Preliminary study on the application of guar gum-based hydrogel in sepsis therapy

Estudo preliminar sobre a aplicação de hidrogel à base de goma guar no tratamento da sepse

Abstract

The oxidized guar gum-based hydrogel crosslinked with gelatin (OxGG:Gel), presenting antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), high cell viability and non-irritating nature, was evaluated in the rat experimental model of sepsis. Sepsis was induced by cecal ligation and puncture (CLP) and the controls (SHAM) underwent a laparotomy and cecal exposure. After 6 h, CLP and SHAM received the precursor solution mixture of OxGG:Gel (OxGG and gelatin) at 2% concentration in single dose (20 mg/kg; i.p.) or daily at 5% concentration (50 mg/kg; p.o.) for 5 days. Clinical signs and survival rate were analyzed before and after induction. The treatment of the CLP group with 2% solution (20 mg/kg i.p.) reduced signs of prostration and piloerection and was protective in parameters of temperature and glycemia compared to CLP. However, the per oral application of a 5% concentrated solution (50 mg/kg), not only lacked effect but also seemed to induce side effects (blindness, suffocation, and increased respiratory rate). In conclusion, OxGG:Gel administered in septic rats by intraperitoneal route at 20 mg/kg, but not per oral at 50 mg/kg, reduced signs of prostration and piloerection and showed a protective effect on temperature and glycemia. The adhesion of the viscous 5% solution to the mucosa, and rapid gelation may obstruct the airways, leading to respiratory distress and subsequent animal death. Since these adverse effects appeared in both SHAM and CLP groups, they can be assigned to the administration route rather than the hydrogel’s chemical or biological properties. The administration route and concentration modulate the therapeutic efficacy of hydrogels for sepsis management.

Keywords:
galactomannan; gelatin; OxGG:Gel; administration route; sepsis

Resumo

O hidrogel à base de goma guar oxidada reticulada com gelatina (OxGG:Gel), que apresenta atividade antibacteriana contra Staphylococcus aureus resistente à meticilina (MRSA), alta viabilidade celular e natureza não irritante, foi avaliado em modelo experimental de sepse em ratos. A sepse foi induzida por ligadura e punção cecal (CLP) e os controles (SHAM) foram submetidos à laparotomia e exposição cecal. Após 6 h, CLP e SHAM receberam a solução precursora de OxGG:Gel (OxGG e gelatina) na concentração de 2% em dose única (20 mg/kg; i.p.) ou diariamente na concentração de 5% (50 mg/kg; v.o.) por 5 dias. Os sinais clínicos e a taxa de sobrevida foram analisados ​​antes e após a indução. O tratamento do grupo CLP com solução a 2% (20 mg/kg i.p.) reduziu os sinais de prostração e piloereção, e foi protetor em relação aos parâmetros temperatura e glicemia em comparação ao CLP. No entanto, a aplicação oral de uma solução concentrada a 5% (50 mg/kg) não foi eficaz e induziu efeitos colaterais (cegueira, sufocação e aumento da frequência respiratória). Em conclusão, OxGG:Gel administrado em ratos sépticos por via intraperitoneal a 20 mg/kg, mas não por via oral a 50 mg/kg, reduziu os sinais de prostração e piloereção e efeito protetor na temperatura e glicemia. A adesão da solução viscosa a 5% à mucosa e a rápida gelificação podem obstruir as vias aéreas, levando à dificuldade respiratória e subsequente morte do animal. Como esses efeitos adversos apareceram nos grupos SHAM e CLP, eles podem ser atribuídos à via de administração e não às propriedades químicas ou biológicas do hidrogel. A via de administração e a concentração modulam a eficácia terapêutica dos hidrogéis no manejo da sepse.

Palavras-chave:
galactomanana; gelatina; OxGG:Gel; via de administração; sepse

1. Introduction

Sepsis affects over 48 million people annually, with a global mortality rate of 20–40% (Xiong et al., 2025). Sepsis is life-threatening organ dysfunction from dysregulated host response to infection (Singer et al., 2016; Kumar et al., 2024), that presents fever, rapid breathing, hypotension, and can progress to multiorgan failure (Su et al., 2023). Despite advances in critical care, sepsis remains a leading cause of death in Intensive Care Units, complicated by clinical heterogeneity, delayed diagnosis, and antimicrobial resistance, highlighting the urgent need for novel therapies (Giamarellos-Bourboulis et al., 2024; Wang et al., 2025; Tang et al., 2025).

