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. 2025 Nov 19;11(1):2587305. doi: 10.1080/20565623.2025.2587305

Hydrogel-based devices for cancer diagnostics: a systematic review of materials and biomarkers

Rosalina Intan Saputri a, Adelaide Mensah a, Aoife M Rodgers b, Petra G Clark a, Deborah Lowry a, Ahmed Abuelhana a, Aaron J Courtenay a,✉
PMCID: PMC12645877  PMID: 41261726

Abstract

A promising trend in complex cancer care is personalized therapy, a molecular profiling to tailor treatments to each patient’s unique tumor attributes. Different methodologies have been used to identify cancer’s mutation profile, including the use of hydrogel in liquid biopsy. This review aims to assess published works describing the performance of hydrogels as diagnostic devices for cancer biomarker detection. A systematic search was conducted following PRISMA guidelines across five databases: PubMed, Scopus, Embase, MEDLINE, and EBSCO. Studies were screened, selected, and assessed for quality. Relevant data were extracted, including the demographics of the studies, characteristics of the hydrogel, cancer, sample characteristics captured, and detection methods. From 33 studies, various types and forms of hydrogels were discussed. This review identified the most used hydrogel polymers, including acrylamide, PEG, DNA, and alginate. The most frequently observed cancer sites were breast, liver, and cervical uteri. In addition, this work reports that the most captured biomarkers were CTCs and protein markers. Hydrogels have demonstrated a promising platform for detecting cancer biomarkers in the early stages of research. Future investigations are required to optimize and validate the hydrogel application as a diagnostic device in the translational stage.

Keywords: Hydrogel, cancer, diagnosis, early detection, sampling, systematic review

PLAIN LANGUAGE SUMMARY

In past years, cancer treatment has improved. One innovation is a therapy focusing on specific gene changes or mutations that cause the disease in each patient. This approach is called personalized therapy. Because mutations vary from one cancer case to another, detecting the mutation before performing the therapy is necessary. Various devices have been developed to profile mutations related to specific cancers by detecting small molecules inside our body called biomarkers. This study aims to compile and summarize published studies that look at a particular material, called hydrogel, used for cancer biomarker detection. The main advantage of hydrogel as a cancer detector is the potential use for non-painful diagnostic tools, using body fluid. Published studies about hydrogel as a cancer biomarker detection were searched, selected according to relevant criteria, and recorded. From the included studies, several information were compiled, including the studies’ characteristics, source materials of hydrogels, types of cancer being observed, and the biomarkers being detected. From this review, we can identify the stage and potential of using hydrogel as a diagnostic device for cancer, and use it as a reference for relevant studies, which have a greater purpose in earlier cancer detection and overall treatment outcomes.

ARTICLE HIGHLIGHTS

  • This review provides a comprehensive systematic review of hydrogels and their applications in cancer biomarker detection.

  • Hydrogel offers potential alternatives to biofluid diagnostic devices in early pre-clinical research.

  • Further optimization and validation are needed to establish reliable hydrogel-based diagnostics in clinical settings.

1. Introduction

Cancer is a global health concern. According to the International Agency for Research on Cancer (IARC), there were around 20 million new cases of cancer in 2022, and it is predicted to reach 35 million (a 77% increase) by 2050 [1]. Cancer is one of the top three mortality causes in 177 countries at age 30–70 years [2]. It has overtaken cardiovascular disease as the number one cause of death in a high-income country [2,3]. It is estimated that 1 in 5 individuals develop cancer in their lifetime, and 1 in 9 men and 1 in 12 women die from it [1]. With this growing burden, a cancer control strategy is crucial.

Given the complexity of the disease, different modalities have been developed for cancer treatment. Chemotherapy was created in the early 1900s and has been used as the most common cancer treatment until now [4]. In 1960, surgery and radiotherapy were the primary treatments, especially for solid cancers. Later on, the combination of different therapies was utilized to overcome relapse and micrometastases [4,5]. The advancement of molecular biology and genomic technology led to improved targeted chemotherapy for specific molecular targets in 1990 [5]. Since then, targeted or personalized therapy has been developed and has shown promising results in various cancers.

Related to the development of targeted therapy, cancer research has evolved around two main topics: identifying the tumor (1) molecular profiling, and (2) molecular target [6]. Identifying the mutation profile of a particular cancer is the first step in discovering a target and subsequent therapy. The molecular profile or target can be cancer genomic, epigenetic, or microenvironmental. This review systematically examines the role of hydrogel platforms in the initial stages of molecular biomarker profiling, which is used for cancer diagnosis.

