Review maps antioxidant biohybrid matrices for organ repair

A review of regenerative biomaterials concludes that scaffolds used in organs exposed to oxidative stress and inflammation should do more than provide mechanical support: they should actively regulate the hostile tissue environment. The analysis, published in Frontiers in Biomaterials Science, examines biohybrid matrices that combine a supportive structure with extracellular vesicles, plant-derived polyphenols, endogenous enzymes or catalytic nanomaterials. These materials are designed to control reactive oxygen species, protect vulnerable therapeutic cargo and shift immune activity toward resolution. The authors argue that this redox and immune control is a core requirement for repair after severe injury, not an optional addition to a structurally sound scaffold, although manufacturing, potency testing and clinically representative validation remain major barriers to clinical translation.

The biological target is a self-reinforcing cycle between oxidation and inflammation. Reactive oxygen species produced by mitochondria and NADPH oxidases include superoxide, hydrogen peroxide and the hydroxyl radical, which differ in reactivity, diffusion range and biological effects. Some act as signals at physiological concentrations, but excess production can overwhelm superoxide dismutase, catalase and glutathione peroxidase. Lipid peroxidation then damages membranes and proteins, while iron-dependent, lipid-peroxidation-mediated ferroptosis can contribute to organ injury. Ischemia followed by reoxygenation can produce a sudden oxidant surge, glutathione depletion and widespread cellular damage in the heart, liver and kidney. A material therefore cannot treat all reactive species as one interchangeable target: its activity must match the species, concentration, location and timing characteristic of a particular injury.

Oxidized lipids, mitochondrial DNA, HMGB1 protein and other damage-associated molecular patterns activate innate immune sensors and NF-κB signaling, increasing expression of cytokines such as TNF-α, IL-1β and IL-6. Neutrophils and macrophages recruited to the injury then generate additional reactive species through respiratory and NADPH oxidase activity. Reactive oxygen species can also activate the NLRP3 inflammasome, mature IL-1β and favor pro-inflammatory, M1-like macrophages over the M2-like state associated with debris clearance and repair. The Nrf2/Keap1 pathway provides a counter-regulatory mechanism: under oxidative stress, Nrf2 separates from Keap1, enters the nucleus and activates protective genes including HO-1 and NQO1, while also suppressing some macrophage cytokine responses. The review uses the ROS–NF-κB–Nrf2 axis as a design framework, while stressing that these pathways are not a simple linear circuit and can vary by cell type, tissue and repair stage.

Under these conditions, conventional scaffolds can inadvertently amplify injury. Their mechanics, porosity and degradation rate may be appropriate for tissue formation, but passive architecture does not manage local redox or immune state. Oxidants can deactivate growth factors, cells and vesicles, while implant surfaces may provoke a foreign-body response in which macrophages fuse into giant cells and surround the material with an avascular fibrous capsule. Biodegradation can add further stress: acidic products released by common aliphatic polyesters such as PLGA can burden tissue already struggling with oxidative stress. The review consequently treats scaffolds as active participants in implantation outcomes. An effective construct should scavenge excessive reactive species without eliminating the lower concentrations needed for normal signaling, while helping immune cells progress from destructive inflammation toward reparative activity.

The available bioactive agents make different trade-offs. Endogenous enzymes such as superoxide dismutase and catalase are specific and biocompatible, but they are fragile outside a protective matrix. They also function as a cascade: superoxide dismutase converts superoxide to hydrogen peroxide, which catalase or glutathione peroxidase must subsequently remove, so delivering one enzyme without an appropriate partner can leave peroxide accumulating. Plant polyphenols including curcumin, tannic acid, resveratrol and quercetin can directly trap radicals and influence Nrf2 and NF-κB signaling, but they are consumed stoichiometrically and have a finite protective window. Curcumin also presents poor bioavailability and hydrophobicity. Extracellular vesicles provide broader, cargo-driven immunomodulation without the uncontrolled engraftment risks of whole cells, yet their heterogeneous composition, rapid clearance and difficult standardization are major liabilities. Catalytic nanomaterials offer another profile: ceria, manganese-based nanozymes and Prussian blue can cycle between chemical states and continue scavenging after small-molecule antioxidants are depleted, although toxicity, intracellular accumulation and clearance remain unresolved concerns.