Macromolecular drugs (>1000 Da) have emerged as promising candidates for sepsis therapy, offering greater specificity, efficacy, and half-life than small molecules (Su and Shuai, 2020). Polysaccharides, natural macromolecules of glycosidic-linked monosaccharides, are gaining attention in sepsis therapy. Recent studies highlight guar gum (Tang et al., 2025), Astragalus (Chai et al., 2025), polygalacturonic acid (Xiong et al., 2025), Poria cocos (Yang et al., 2025), hyaluronic acid and heparan sulfate (Li et al., 2025), red ginseng (Liu et al., 2025), and chitosan (Qian et al., 2021), some as hydrogel formulations.

Hydrogels are versatile biomaterials showing emerging potential in sepsis therapy, though still underexplored (Amengual-Tugores et al., 2023). Recent studies report their ability to suppress inflammation and protect organs using diverse formulations, including polygalacturonic acid–coated, antibiotic-loaded silica nanoparticles (Xiong et al., 2025), cobalt-containing hyaluronic acid/chitosan systems (Wang et al., 2025), curcumin-loaded chitosan/polyacrylamide (Qian et al., 2021), and resveratrol-based nanopeptides (Wang et al., 2025). These studies highlight the promise of macromolecular hydrogels as innovative platforms for sepsis therapy, while emphasizing the need for further research, particularly given the experimental challenges.

Most studies on sepsis therapy rely on in vitro assays focusing on physicochemical characterization, biochemical and histological parameters, and bactericidal properties. In vivo models, however, lack a standardized protocol for hydrogel administration. Ji et al. (2025) and Koide et al. (2021) employed intravenous injection via the tail vein but referred to their systems as nanogels or hydrogel nanoparticles, being Ji et al. (2022) describing them as a “nano gel solution”. For other diseases, hydrogel delivery routes have varied, including subcutaneous administration of injectable hydrogels (Lin et al., 2023) or precursor solutions prior to gelation (Wang et al., 2023), topical application to dorsal skin or intercostal spaces (Xiang et al., 2025; Xia et al., 2022), and intraperitoneal administration (Shi et al., 2020). Thus, administration routes must be carefully considered, as hydrogels are not a soluble material and their behavior depends on the delivery strategy.

Hydrogels based on oxidized guar gum (OxGG), combined with N-succinyl chitosan or gelatin (Gel), exhibit strong intrinsic antibacterial activity against common pathogens, including E. coli, S. aureus, and MRSA, while providing biocompatibility, self-healing, and injectability (Oliveira et al., 2023; Canafístula et al., 2025). Notably, the OxGG:Gel hydrogel demonstrates even more potent antibacterial activity (Canafístula et al., 2025).

Since S. aureus, E. coli, and multidrug-resistant pathogens such as MRSA are among the most frequently isolated organisms in sepsis patients (Kumar et al., 2024), these findings indicate that the OxGG:Gel hydrogel may have therapeutic potential in sepsis management. Therefore, this study aimed to assess the efficacy of OxGG:Gel hydrogel in a rat model of sepsis and to investigate potential routes of administration.

2. Materials and Methods

2.1. Preparation of hydrogel

The hydrogel was prepared by combining oxidized guar gum (OxGG) and gelatin via Schiff base chemistry to form stable imine linkages. Guar gum was partially hydrolyzed and oxidized (61% oxidation) following modified protocols (Tang et al., 2025; Silva et al., 2020), purified by dialysis, and freeze-dried. Detailed physicochemical characterization is reported by Canafístula et al. (2025). Two hydrogel formulations were prepared: OxGG:Gel5 and OxGG:Gel2. The OxGG:Gel5 hydrogel was obtained by mixing 5% (w/v) OxGG and 5% (w/v) gelatin solutions in PBS at 30:70 ratio, whereas OxGG:Gel2 was prepared using 2% (w/v) solutions under the same conditions. The OxGG:Gel5 formulation underwent gelation at 25 ± 2 °C within 90 minutes, forming a highly porous network with an average pore size of ~190 µm. Notably, this hydrogel is injectable: the precursor solutions can be mixed and administered in liquid form, where gelation subsequently occurs in situ.

