Inflammation-Responsive Hydrogels in Perioperative Pain and Wound Management: Design Strategies and Emerging Potential
Abstract
1. Introduction
2. Pathophysiology and Design Implications of Perioperative Inflammation
2.1. Inflammatory Cascade Triggered by Surgical Trauma
2.2. Spatiotemporal Dynamics of the Inflammatory Response
2.3. Interplay Between Inflammation, Nociception, and Tissue Regeneration
2.4. Biomarkers as Triggers for Responsive Drug Release
- pH shifts: Local acidosis, typically driven by hypoxia and lactic acid accumulation, can lower the extracellular pH to approximately 6.5 during the acute inflammatory phase [45]. Hydrogels incorporating acid-labile linkers, such as orthoesters, imines, and acetals, can be engineered to swell, degrade, or release therapeutic agents selectively under mildly acidic conditions, thereby enabling rapid and localized drug delivery [46].
- ROS: Neutrophil-derived ROS, including hydrogen peroxide and superoxide, are elevated in inflamed and ischemic tissues following surgical injury [47]. Hydrogels containing ROS-sensitive moieties such as thioketal or boronic ester groups can undergo cleavage or structural transitions in response to oxidative stress, allowing either burst or sustained drug release [19].
- Proteolytic enzymes: Proteases such as MMP-2, MMP-9, and NE are commonly upregulated in inflamed surgical wounds [32]. Peptide-based crosslinkers designed to be cleaved by these enzymes enable site-specific degradation of hydrogels, facilitating targeted therapeutic release at protease-rich sites [48].
- Cytokine gradients: Although more challenging to directly exploit, inflammatory cytokines such as IL-1β and TNF-α can inform the development of feedback-controlled delivery systems. Aptamers are short, single-stranded nucleic acids that bind specific molecular targets with high affinity and selectivity. When incorporated into a hydrogel matrix, these aptamer-functionalized systems can undergo conformational or charge-based changes upon binding their target cytokine, triggering structural transitions or payload release. Alternatively, nanoparticle-integrated hydrogel matrices can be engineered to sense cytokine concentrations through particle surface chemistry or embedded biosensing elements, enabling dynamic modulation of drug release in response to inflammatory status [49,50].
3. Design Principles of Inflammation-Responsive Hydrogels
3.1. pH-Responsive Hydrogels
- Schiff base (imine) bonds: Formed through aldehyde–amine condensation, these bonds are relatively stable at physiological pH, but hydrolyze rapidly under acidic conditions [57].
- Poly(acrylic acid) (PAA) derivatives: These polymers undergo pH-dependent ionization of the carboxyl groups, enabling reversible swelling through protonation and deprotonation [58].
- A mesoporous glass–hydroxyapatite scaffold incorporating orthoester linkers achieved pH-triggered levofloxacin release under acidic conditions (pH 5.5–6.7), enhancing bacterial clearance while preserving osteoblast viability [60]. Although developed for bone infections, this platform can be adapted for localized anti-inflammatory delivery in acidified surgical wounds.
- A self-healing polyethylene glycol (PEG)-based hydrogel, crosslinked via imine bonds between aldehyde- and amine-functionalized poly(ether urethane)s, remained stable at pH 7.4, but was hydrolyzed in acidic environments. It supported sustained drug release for up to 17 days and was injectable through a 21 G needle, suggesting promise for minimally invasive perioperative applications in spatially and temporally confined inflammation [61].
- A semi-interpenetrating κ-carrageenan–PAA hydrogel, originally developed for gastrointestinal diclofenac delivery, exhibited pH-dependent diffusion (~80% at pH 7.4 vs. ~40% at pH 1.2) [62]. This behavior may be repurposed to match drug availability with wound pH normalization during postoperative recovery.
3.2. ROS-Responsive Hydrogels
- Thioketal linkages (–S–C–S–): These linkages are selectively cleaved in the presence of ROS, resulting in hydrogel disassembly and controlled drug release [65].
- Boronic esters or acids: These groups react specifically with hydrogen peroxide to form phenols and boric acid, triggering gel degradation or drug release [66].
- Selenium-containing moieties (e.g., diselenide bonds): Upon oxidation, these are converted to selenoxide derivatives, modulating the crosslink density and often imparting intrinsic antioxidant activity [67].