Hydrogel, a polymer multinetwork, has been utilized for various purposes in biomedicine. In the past 15 years, hydrogel, in its bulk form or integrated into other devices, has been developed to capture cancer-related biomarkers from body fluids and tissues [7–39]. These innovations are related to the superior properties of hydrogels. The main property of hydrogels is that they can swell and retain water without easily dissolving [40]. It is because of the hydrogel’s hydrophilic functional groups, such as hydroxide and carboxylic acid groups, which allow rapid water absorption and expansion multiple times its weight [41]. When in contact with a solution such as tissue-derived fluid from a liquid biopsy, the molecule adheres to the hydrogel surface and gradually diffuses through the network meshes. This exposure also allows the enlargement of the network meshes and transportation of more/larger molecules [40].

Besides its swelling ability, the characteristics of hydrogels can be tailored according to the intended use. Hydrogels can be fabricated in a wide range of sizes, including macrogels, microgels, and nanogels [42]. The ability to precisely control the size of hydrogels enables their integration into various device platforms or molecules, including biological probes. This ability facilitates the selective capture of specific biomarkers, or for other diagnostic purposes, such as imaging [42–44]. Another distinctive advantage of hydrogels is their ability to respond to various external stimuli, enabling on-demand control of their functional properties, which is not typically possessed by other bioreceptors, such as antibodies [43,45]. These properties might be useful since tumor tissues and their microenvironment differ significantly in pH, temperature, reactive oxygen species, and enzyme expression compared with healthy tissues [42].

In terms of functionality, the application of hydrogels in biomarker capture is projected for liquid biopsy. Until now, tissue biopsy is still a standard for cancer diagnosis, with the aid of imaging techniques such as Computed Tomography or Positron Emission Tomography [46]. Compared to tissue biopsies, liquid biopsies, such as blood, urine, or saliva, are a less invasive method and more accessible for certain types of cancer. For cancer patients, a noninvasive method offers greater comfort, which may enhance patient compliance with early detection protocols and increase the feasibility of ongoing disease monitoring [47]. Therefore, this review aims to evaluate the current performance of hydrogels as diagnostic devices for detecting cancer biomarkers. The objective of this review is to systematically search the literature, compile relevant data, and analyze emerging trends in the application of hydrogels as diagnostic devices for cancer biomarkers.

2. Methods

2.1. Search strategy

The systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The research question is: What is the effectiveness of hydrogels as diagnostic tools for detecting cancer biomarkers? The research question was established based on population criteria: research articles with cancer subjects, exposure: hydrogel used as a direct biomarker sampling tool for cancer detection or diagnosis, and outcome: detection of cancer biomarker.

The search was conducted across five databases: PubMed, Scopus, Embase, MEDLINE, and EBSCO (Dentistry & Oral Sciences) until 31st October 2024. Search terminologies used were Neoplasm (OR Cancer OR Carcinoma OR Tumor OR Tumour) AND Hydrogel (OR Cryogel OR Microgel OR Nanogel OR Moleculary Imprinted Polymer OR Stimuli Responsive Polymer) AND Diagnosis (OR Detection OR Decision OR Biomarker) according to exploded Medical Subject Headings (MeSH) terms, Embase Subject Headings (Emtree), and INDEXTERM. Full search terms and strategies for each database are compiled in Supplementary Table S1.

2.2. Articles selection and data extraction

The search results were managed by Covidence. Duplicates were automatically removed by Covidence and manually removed by the reviewers. Two reviewers independently screened based on the inclusion criteria: (1) Hydrogel as a direct biomarker sampling tool for diagnosing or detecting cancer biomarkers. In this context, ‘direct’ refers to the hydrogel being in immediate contact with the sample, whereby the contained biomarkers are captured intrinsically by the hydrogel matrix itself, rather than using an attached biosensor. For example, a hydrogel microneedle that penetrates the skin of mice in a cancer model [25]; (2) All types of research, such as in vitro, in vivo, preclinical, and/or clinical research, looking at cancer biomarkers; (3) Written in English or Indonesian.

Articles about hydrogel used as a biomarker sampling method for cancer prognosis or treatment, and hydrogel used as an indirect biomarker detection (i.e., combination with receptors or antibodies to capture biomarkers), systematic reviews, literature reviews, conference abstracts, conference posters, conference presentations, books, book chapters, editorials, and letters to the editor were excluded from the analysis. There were no restrictions on publication year.

The first study selection was executed by screening the title and abstract. In cases of doubt, the article was retained for further consideration in the subsequent selection phase. The second study selection was achieved by reading the full article. After the second selection, the included article underwent a qualification assessment using ToxRtool. In case of a disagreement between two reviewers regarding a qualification assessment, a third reviewer was invited, and the majority of the results were used. The reliable studies were continued for data extraction. Extracted variable including hydrogel’s material and characteristics, research type (in vitro/in vivo), cancer sites and types, observed sample, biomarker captured, detection methods, and publication’s year and country. The protocol for this systematic review is registered in PROSPERO (CRD42024600282).