2.2. Animals

Male Wistar rats (250 – 300 g) were maintained under adequate conditions (22- 25 °C, 12 h light/dark cycle), receiving filtered water and food ad libitum, and were handled according to protocols approved by the Ethics Committee on Animal Use (CEUA) of the State University of Ceará (nº 31032.001150/2023-91), following the National Research Council Committee for the Update of the Guide for the Care and Use of Laboratory Animals (2011).

2.3. Sepsis induction

Sepsis was induced after intraperitoneal (i.p.) anesthesia with ketamine (90 mg/kg) and xylazine (10 mg/kg) in male Wistar rats by cecal ligation and puncture (CLP) (adapted from Hubbard et al., 2005). The septic animals (CLP) had the cecum exposed, ligated, perforated (sterile needle 18-gauge) ten times, pressed for extravasation of fecal content, being the musculature and skin sutured (sterile 4-0 silk line). Control animals (SHAM) underwent similar laparotomy and cecal exposure. Six hours after surgery, CLP and SHAM animals received either single intraperitoneal (i.p.) dose of the OxGG:Gel2 precursors solution mixture (20 mg/kg, ~250-300 µL) or a daily oral dose of the OxGG:Gel5 precursors solution mixture (50 mg/kg, ~250-300 µL) for five consecutive days. Although sepsis is treated by intravenous administration, due to the viscosity of the precursors solution and the possibility of generating embolism, precursors solution mixture of OxGG:Gel hydrogels were administered per oral and intraperitoneal routes (Figure 1).

Figure 1
Schematic representation of experimental protocols to evaluate the OxGG:Gel effect in septic rats. Sepsis was induced by cecal ligation and puncture (CLP), and control animals (SHAM) underwent to laparotomy and cecal exposure only. After 6 h, CLP and SHAM received OxGG:Gel in single dose (20 mg/kg; i.p.) or daily (50 mg/kg; p.o.) for 5 days. Clinical signs and survival were analyzed before and after induction.

2.4. Survival rate

The animal’s survival rate and clinical signs (piloerection, prostration, bleeding, tremor, diarrhea, temperature and glycemia) were evaluated at 6, 8, and 12 h, and every 24 h for 7 days (Figure 1). The clinical signs scale was established and adapted from Mai et al. (2018): (0) absent; (1) slight; (2) moderate; (3) intense.

2.5. Statistical analysis

Data are presented as mean ± S.E.M. (n = 5-7) and analyzed using Graph Pad Prism version 9.3.1. by One-way or Two-way ANOVA followed by Tukey's multiple comparison test. Nonparametric data (clinical sepsis signs) were expressed as median (minimum-maximum) and analyzed by the Mann-Whitney test. The survival rate was evaluated using the Kaplan–Meier survival curve, being analyzed using the log-rank test, and the Shapiro Wilk test used to check the normality of data distribution. Statistical differences were considered at p ˂0.05.

3. Results

3.1. Effect of the OxGG:Gel2 hydrogel by intraperitoneal treatment in septic rats

Figure 2 shows that SHAM animals treated or not with the precursors solution mixture OxGG:Gel2 (20 mg/kg; i.p.) presented a 100% survive rate (7/7), while CLP presented only 28.6% (2/7) at the 3^rd day after induction. In addition, OxGG:Gel2 treatment did not reduce mortality, with a survival rate of 14.3% (1/7).

Figure 2
Effect of intraperitoneal treatment with OxGG:Gel on the survival rate of septic rats. CLP or SHAM received precursor’s solution of hydrogels OxGG:Gel2 (20 mg/kg; i.p.) 6 h after surgery and the animals’ survival was evaluated for 7 days. Mean ± S.E.M. (n = 7). *p<0.05 vs. SHAM; #p< 0.05 vs. CLP.