- A PEG hydrogel crosslinked with thioketal linkages was developed for the ROS-responsive delivery of epidermal growth factor. Upon ROS exposure, thioketal cleavage accelerated growth factor release, leading to enhanced angiogenesis, reduced oxidative stress, and improved re-epithelialization in a full-thickness wound model [68]. Compared with non-responsive controls, this system significantly improved wound closure, demonstrating direct applicability to surgical incisions with oxidative injury.
- A dual-responsive gelatin–poly(vinyl alcohol) (PVA) hydrogel incorporating boronic ester crosslinks and pH-sensitive micelles enabled the sequential release of vancomycin–silver nanoclusters and nimesulide. ROS triggered rapid antimicrobial delivery, while acidic pH sustained anti-inflammatory release. In a diabetic infected wound model, this system outperformed commercial dressings and single-drug controls in bacterial clearance, cytokine suppression, and hemostasis [69]. Although developed for chronic wounds, its dual-triggered logic and infection-modulating capacity are relevant in perioperative settings, particularly at contaminated or high-risk surgical sites.
- A selenium-based polyurethane hydrogel incorporating diselenide crosslinkers responded to oxidative stress by forming selenoxide, softening the matrix, and delivering antioxidant effects. In a rat myocardial infarction model, this system reduced fibrosis, suppressed inflammatory cytokines, and improved cardiac function relative to non-selenium controls [70]. Its redox-adaptive behavior is especially pertinent to cardiovascular and thoracic surgeries that involve localized oxidative injury.
3.3. Enzyme-Responsive Hydrogels
- MMP-cleavable linkers (e.g., GPLGIAGQ, CVPLSLYSG) integrated into PEG-based matrices to enable enzyme-responsive degradation and drug release [72].
- NE-sensitive motifs (e.g., AAPV) for targeted activation in neutrophil-rich tissues, especially during early postoperative inflammation [73].
- Microneedle and nanoparticle–hydrogel hybrids that combine physical precision with enzyme-triggered delivery, supporting minimally invasive surgical applications [74].
- A tetra-PEG hydrogel crosslinked with GPLGIAGQ peptides was used for the MMP-2-responsive delivery of phosphatidylserine. This system promoted M2 macrophage polarization, suppressed IL-1β and TNF-α expression, and enhanced bone regeneration in a rat calvarial defect model. Compared with drug-free and non-responsive controls, the hydrogel showed superior immunomodulatory effects, supporting its relevance for surgical tissue repair [75].
- A PEG hydrogel incorporating CVPLSLYSG linkers was engineered for MMP-2/9-responsive delivery of docetaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles. Upon enzyme exposure, the matrix degraded, releasing nanoparticles that achieved over five-fold higher cytotoxicity against glioma cells compared to free docetaxel, and over 20-fold compared to non-degradable controls [76]. Although developed for post-resection chemotherapy, this design underscores the spatial precision achievable in surgical oncology.
- An NE-responsive RADA16-I hydrogel functionalized with AAPV-cleavable sequences and regenerative peptides (GHK, KGHK, and RDKVYR) released bioactive cues upon NE exposure. In a murine full-thickness wound model, the system accelerated re-epithelialization, enhanced fibroblast activity, and promoted collagen deposition, demonstrating its efficacy in protease-rich wound environments [77].
- A microneedle patch composed of gelatin methacryloyl (GelMA) and ε-poly-L-lysine loaded with curcumin nanoparticles was developed for MMP-triggered degradation. In infected wound models, the patch enhanced closure, suppressed TNF-α, and upregulated IL-10 and vascular endothelial growth factor (VEGF) expression [78].
3.4. Multi-Stimuli and Feedback-Controlled Systems
4. Anti-Inflammatory and Analgesic Payloads for Hydrogel Delivery
4.1. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
4.2. Corticosteroids
4.3. α2-Adrenergic Agonists
4.4. Biologics and Regenerative Factors
4.5. Dual and Synergistic Payload Systems
5. Preclinical Applications in Perioperative Models
5.1. Soft Tissue Surgery
5.2. Orthopedic Surgery
5.3. Thoracic and Abdominal Surgery
5.4. Comparative Delivery Strategies in Preclinical Perioperative Models
6. Translational Outlook and Future Directions: From Proof-of-Concept to Surgical Integration
6.1. Translational Gaps and Preclinical Readiness
- Trigger fidelity—specificity and sensitivity to pathological pH, ROS, or protease thresholds.
