin gum-carboxymethyl chitosan bio-nanocomposite wound dressing with silver-titanium nanoparticles using freeze-drying method. Materials Chemistry and Physics 2022; 279:125770
- Khademi A, Khandan A, Iranmanesh P, and Heydari M. Development of a 3D Bioprinted Alginate-Gelatin Hydrogel Scaffold Loaded with Calcium Phosphates for Dental Pulp Tissue Regeneration. Iranian Journal of Chemistry and Chemical Engineering 2025; 44:1–16. doi: 10.30492/ijcce.2024. 2038072.6738
- Vakili N, Asefnejad A, Mohammadi M, Rezaei H, and Khandan A. Improving physicochemical, mechanical, and biological properties of a porous polyvinyl alcohol/chitosan matrix via modification with magnesium and silicon agents. Nanomedicine Journal 2025; 12
- Jasemi A, Moghadas BK, Khandan A, and Saber-Samandari S. A porous calcium-zirconia scaffolds composed of magnetic nanoparticles for bone cancer treatment: Fabrication, characterization and FEM analysis. Ceramics International 2022; 48:1314–25
- Rajaei A, Kazemian M, and Khandan A. Investigation of mechanical stability of lithium disilicate ceramic reinforced with titanium nanoparticles. Nanomedicine Research Journal 2022; 7:350–9
- Safaei MM, Abedinzadeh R, Khandan A, Barbaz-Isfahani R, and Toghraie D. Synergistic effect of graphene nanosheets and copper oxide nanoparticles on mechanical and thermal properties of composites: Experimental and simulation investigations. Materials Science and Engineering: B 2023; 289:116248
- Moarrefzadeh A, Morovvati MR, Angili SN, Smaisim GF, Khandan A, and Toghraie D. Fabrication and finite element simulation of 3D printed poly L-lactic acid scaffolds coated with alginate/-carbon nanotubes for bone engineering applications. International Journal of Biological Macro-molecules 2023; 224:1496–508
- Angili SN, Morovvati MR, Kardan-Halvaei M, Saber-Samandari S, Razmjooee K, Abed AM, et al. Fabrication and finite element simulation of antibacterial 3D printed poly L-lactic acid scaffolds coated with alginate/magnesium oxide for bone tissue regeneration. International Journal of Biological Macromolecules 2023; 224:1152–65
- Azimi R, Shahgholi M, and Khandan A. Fabrication and characterization of reinforced glass ionomer cement by zinc oxide and hydroxyapatite nanoparticles. Heliyon 2024; 10
- Barbaz Isfahani R, Shahbaz A, Khademi A, Iran-manesh P, Khandan A, and Sheikhbahaei E. Mechanical and chemical behaviour of nanoparticles in multicomponent dressings: Promoting wound healing with novel materials, intelligent monitoring, and enhanced healing outcomes. Nanochemistry Research 2025; 10:482–515
- Barbaz-Isfahani R, Shahbaz A, Jamali M, Khademi A, Iranmanesh F, Iranmanesh P, et al. Advanced bioprinting methodologies: A quantitative analysis and exploration of innovative techniques for tissue engineering. Nanomedicine Research Journal 2025; 10:95–113
- Barbaz-Isfahani R, Jamali M, Pourkhamisi N, Khademi A, Iranmanesh P, Torabinia N, and Khan-dan A. Comparative analysis of ceramic nanoparticle properties for biomaterials: Implications for applications and material selection using statistical analysis. Nanochemistry Research 2026; 11:133–51
- Khademi A, Khandan A, and Iranmanesh P. Hydrogels for dental pulp repair: Enhancing physicochemical and regenerative potential with CaP-loaded alginate-gelatin hydrogel scaffolds-A FEM and ANN modeling. Nanomedicine Journal 2026; 13
- Iranmanesh P, Ehsani A, Khademi A, Asefnejad A, Shahriari S, Soleimani M, et al. Application of 3D bioprinters for dental pulp regeneration and tissue engineering (porous architecture). Transport in Porous Media 2022; 142:265–93
- Fatalla AA, Arzani S, Veseli E, Khademi A, Khan-dan A, Fahmy MD, et al. Revolutionizing systematic reviews and meta-analyses: The role of artificial intelligence in evidence synthesis. Dental Hypotheses 2023; 14:93–4