CLP septic group showed increased prostration, piloerection, nasal and/or eye bleeding and tremor up to 12 hours compared to SHAM. The treatment of CLP animals with precursors solution mixture of OxGG:Gel2 (20 mg/kg; i.p.) reduced signs of prostration at 12 hours [2 (0-3) vs. CLP: 3 (3-3)] also as, piloerection at 8 hours [1 (0-2) vs. CLP: 2 (1-3)] and 12 hours [1 (0-2) vs. CLP: 3 (2-3)] (Figure 3AB). SHAM animals, treated or not with OxGG:Gel (20 mg/kg; i.p.), showed no alteration.

Figure 3
Effect of intraperitoneal treatment with OxGG:Gel2 on temperature and glycemia of septic rats. CLP or SHAM animals received OxGG:Gel2 (20 mg/kg; i.p.) 6 h after surgery. Prostration (A), piloerection (B), temperature (C) and glycemia (D) were determined and accompanied for 7 days. Mean ± SEM (n = 5-7). *p<0.05 vs. SHAM; #p<0.05 vs. CLP.

Temperature (Figure 3C) and glycemia (Figure 3D) were also evaluated for 7 days after surgery. CLP animals reduced glycemia at the 6^th hour (246.4 ± 34.20 vs. SHAM: 317 ±14.52 mg/dL) and at the 8^th hour (170.2 ± 36.43 vs. SHAM: 229.7 ± 26.86 mg/dL). OxGG:Gel2 treatment (20 mg/kg; i.p.) increased glycemia at the 6^th hour (p<0.0001; 22%) and at the 8^th hour (p=0,0196; 26%) compared to CLP (Figure 3D). Temperature in CLP was increased at the 6^th hour (35.25 ± 0.16 vs. SHAM: 33.65 ± 0.41 ºC) and decreased at the 8^th (34.85 ± 0.38 vs. SHAM: 35.55 ± 0.22 ºC) and the 12^th hour (33.66 ± 0.30 vs. SHAM: 35.35 ± 0.26 ºC (Figure 3C). CLP + OxGG:Gel2 treated animals presented decreased temperature at the 6^th hour (p=0,0005; 5%), similar to CLP (Figure 3C). SHAM animals showed no changes in glycemia or temperature.

3.2. Effect of OxGG:Gel5 treatment per oral in septic rats

Potent antibacterial activity was achieved with the OxGG:Gel5 hydrogel (Canafístula et al., 2025), which justified its selection for evaluation in septic rats. However, oral administration of the precursor solution mixture at 5% concentration in CLP and SHAM, given at the highest dose (50 mg/kg/day) during the survival study, not only failed to produce therapeutic benefit but also exhibited blindness, respiratory distress within hours after gavage, and increased respiratory rate up to 24 h. Moreover, all CLP animals receiving oral hydrogel died within 24 h (data not shown).

4. Discussion

In this research we used an animal model of sepsis induced by CLP, a model considered the gold standard for pathophysiological processes of sepsis in humans (Dejager et al., 2011). In agreement with our results, the literature shows that the survival rate of septic animals induced by CLP is between 20 and 40%, reaching this range until the third day of the survival curve (Fang et al., 2020; He et al., 2023).

Sepsis is currently treated in hospital with intravenous administration of fluids, antibiotics, and vasopressor medications, and mechanical ventilation, when necessary (Evans et al., 2021). However, due to the viscosity of the precursor’s solution of OxGG:Gel2 hydrogels (oxidized guar gum and gelatine) and the possibility of generating embolism, we decided to administer the mixture per intraperitoneal. Al Shoyaib et al. (2019) demonstrated that large volumes of solution (up to 10 mL/kg) can be safely intraperitoneal administered to rodents, which may be advantageous for agents of poor solubility. This route is especially common in chronic studies involving mice for which repetitive intravenous access is challenging. The main disadvantage of this route is that it is minimally used in clinics, since experimental studies indicate that molecules are absorbed from visceral peritoneum by diffusion through splenic, inferior and superior mesenteric capillaries and drain into the portal vein or by the lymphatic vessels (Al Shoyaib et al., 2019).