- Release kinetics—under both simulated and in vivo perioperative inflammatory conditions.
- Mechanical stability and degradation—including timeline and identification of degradation byproducts.
- Inflammatory biomarker modulation—e.g., TNF-α, IL-6 at defined postoperative timepoints.
- Therapeutic window—duration of analgesic or anti-inflammatory effects compared with current clinical standards.
- Functional endpoints—standardized nociceptive assays, mobility scores, or tissue regeneration quality.
- Safety—assessment of local tissue compatibility and systemic toxicity.
6.2. Regulatory Compatibility and Surgical Integration
6.3. Key Barriers: Biocompatibility and Responsiveness
6.4. Next-Generation Strategies for Precision Translation
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
NSAID | Non-steroidal anti-inflammatory drug |
ROS | Reactive oxygen species |
IL | Interleukin |
TNF-α | Tumor necrosis factor-α |
NE | Neutrophil elastase |
MMP | Matrix metalloproteinase |
ECM | Extracellular matrix |
COX | Cyclooxygenase |
PAA | Poly(acrylic acid) |
PEG | Polyethylene glycol |
PVA | Poly(vinyl alcohol) |
PLGA | Poly(lactic-co-glycolic acid) |
GelMA | Gelatin methacryloyl |
VEGF | Vascular endothelial growth factor |
OCP | Octacalcium phosphate |
CPBA | Carboxyphenylboronic acid |
CS | Chondroitin sulfate |
CMCS | Carboxymethyl chitosan |
HA | Hyaluronic Acid |
BMP | Bone morphogenetic protein |
AI | Artificial intelligence |
FDA | Food and Drug Administration |
ISO | International Organization for Standardization |
GMP | Good Manufacturing Practice |
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Inflammatory Phase | Key Triggers | Design Implications |
---|---|---|
Acute (0–72 h) | ROS, low pH, NE, MMPs, IL-1β | Burst or early-phase release via ROS-, pH-, or enzyme-responsive linkers |
Resolution (>72 h) | MMP-2/9, IL-10 | Sustained release of regenerative agents; ECM-mimetic or degradable scaffolds |
Spatial variation | Local hypoxia, edema, cytokine gradients | Injectable, conformal, or multi-stimuli systems for site-specific delivery |
Hydrogel Class | Primary Trigger | Mechanism of Response | Representative Design Strategy |
---|---|---|---|
pH-responsive | Local acidosis (pH 6.0–6.8) | Hydrolytic cleavage or ionic swelling | Orthoester, acetal, imine linkers; ionizable PAA |
ROS-responsive | H2O2, O2−, OH− radical | Oxidative cleavage or crosslink disruption | Thioketal, boronic ester, diselenide bonds |
Enzyme-responsive | MMP-2/9, NE | Protease-mediated peptide cleavage | GPLGIAGQ or AAPV peptide crosslinkers |
Multi-stimuli/feedback | ROS + pH, MMP + pH, cytokines | Boolean logic (AND/OR), biosensor-mediated release | Dual-labile networks, aptamer-functionalized matrices, redox-switchable gels |
Payload Class | Key Examples | Delivery Features |
---|---|---|
NSAIDs | Diclofenac, Ketoprofen, Celecoxib | pH-/ROS-responsive; improved local efficacy |
Corticosteroids | Dexamethasone, Triamcinolone | Sustained release; enzyme-triggered systems |
α2-Adrenergic Agonists | Dexmedetomidine, Clonidine | Mucoadhesive or thermosensitive hydrogels |
Biologics/Regenerative Factors | IL-1Ra, TNF-α blockers, BMP-2, VEGF | Cytokine/ECM-targeted; protease-responsive |
Dual-Payload Systems | Ropivacaine + Dexmedetomidine or Ketorolac | Synergistic release; compartmental structures |
Hydrogel Example | Trigger Type | Payload | Model | Comparator | Key Quantitative Outcomes | Ref. |
---|---|---|---|---|---|---|