3. Results

As described in the PRISMA flow diagram (Figure 1), 3111 journal articles were retrieved from five databases, with 1010 duplicates detected by both automatic and manual screening. A total of 2101 articles were screened, of which 177 remained for full article reading. Following this, 104 articles were excluded because of following reason: Ineligible outcome or not measuring cancer-related biomarker (7 articles); excluded indication or not for diagnosis (24 articles); non-eligible intervention or not directly capturing biomarker/cancer cell (40 articles); ineligible types of materials or is not hydrogel (56 articles); out-of-scope literatures, including systematic review, literature review, letter to editors, and conference abstract (17 articles). The remaining 33 articles were included for quality assessment with ToxRTool.

Figure 1.

Figure 1.

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PRISMA flow diagram of the hydrogel system for cancer biomarker detection

3.1. Quality assessment

Between the two raters, 81.82% of the included studies were in agreement regarding the final ranking of the ToxRTool. The inter-rater reliability was measured using Gwet’s gamma [48] and yielded a coefficient of 0.801. From the 33 pieces of literature, 31 studies (93.94%) were in vitro, and 2 studies (6.06%) were in vivo. After disagreement evaluation with a third rater of the 31 in vitro studies evaluated, 29 articles were determined to be “reliable without restriction” and 2 articles were determined to be “reliable with restriction”. While all in vivo studies were determined to be “reliable without restriction”. The ToxRTool quality assessment scoring is described in Supplementary Table S3, and the result is summarized in Figure 2. From the quality assessment result, all 33 studies were continued for data extraction [7–39].

Figure 2.

Figure 2.

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ToxRTool quality assessment results from the included in vitro and in vivo studies. Reliability rank 1 (dark grey):”reliable without restriction” and rank 2 (light grey): “reliable with restriction”.

3.2. Literatures demographic

All 33 articles were published after 2010. The number of articles has increased in recent years, with the most published between 2020 and 2024 (48.48%). In comparison, 12.12% of the articles were published between 2010 and 2014, and 39.39% between 2015 and 2019. The distribution of published years is illustrated in Figure 3. Most of the articles were published in China (51.52%), followed by Italy and the United States of America (12.12% each). Published country distributions are illustrated in Figure 4.

Figure 3.

Figure 3.

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Publication year distribution of the included literature.

Figure 4.

Figure 4.

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Publication country distribution of the included literature (created with mapchart.net).

3.3. Cancer sample

Figure 5 maps various sites of cancers and biomarkers observed in the included studies. Breast cancer (42.42%), followed by cancer of the liver (15.15%) and cervix uteri (15.15%), were the most studied cancers for biomarker detection by the hydrogel system. Observed biomarkers were divided into two groups: (1) clinical sample, which was collected from cancer patients’ tissue, and (2) non-clinical sample, which was not collected from cell lines. Eight studies (24.24%) observed clinical samples, 14 studies (42.42%) observed non-clinical samples, and 11 studies (33.33%) observed both clinical and non-clinical samples.

Figure 5.

Figure 5.

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Mapping of cancer sites and biomarkers of the included studies (created with BioRender.com).

3.4. Hydrogel and detected biomarker

Various types and forms of hydrogel were used in the included studies, including bulk hydrogel (36.36%), cell/molecular imprinted hydrogel (21.21%), hydrogel layer/coating (15.15%), nanogel/nanoparticle (12.12%), and hydrogel as a part device or hydrogel microneedle (8.08%). Although each device has different derivatives used for formulation, the most prevalent polymers (including mixtures of different polymers) are acrylamide-based (36.33%), Polyethylene glycol-based (PEG-based) (21.21%), Deoxyribonucleic acid-based (DNA-based) (12.12%), and alginate-based (12.12%). Other polymers used include gelatin, chondroitin sulfate, and chitosan. Some studies also used mixtures of polymers, such as PEG, acrylamide, acrylate, cellulose, polyvinyl alcohol, and tripeptide. Full characteristics of the hydrogel studied are presented in Table 1.

Table 1.