- Ghanbari N, Moghadas BK, Samadi F, and Khandan A. Fabrication and analysis of a PVP-carboxymethyl chitosan/forsterite nanocomposite scaffold with stainless steel base via freeze-drying and neural network techniques. Iranian Journal of Basic Medical Sciences 2026; 29:101
- Mirmohammadi H, Kolahi J, and Khandan A. Bibliometric analysis of dental preprints which published in 2022. Dental Hypotheses 2023; 14:1–2
- Wang W, Cai T, Shao C, Xiao Y, Xiang Y, and Jiang Y. MXene-based responsive hydrogels and applications in wound healing. ChemistrySelect 2024; 9:e202402073
- Nouri A, Rabbath J, Khademi A, Khandan A, Iranmanesh P, and Fahmy M. Reconstruction of pathology induced anterior maxillary defect: A case report. Scientific Hypotheses 2024; 1:72–8
- Barbaz-Isfahani R, Khademi A, Iranmanesh P, Yeganeh MG, Gholizadeh S, Iranmanesh F, et al. Performance and prospects of bioactive endodontic cements: A comparative mechanobiological assess-ment of mineral trioxide aggregate and calcium-enriched mixture cement. Progress in Biomaterials 2025; 14
- Isfahani RB, Nasri P, Khandan A, and Asefnejad Biological esophageal stents: Types, material innovations, clinical applications, and performance for treating burn injuries in biomedical application. Progress in Biomaterials 2025; 14
- Chamlanian Esfahani M, Salimi K, Ahmadi M, Kamyab-Moghadas B, and Khandan A. Biomaterials in nanoparticle-mediated hyperthermia: Revolutionizing cancer treatments with precision heat delivery and enhanced therapeutic efficacy. Nanochemistry Research 2025 :e237536
- Guo X, Li J, Wu Y, and Xu L. Recent advancements in hydrogels as novel tissue engineering scaffolds for dental pulp regeneration. International Journal of Biological Macromolecules 2024; 264:130708
- Janarthanan G, Uthaman SK, Murugesh K, and Vijayavenkataraman S. Exploring the potential of supramolecular hydrogels as advanced bioinks for bioprinting and biomedical applications. International Journal of Bioprinting 2024; 10:3223
- Liu J, Chen J, Liu S, Li T, Chen Y, Chen L, et al. Mechanical training drives structural remodeling of zwitterionic hydrogels. Materials Horizons 2025; 12:7473–85
- Xu Y, Zhang F, Zhai W, Cheng S, Li J, and Wang Y. Unraveling of advances in 3D-printed polymer-based bone scaffolds. Polymers 2022; 14
- Wang Y, Xu Y, Song J, Liu X, Liu S, Yang N, et al. Tumor cell-targeting and tumor microenvironment–responsive nanoplatforms for the multi-modal imaging-guided photodynamic/photother-mal/chemodynamic treatment of cervical cancer. International Journal of Nanomedicine 2024; 19:5837–58
- Pei W, Zhang Y, Zhu X, Zhao C, Li X, Lu¨ H, et al. Multitargeted immunomodulatory therapy for viral myocarditis by engineered extracellular vesicles. ACS Nano 2024; 18:2782–99
- Sun D, Hu Y, Li X, Peng J, Dai Z, and Wang S. Unlocking the full potential of memory T cells in adoptive T cell therapy for hematologic malignancies. International Immunopharmacology 2025; 144:113392
- Yang J, Zhu J, Lu S, Qin H, and Zhou W. Transdermal psoriasis treatment inspired by tumor microenvironment-mediated immunomodulation and advanced by exosomal engineering. Journal of Controlled Release 2025; 382:113664
- Shui G, Zhao Q, Chu H, Zhou X, and Zhang Y. Engineering the surface wettability: Recent advances in oil-water separation membranes. Energy & Environmental Sustainability 2025; 1:100040
- Wong WK, Yin B, Lam CYK, Huang Y, Yan J, Tan Z, and Wong SHD. The interplay between epigenetic regulation and CD8+ T cell differentiation/exhaustion for T cell immunotherapy. Frontiers in cell and developmental biology 2022; 9:783227
- Wong SHD, Yin B, Li Z, Yuan W, Zhang Q, Xie X, et al. Mechanical manipulation of cancer cell tumorigenicity via heat shock protein signaling. Science advances 2023; 9:eadg9593
10.57647/pibm-2025-17331