Dual-responsive gelatin–PVA | ROS + pH | Vancomycin–Ag NCs + nimesulide | Rat diabetic infected wound | Commercial dressing | Wound closure ↑ (92% vs. 74%, p < 0.01), TNF-α ↓ (~45%, p < 0.01), Bacterial clearance ↑ (96% vs. 62%, p < 0.001) | [69] |
MMP-cleavable tetra-PEG | Enzyme (MMP-2/9) | Phosphatidylserine | Rat calvarial defect | Non-responsive hydrogel | Bone regeneration ↑ (78% vs. 54%, p < 0.05), IL-1β ↓ (~40%, p < 0.05), M2/M1 ratio ↑ (~3.2-fold, p < 0.01) | [75] |
MMP-13-responsive HAMA microsphere | Enzyme (MMP-13) | Celecoxib | Rat OA model (ACLT + MMx) | Non-responsive hydrogel | OARSI score ↓ (~75%, p < 0.05), Joint space width maintained, Col2 preserved | [100] |
MMP-cleavable PEG | Enzyme (MMP-1/2) | IL-1Ra | Rat cortical LPS-induced neuroinflammation model | Uncoated implant | IgG leakage ↓ to sham level (p < 0.05), Neuronal survival ↑ (p < 0.05) | [123] |
ROS-degradable HA–EGCG | ROS | EGCG | Rat cecum–sidewall abrasion adhesion model | Commercial HA hydrogel | Adhesion score ↓ (1.2 vs. 3.8, p < 0.05), Fibrosis markers ↓, M2 macrophages ↑ | [145] |
ROS-responsive HA–PBA/ADH + PVA–SB–CHO | ROS | Chlorogenic acid | Rat cecum–sidewall abrasion adhesion model | Commercial HA hydrogel | Adhesion score ↓ (1.0–1.125 vs. 3.5+, p < 0.0001), 20% adhesion-free | [146] |
Surgical Model | Responsive Cue | Main Outcome |
---|---|---|
Incisional wound | ROS, pH | Reduced inflammation, faster healing |
Burn injury | ROS | Lower cytokines, improved repair |
Bone fracture | MMP, pH | Enhanced bone regeneration |
Joint surgery | Enzyme | Cartilage protection |
VATS/laparotomy | pH, ROS | Nerve protection, reduced pain |
Challenge Area | Current Limitation | Emerging Strategy |
---|---|---|
Preclinical Models | Non-surgical, short-term, poor benchmarking | Standardized surgical inflammation models incorporating clinically relevant injury mechanisms (e.g., electrocautery, ischemia–reperfusion, multi-tissue handling) and harmonized benchmark endpoints (trigger fidelity, release kinetics, mechanical stability, biomarker modulation, therapeutic window, functional recovery, safety) |
Responsiveness Fidelity | Off-target release, low specificity | Logic-gated or biosensor-integrated systems |
Biocompatibility | Immunogenicity, unstable degradation byproducts | Modular, clinically validated chemistries |
Workflow Integration | Complex delivery, poor fit with surgical pace | Injectable, sprayable, or thermogelling formats |
Regulatory Translation | Combination product hurdles, GMP gaps | Use of ISO-approved polymers, early alignment |
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Moon, Y.E.; Jeong, J.-O.; Choi, H. Inflammation-Responsive Hydrogels in Perioperative Pain and Wound Management: Design Strategies and Emerging Potential. Gels 2025, 11, 691. https://doi.org/10.3390/gels11090691
Moon YE, Jeong J-O, Choi H. Inflammation-Responsive Hydrogels in Perioperative Pain and Wound Management: Design Strategies and Emerging Potential. Gels. 2025; 11(9):691. https://doi.org/10.3390/gels11090691
Chicago/Turabian StyleMoon, Young Eun, Jin-Oh Jeong, and Hoon Choi. 2025. "Inflammation-Responsive Hydrogels in Perioperative Pain and Wound Management: Design Strategies and Emerging Potential" Gels 11, no. 9: 691. https://doi.org/10.3390/gels11090691
APA StyleMoon, Y. E., Jeong, J.-O., & Choi, H. (2025). Inflammation-Responsive Hydrogels in Perioperative Pain and Wound Management: Design Strategies and Emerging Potential. Gels, 11(9), 691. https://doi.org/10.3390/gels11090691