Hydrogel characterization from the capturing device

No. Reference Hydrogel Source Structure Size Composition Crosslinking Ionic charge Responsiveness
1 Aktan et al. 2017 [7] PEG-methacrylate-based maleimide-bearing copolymer nanogel Synthetic Amorphous Nano Copolymer Chemical (thiol-reactive crosslinking) Non-ionic Temperature-responsive
2 Bichsel et al. 2012 [8] PEG-based hydrogel (integrated into microfluidic chip) Synthetic Amorphous Macro Copolymer Chemical (covalent bonding) Non-ionic Conventional hydrogel
3 Chen et al. 2022 [9] Glass layer of CSMA hydrogel Semi-synthetic Amorphous Macro Copolymer Chemical (photo crosslinking) Anionic Photo-responsive
4 Chen et al. 2024 [11] DNA hydrogel for spatially engineered magnetic response (MATCH) Semi-synthetic Chrystalline Macro Semi-IPN Physical (DNA hybridization) + Chemical Anionic Magneto-responsive
5 Chen et al. 2024 [10] Multi-component double-network DNA hydrogel Semi-synthetic Semi-chrystalline Macro IPN Physical (DNA hybridization) + Chemical Anionic Bio-responsive
6 Cheng et al. 2017 [12] Gelatin hydrogel coating on PDMS Scaffold Semi-synthetic Amorphous Macro Homopolymer Physical (thermally reversible gelation) Non-ionic Temperature-responsive
7 Conti et al. 2015 [13] NIPAm-BIS nanoparticle Synthetic Amorphous Nano Copolymer Chemical (covalent bonding) Anionic (VSA shell) Conventional hydrogel
8 Dong et al. 2016 [14] Starch-dithiol-functionalized PEG hydrogel Semi-synthetic Amorphous Macro Copolymer Chemical (thiol-ene reaction) Ampholytic Conventional hydrogel
9 Fredolini et al. 2010 [15] NIPAm-BIS-acrylic acid nanoparticle Synthetic Amorphous Nano Copolymer Chemical (covalent bonding) Anionic Conventional hydrogel
10 Gao et al. 2021 [16] Cell imprinted alginate hydrogel Semi-synthetic Amorphous Macro Homopolymer Physical (ionic crosslinking) Anionic Conventional hydrogel
11 Kim et al. 2021 [17] Alginate-PVA hydrogel sphere Semi-synthetic Amorphous Micro Semi-IPN Physical (ionic crosslinking) + Chemical (PVA) Non-ionic Bio-responsive (degradation)
12 LeValley et al. 2019 [18] PEG-based photopolymerizable hydrogel Synthetic Amorphous Macro Copolymer Chemical (photo crosslinking) Non-ionic Photo-responsive
13 Li et al. 2020 [19] Dually cross-linked acrylamide based hydrogel Semi-synthetic Amorphous Macro Copolymer Physical (hydrogen bonding) + Chemical (covalent bonding) Non-ionic Multi-responsive (pH, optical, chemical)
14 Li et al. 2016 [20] Glycocholic acid molecular imprinted hydrogel Synthetic Amorphous Macro Copolymer Chemical (covalent bonding) Cationic (APMA.HCl) + Neutral (PMMA) Conventional hydrogel
15 Li et al. 2013 [21] Polyacrylamide hydrogel coating on silanized glass Synthetic Amorphous Macro Homopolymer Chemical (covalent bonding) Non-ionic Conventional hydrogel
16 Liu et al. 2020 [22] Phenylboronic acid-functional imprinted hydrogel Synthetic Amorphous Macro Copolymer Chemical (covalent bonding) Non-ionic + ampholytic (boronate affinity) Bio-responsive (sugar)
17 Liu et al. 2019 [23] Acrylamide-based cell imprinted hydrogel matrix Synthetic Amorphous Macro Homopolymer Chemical (covalent bonding) Non-ionic Conventional hydrogel (static imprinting)
18 Pan et al. 2022 [24] Magnetic polyethyleneimine nanoparticle Synthetic Amorphous Nano Copolymer Chemical (covalent bonding) Ampholytic Multi-responsive (magnetic, biomolecular interaction)
19 Park et al. 2023 [25] Alginate hydrogel microneedle Semi-synthetic Amorphous Micro Homopolymer Physical (ionic crosslinking) Anionic Conventional hydrogel
20 Piloto et al. 2022 [26] Molecular imprinted cellulose hydrogel Semi-synthetic Semi-chrystalline Macro Semi-IPN Physical (hydrogen bonding) Non-ionic Conventional hydrogel
21 Schmidt et al. 2021 [27] HA-PNIPAM microgel coating on glass culture Semi-synthetic Amorphous Micro Copolymer Physical (thermal aggregation) + Chemical (covalent) Anionic (HA) Multi-responsive (temperature, pH)
22 Shohatee et al. 2018 [28] PEGDA microparticle Synthetic Amorphous Micro Homopolymer Chemical (photocrosslinking) Non-ionic Conventional hydrogel
23 Sun et al. 2024 [29] PEG-acrylamide imprinted hydrogel Synthetic Amorphous Macro Copolymer Chemical (covalent bonding) Non-ionic Conventional hydrogel (static imprinting)
24 Tang et al. 2023 [30] Engineered DNA hydrogels  Semi-synthetic (rolling circle amplification) Chrystalline Macro Homopolymer Physical (DNA hybridization) Anionic Bio-responsive
25 Taverna et al. 2017 [31] Polyacrylamide hydrogel Synthetic Amorphous Macro Homopolymer Chemical (covalent bonding) Non-ionic Conventional hydrogel
26 Taverna et al. 2019 [32] Polyacrylamide hydrogel Synthetic Amorphous Macro Homopolymer Chemical (covalent bonding) Non-ionic Conventional hydrogel
27 Wang et al. 2017 [33] Collagen-polyacrylamide hydrogel Semi-synthetic Amorphous Macro Copolymer Chemical (covalent bonding) Non-ionic Conventional hydrogel
28 Wang et al. 2021 [34] Anti-EpCAM Magnetic Nanoparticle Hydrogel from various methacrylate Synthetic Amorphous Nano Copolymer Chemical (covalent bonding) + Physical (magnetic interaction) Ampholytic Multi-responsive (magnetic, biomolecular interaction)
29 Wei et al. 2019 [35] Calcium alginate encapsulation matrix Semi-synthetic Amorphous Micro Homopolymer Physical (ionic crosslinking) Anionic Conventional hydrogel
30 Ye et al. 2020 [36] Engineered DNA hydrogels  Semi-synthetic (hybridization chain reaction) Chrystalline Macro Homopolymer Physical (DNA hybridization) Anionic Bio-responsive
31 Yoshino et al. 2016 [37] PEGDA photopolymerized hydrogel Synthetic Amorphous Macro Homopolymer Chemical (photo crosslinking) Non-ionic Conventional hydrogel
32 Zhang et al. 2024 [38] Chitosan based hydrogel Semi-synthetic Semi-chrystalline Macro Copolymer Physical (hydrogen bonding) + Chemical (covalent bonding) Non-ionic Bio-responsive
33 Zhou et al. 2016 [39] Peptide nanonet/hydrogel Semi-synthetic Amorphous Nano Homopolymer Physical (self-assembly and hydrogen bonding) Ampholytic Bio-responsive
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PEG = Polyethylene glycol; CSMA = Chondroitin sulfate methacryloyl; DNA = Deoxyribonucleic acid; PDMS = Polydimethylsiloxane; NIPAm = N-isopropylacrylamide; BIS = N,N’-methylenebisacrylamide; PVA = Polyvinyl alcohol; HA = Hyaluronic acid; PNIPAM = Poly N-Isopropylacrylamide; EpCAM = Epithelial cell adhesion molecule; PEGDA = Polyethylene glycol diacrylate; VSA = Vinylsulfonic acid; APMA.HCl = N-(3-Aminopropyl)methacrylamide Hydrochloride; PMMA = Polymethyl methacrylate; IPN = Interpenetrating polymer network.