During the survival assessment, clinical signs observed in the septic animals were significantly altered, presenting prostration, bleeding, piloerection, tremor, glycemia and high temperature, signs consistent with other studies (Nakagawa et al., 2007; Mai et al., 2018). The precursor’s solution of hydrogels OxGG:Gel2 administered in a single dose via intraperitoneal increased the mortality rate despite having presented discrete alterations of the clinical signs in septic animals, suggesting that the treatment had no effect at tested dose and/or in this model. These results are aligned with the cytotoxicity against L929 cells using the MTT assay, since the cell viability of the hydrogels was higher than 70%, whereas OxGG, without gelatin, proved to be highly toxic (Canafistula et al., 2025). It could be possible that in sepsis, a model of high mortality, the previous reported high toxicity of oxidized guar gum could not be neutralized by the hydrogel synthesis (OxGG+Gelatin). In addition, it had been shown that food additive guar gum adversely impacts the gut microbiota activity and colonic immune response and increases susceptibility to colonic inflammation in mice (Paudel et al., 2022), an effect that could augment the gravity of sepsis induced by intestinal barrier disruption-but not alter the sham animals group.

The oral route is the most convenient, patient-compliant, and preferred method of administration (Aminabhavi et al., 2014). Previous studies have reported beneficial effects of hydrogels when administered orally (Yang et al., 2021; Haseeb et al., 2018). Additionally, the high viscosity of the precursor solution (5% concentration) hinders intraperitoneal administration at higher doses (50 mg/kg). However, oral administration in this study was associated with adverse effects, indicating that the severe condition of sepsis was exacerbated by OxGG:Gel5 treatment.

At 25 °C, in a 1 mL volume the OxGG:Gel5 precursor solution mixture undergoes gelation after approximately 90 min at rest. When 0.3 mL of the mixture is administered by syringe extrusion, two outcomes may occur: (i) adhesion of the viscous solution to the esophageal mucosa, and (ii) gelation in less than 90 min, since shear stress during extrusion and the reduced volume contribute to shortening gelation time. The injectability and adhesiveness of the hydrogel support these possibilities (Canafístula et al., 2025). Once formed, the hydrogel may obstruct the airways, leading to respiratory distress and subsequent animal death. Since these effects appeared in both SHAM and CLP animals, they can be attributed to the administration route rather than the hydrogel’s chemical or biological properties.

A detailed analysis shows that, although the oral route is often cited, hydrogels are rarely administered in their native form. Instead, they are modified before delivery, for example by mixing with food (Haseeb et al., 2018), suspending in saline (Malik et al., 2021), processing into microparticles solution (Yang et al., 2021) or powders (Kumar-chaudhary et al., 2024), or administering by gavage (Athira et al., 2023). This issue appears to be primarily physical and related to the route of administration rather than to the chemical properties or the previously demonstrated biological activities of OxGG:Gel, including its antimicrobial efficacy and lack of toxicity (Canafístula et al., 2025).

Further tests need to be conducted to explain the OxGG:Gel effects or to investigate its adjuvant effect in association with the sepsis therapeutical approach used in the clinical practice.

5. Conclusions

In conclusion, OxGG:Gel pre-hydrogel administered intraperitoneally at 20 mg/kg effectively reduced signs of prostration and piloerection and presented protective effect at temperature and glycemia in septic rats, whereas oral administration of the 5% solution at 50 mg/kg was associated with adverse effects. As these adverse outcomes occurred in both SHAM and CLP, they are likely due to the administration route rather than the hydrogel’s chemical or biological properties. These findings highlight that both the route of administration and formulation concentration critically influence the therapeutic efficacy of hydrogels in sepsis management.

Acknowledgements

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil) Finance Code 001 (PROEX 23038.000509/2020-82); INOMAT/INCT (Brazil); INCT/Polysaccharides MCTI/CNPq (Grant #406973/2022-9); FUNCAP (Brazil) (MLC-0191-000153.01.00/22) and CNPq (Grant numbers: 408511/2016-8). The authors express gratitude to the Central Analítica - UFC/CT - INFRA/MCTI-SISNANO/Pro-Equipamentos CAPES for support with SEM images and to CENAURENM for NMR analysis.

Data Availability Statement

The dataset analyzed or produced in this study can be requested from the corresponding author.

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Edited by

• Editor:
  Marcelo A. M. Esquisatto

Publication Dates

• Publication in this collection
  22 May 2026
• Date of issue
  2026

History

• Received
  18 Sept 2025
• Accepted
  26 Jan 2026