Circulating tumor cells (CTCs) were the main biomarkers captured with hydrogels (60.61%). CTCs were isolated from patient-derived fluids and mostly from cancer cell line models. From the captured CTCs, additional biomarkers were observed, including DNA, ribonucleic acid (RNA), micro ribonucleic acid (miRNA), exosomes, and proteins. Other cancer-related biomarkers have been observed, including leukocytes and natural killer cells (NK cells), derivatives of carbohydrates and lipids, and gene mutations. Table 2 summarizes the hydrogel and captured biomarkers.

Table 2.

Hydrogel and detected cancer biomarkers

No. Main hydrogel component Monomer/molecule chemical structurea Detected biomarkers
1 Acrylamide graphic file with name IFSO_A_2587305_ILG0001_C.jpg CTCs
Proteins/Peptides (including CD44)
Lysophosphatidic acid
Glycocholic acid
Cholic acid
2 (P)EG graphic file with name IFSO_A_2587305_ILG0002_C.jpg CTCs
VEGF
EGFR
3 DNA graphic file with name IFSO_A_2587305_ILG0003_C.jpg CTCs
miRNAs
Proteins
Exosomal miRNA
4 Alginate graphic file with name IFSO_A_2587305_ILG0004_C.jpg CTCs (and gene mutations)
Exosomes
5 Chondroitin sulfate graphic file with name IFSO_A_2587305_ILG0005_C.jpg CTCs (and gene mutations)
Leukocytes
6 Gelatin graphic file with name IFSO_A_2587305_ILG0006_C.jpg CTCs
DNA
RNA
7 Chitosan graphic file with name IFSO_A_2587305_ILG0007_C.jpg Glycoproteins
8 Methacrylate graphic file with name IFSO_A_2587305_ILG0008_C.jpg CTCs
9 PEG and Methacrylate graphic file with name IFSO_A_2587305_ILG0009_C.jpg CTCs
10 PEG and Acrylamide graphic file with name IFSO_A_2587305_ILG0010_C.jpg CTCs
Alpha-fetiprotein
NK Cells
TP53
mRNA
Proteins
11 Alginate and PVA graphic file with name IFSO_A_2587305_ILG0011_C.jpg CTCs and Exosomes
12 PEI and Methacrylate graphic file with name IFSO_A_2587305_ILG0012_C.jpg CTCs
13 Cellulose and PVA graphic file with name IFSO_A_2587305_ILG0013_C.jpg CA19-9
14 Tripeptide of D-Phenylalanine and D-Tyrosine graphic file with name IFSO_A_2587305_ILG0014_C.jpg Proteins
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CTC = Circulating tumor cells; CD44 = Cluster of differentiation 44; PEG = Polyethylene glycol; VEGF = Vascular endothelial growth factor; EGFR = Epidermal growth factor receptor; DNA = Deoxyribonucleic acid; miRNA = Micro ribonucleic acid; NK = Natural killer; TP53 = Tumor protein p53; mRNA = Messenger ribonucleic acid; PEI = Polyetherimide; PVA = Polyvinyl alcohol; CA19-9 = Carbohydrate Antigen 19-9.

a

Generated from ChemSpider.com.

Various detection methods have been employed for biomarkers. Fluorescent imaging was primarily used to visualize CTCs and cellular organelles. Meanwhile, detection methods for protein components vary from liquid chromatography to mass spectrometry or enzyme-linked immunosorbent assay (ELISA). Further assessment, such as sequencing, was also performed to observe gene mutation. Complete literature data extraction is presented in Supplementary Table S2.

4. Discussion

With advancements in molecular analysis and precision oncology strategy, liquid biopsy is now being explored as a less invasive alternative to surgical biopsy [47,49]. Additionally, liquid biopsy has demonstrated the ability to sensitively detect cancer biomarkers such as CTCs and circulating tumor DNA (ctDNA), significantly enhancing current cancer diagnosis and early detection, progression monitoring, providing prognostic information, and supporting therapy decisions [49–51]. To improve the efficiency of liquid biopsies, researchers are investigating standardized approaches, such as the incorporation of specialized sampling devices. Hydrogel has been used for transporting molecules, especially drugs [52]. Following the same principle, hydrogels have been studied as devices to capture body fluids and their contents. According to studies included in the current review, hydrogels have been developed as detection devices for cancer-related biomarkers within the past 15 years. This recent innovation has highlighted the potential of hydrogels as a diagnostic alternative. However, a gap remains in the current stages of research and development.

From the 33 included studies, only one, out of the two in vivo studies, reported the biomarkers captured in a mouse model. This study is from Park et al., which utilized a hydrogel microneedle to collect exosomes from the back skin of mice with colorectal and skin cancer models [25]. Although a study has demonstrated the potential of using hydrogel application on cancer tissue, the remaining 31 studies have focused on developing specific devices and establishing proof of concept through in vitro research. These findings illustrate that research on hydrogels as devices for cancer biomarker detection is still in its early stages, even when patient samples are employed. Meanwhile, in clinical settings, hydrogels are mostly used for drug delivery, tissue regeneration or scaffolds [53], but there is no known ongoing clinical trial for cancer diagnostics. Future studies could aim to develop the device’s application in in vivo cancer models that more closely resemble the clinical characteristics of cancer.

This systematic review classified hydrogel materials according to the primary polymer used in their formulation. For formulations containing multiple polymers, the classification was based on the polymer present in the largest proportion. If two or more polymers were present in equal amounts or were both considered primary components, the hydrogel was classified as a mixture of those polymers, as described in Table 2. Characterization of hydrogels used in each study was also described (Table 1). One of the characteristics is the hydrogel’s source. Some hydrogels, such as DNA and alginate, are classified as semi-synthetic, despite their natural origin. This is because the fabrication of natural hydrogels in all included studies was combined with synthetic materials, such as derivatives of synthetic polymers or crosslinkers.

Acrylamide emerged as the most frequently used primary polymer, being investigated in 12 studies. It has also been shown to capture most biomarkers (Table 2). To form the gel, acrylamide monomers bind with bis-acrylamide crosslinkers and ammonium persulfate (APS) and/or N,N,N’,N’-tetramethylethylenediamine (TEMED) as initiators/catalysts, with a method called free radical polymerization [13,31,32]. This method allows for tailoring the properties of hydrogels by adjusting the concentration of the crosslinker or initiators/catalysts. Increasing the crosslinker will result in higher cross-linking, shorter polymer chains, increase polymer strength, but lower the swelling ability. Meanwhile, decreasing the initiators will slow down the polymerization, increasing the length of the polymer chain, producing a hydrogel with high porosity and higher swelling [54,55].

Acrylamide-based hydrogel has a high absorption capacity, which is up to 48.39 g water/g gel, and up to 10.87 × 10−4 cm2 s−1 diffusion rate [56]. For cancer biomarker detections, acrylamide was utilized in different hydrogel forms, including nanoparticles [13,15], film [19], coating [21,27], molecular/cell-imprinted hydrogel [20,22,23], and bulk hydrogel [31–33]. Acrylamide-based hydrogel has been shown to have effective retention capabilities for a significant variety of proteins [31,32]. Studies that fabricated acrylamide as nanoparticles incorporated size exclusion, enabling only low-molecular-weight proteins and peptides to penetrate and be entrapped by the hydrogels [13,15]. Acrylamide hydrogels are also engineered as cell-imprinted hydrogels and selective-binding hydrogels to capture specific cells and proteins [19,20]. Another approach to the acrylamide hydrogel device is the incorporation of enzymes that digest protein from the tissue region of interest by the hydrogel disc, followed by the extraction of captured proteins [31,32].

Following acrylamide, hydrogel formulations containing PEG were reported in 7 studies. In comparison, DNA and alginate were reported in 4 studies. CTCs were identified as the most frequently captured biomarkers across three hydrogel materials. In the current study, PEG hydrogels were primarily fabricated as conventional hydrogels as encapsulation matrices. However, Aktan et al. developed a hydrogel by combining PEG and methacrylate, resulting in a temperature-responsive material, and LeValley et al. created photo-responsive hydrogels from PEG diacrylate. Both studies demonstrated the ability to capture and release CTCs on demand [7,18].

PEG-based hydrogels can be fabricated through various methods of polymerization and co-polymerized with multiple materials, which enables PEG to be precisely engineered with tailored structures and functions while maintaining robust stability [7,18,29]. Hence, different PEG-based hydrogels have considerable variation in properties. For example, a study on polyethylene glycol diacrylate (PEGDA) hydrogel reported up to a 9.4 swelling ratio, which decreased with lower crosslinking [57]. Meanwhile, a hydrogel from 8-arm PEG has volumetric swelling ratios >1.5 [58]. Additionally, the molecular weight of PEG also influences its properties. Low molecular weight PEG (700 Da) showed a 2–2.3 mesh size, which allowed the diffusion of protein and nutrients, such as glucose and insulin [57]. A study by Wu et al. reported that higher molecular weight PEGs (such as PEG 4700 and PEG 20000) have longer polymer chains, which display a greater tendency to interact with proteins. This effect is likely attributed to the presence of hydrophobic CH2–CH2—groups within the PEG backbone, which promote hydrophobic interactions with protein surfaces [59].

DNA-based hydrogels included in this review are mainly fabricated into stimuli-responsive hydrogels, including magnetic [11] and biological stimuli [10,30,36] to selectively capture targeted components. DNA is fabricated into a hydrogel with chemical crosslinkers, enzyme-catalyzers, or a self-spinning method. Self-spinning DNA is reported to have a swelling ratio of over 600% [60]. For chemically crosslinking DNA, the swelling behavior and pore size of DNA hydrogels depend on the concentration of crosslinkers during fabrication [61]. One superior attribute of DNA as a polymer is its biocompatibility and biodegradation, because nucleotides are naturally safe compounds [61,62]. Because of the biocompatibility and capability to be designed to smart-responsive hydrogels, DNA has developed into an implantable biosensing system and tissue engineering [61]. This review observed further application of DNA hydrogel for cancer detection. A study by Chen et al. modified the surface DNA hydrogel to mimic the structure and molecular binding properties of CTCs, enabling the selective and static capture of live CTCs with real-time fluorescence detection [10]. Another study by Ye et al. incorporated aptamers that specifically bind to epithelial cell adhesion molecule on the CTCs’ surface, leading to the formation of a hydrogel matrix encapsulating CTCs [36]. These studies demonstrated that DNA hydrogels possess bioresponsiveness and biocompatibility, which are essential properties for further in vivo applications.

Another polymer found in the included studies is alginate. In addition to biocompatibility and adaptability, alginate exhibits high swelling and absorption capacities because of its polysaccharide composition [63]. A study by Varaprasad et al. described that the alginate-acrylamide hydrogel with the highest alginate composition has the highest swelling (109.3 g/g) and diffusion coefficient (3.5116 cm2 s−1) [64]. Alginate can be fabricated into a bulk hydrogel in the form of hydrogel spheres/droplets [17,35], cell-imprinted hydrogel [16], and hydrogel microneedles [25]. In a study by Gao et al., alginate was engineered into a cell-imprinted hydrogel, which demonstrated excellent biocompatibility by supporting cell adhesion and proliferation [16]. Relatedly, Wei et al. also fabricated microdroplets of alginate hydrogel to encapsulate targeted cells while preserving their integrity [35]. In addition to being utilized in the only included in vivo studies, the biocompatibility of alginate hydrogel is advantageous for real-time monitoring and advanced cellular analysis.

Due to the wide application of hydrogels for cancer biomarker detection devices, this review focused on the direct capture of biomarkers. This means the molecule should be in contact with the hydrogel matrix and move inside it. There are several examples of hydrogel being used as a detection device, but as a base for bioreceptors that bind to the target biomarkers [65,66], which are then excluded. CTCs are the biomarkers most frequently observed in the included studies. CTCs are cells that detach from the primary tumor and enter the bloodstream to different parts of the body [51]. CTCs possess a mutational profile closely resembling the primary tumor, reflecting its heterogeneity. However, CTCs are more commonly detected in advanced stages of cancer rather than in early stages. As a result, their presence is primarily used as a prognostic or metastatic biomarker, rather than for early cancer detection [47,51]. Therefore, further studies are required to identify reliable biomarkers for early cancer detection, such as circulating tumor DNA or a specific protein marker [51].

There is a wide variation in the methods and results of biomarker detections from the review. Most results were observed at the cellular level using imaging, such as fluorescent microscopy and electron scanning microscopes. Other studies used a variety of assays, such as PCR, ELISA, mass spectrometry, and liquid chromatography, to observe RNA, miRNA, and proteins. Three studies conducted sequencing analyses to identify mutations in the target genes [9,29,35]. Because of this variation, it is challenging to statistically compare the accuracy of detection using meta-analysis. However, the comparison is possible with more published research within a similar hydrogel device or methodology. Further studies could aim to compare specific methods for detecting certain biomarkers to build information on prospective hydrogel materials as cancer diagnostic tools.

While identifying detectable biomarkers, most studies do not quantify their concentrations, reporting only presence or absence. Clinically, these biomarkers are frequently observed at very low concentrations. This low quantity could raise concerns about sampling strategy and analytical challenge, as it can fall below the detection limits of even the most advanced assays. While hydrogel-based sampling methods can enhance the detection of these biomarkers by pre-concentrating them from complex biological samples, there is no standardized diagnostic performance. Therefore, further research and validation are needed to establish standardized protocols and ensure consistent diagnostic accuracy in hydrogel-based sampling.

5. Conclusion

Hydrogels, whether detached or integrated, have demonstrated a promising platform for detecting cancer biomarkers. The classification of hydrogels in relation to various types of biomarkers has been discussed in this review. This advancement offers potential alternatives for a noninvasive diagnosis method and establishes the foundation for improved identification and monitoring in oncology. However, the current preliminary stage of the work and the insufficiency of standardized diagnostic performance highlight the need for further optimization and validation of the application in the translational stage. Establishing reliable and reproducible hydrogel-based diagnostics is clinically relevant, as it could improve early cancer detection, enable prompt and appropriate intervention, and ultimately enhance patient outcomes.

6. Expert opinion

This systematic review highlights the growing development of hydrogel-based devices for cancer biomarker detection and sample collection. With the rise of molecular profiling and big data analytics, hydrogels offer a bridge between the real clinical world, noninvasive sampling, and laboratory precision diagnostics. Their tunable mesh size, affinity chemistries, and stimuli-responsive properties enable pre-concentration and protection of scarce biomarkers, positioning them as a credible next-generation platform for liquid biopsy.

Most current studies remain at the proof-of-concept stage, with limited in vivo data and a predominant focus on CTCs rather than earlier and low-abundance biomarkers such as ctDNA, exosomal RNA, or protein signatures. Translating this promise into clinical utility will require standardized performance metrics, benchmarking against current diagnostic methods, and reproducible large-scale manufacture.

Despite these challenges, the substantial progress of the past decade underscores the strong scientific rationale and translational potential of hydrogel-based diagnostics. With continued optimization, validation, and clinical evaluation, these hydrogel systems could enable minimally invasive, repeatable, and accessible cancer diagnostics that align closely with the vision of personalized therapy and precision oncology. Integrating AI-driven data analysis and design platforms will further accelerate material innovation and diagnostic development, aiding the progress toward clinical adoption of hydrogel-based diagnostic profiling systems.

Supplementary Material

Supplemental Material
IFSO_A_2587305_SM3708.pdf (164.1KB, pdf)

Acknowledgments

The authors would like to acknowledge Joan Atkinson from Ulster University Library for supporting the search strategy and database selection.

Funding Statement

This work was conducted as part of the PhD program funded by the Vice-Chancellors Research Scholarship (VCRS) and the Alan Burges Scholarship at Ulster University.

Author contributions

Study conception and design: RIS and AJC; Articles search and selection: RIS, AM, and AJC; Data extraction, qualify assessment, and synthesis: RIS, AM, PGC, and AJC; Initial manuscript drafting: RIS, AMR, and AJC; Manuscript critical revision and approval: RIS, AM, AMR, PGC, DL, AA, and AJC.

Use of generative AI tools

The authors used Grammarly (v1.2.208.1781) software to improve the manuscript’s grammar accuracy and overall clarity.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

References

Papers of special note have been highlighted as either of interest (*) or of considerable interest (**) to readers.

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