The surrounding matrix determines whether an agent retains enough activity to affect the injury. Collagen, gelatin and decellularized extracellular matrix offer native adhesion and remodeling cues, but can require crosslinking and may vary between batches; donor availability, cost and immunogenicity complicate scale-up. Synthetic polymers permit reproducible tuning of mechanics and degradation, yet may be biologically inert or generate inflammatory byproducts. Gelatin methacryloyl retains collagen-derived binding sites while allowing photocrosslinking and mechanical adjustment. Injectable hydrogels can conform to irregular defects and form through temperature, ion or enzymatic triggers, making them attractive for cardiac, hepatic and renal sites, but their limited load-bearing capacity confines them largely to soft tissues. Crosslinking conditions must also remain gentle enough to preserve cells and vesicles. Intrinsically antioxidant polymers containing polyphenolic or polydopamine groups distribute scavenging capacity through the structure and avoid some release-related uncertainties, although structural damage then reduces therapeutic function and their finite scavenging capacity may still require supplementation with regenerable nanozymes.

Payload protection and timely release can work against each other. A dense network may preserve enzymes or extracellular vesicles while restricting substrate access, cell interaction or timely cargo release. Hydrogel mesh size, fibrous scaffolds, physical binding and covalent conjugation therefore generate different retention–bioactivity balances. Loading bioactive agents after scaffold fabrication can separate delicate cargo from electrospinning solvents, printing shear and crosslinking chemistry. Release can also be tied to the injury itself. Boronic esters, thioketals, diselenides and disulfides can be cleaved by hydrogen peroxide or related oxidants, triggering payload release in proportion to local oxidative stress. Their cleavage may consume reactive species while releasing cargo, and some designs couple cargo release to degradation of the network itself. Systems may also respond to acidic pH or elevated enzyme activity. Multi-compartment structures, core–shell fibers and layered hydrogels can stage an early antioxidant response before slower immunomodulatory or regenerative signals appear, although the review cautions that most current “responsive” systems approximate biological timing through preprogrammed kinetics rather than true closed-loop feedback.

Organ-specific requirements further narrow the appropriate design. In the heart, the acute reactive-oxygen-species surge during reperfusion and the organ’s continuous mechanical activity favor injectable, in situ-forming systems with release timed to the oxidative burst. In preclinical studies, reactive-scavenging, extracellular-matrix-mimetic hydrogels that supported pro-resolving macrophage polarization reduced infarct size and improved contractile function, while metabolism-supporting hydrogels reduced adverse ventricular remodeling. The liver and kidney provide a defined intervention window during transplantation, when cold ischemia and controlled reperfusion create predictable injury. Machine perfusion may allow enzyme-mimetic materials to act before reperfusion, although rapid flow may limit their residence time. Neural repair adds the physical obstruction of the glial scar, requiring oxidative stress to be contained before a mechanically matched substrate can support axonal ingrowth. Chronic skin wounds have a persistent, low-grade inflammatory profile that may be better suited to durable ceria-embedded collagen systems than to rapidly depleted antioxidants.

The preclinical evidence remains uneven and does not establish clinical benefit. Cell models based on hydrogen-peroxide exposure or oxygen–glucose deprivation followed by reoxygenation provide controlled screening, but they cannot reproduce perfusion, mechanical loading, immune-cell trafficking or the spatially structured reactive-oxygen-species profile of an intact organ. Animal models include circulation, immune competence and realistic timing, yet young, healthy rodents differ from the older, diabetic or otherwise comorbid patients most likely to require such implants. Organ-on-chip systems can incorporate human cells, immune interactions and controlled ischemia–reperfusion cycles, but they remain partial models rather than substitutes for animal studies or clinical trials. Cardiac and cutaneous applications are more mature in the reviewed literature, whereas hepatic, renal and neural applications are earlier and more dependent on mechanistic inference. Head-to-head studies are also largely missing, so the evidence does not yet show that every dual-function construct outperforms a well-optimized single-function treatment.

Translation is constrained less by an absence of plausible mechanisms than by the difficulty of producing standardized, defensible products. Extracellular-vesicle cargo is vulnerable to oxidation, and curcumin can become inactive through the same oxidation it is intended to counter. Implantable constructs must also withstand sterilization, yet heat, irradiation and ethylene oxide can damage sensitive biological or polyphenolic payloads. Combination products that unite a device matrix and drug-like cargo face complex regulatory pathways and require reproducible, quantitative potency assays. A construct acting through a measurable node, such as Nrf2 activation, may be easier to characterize than one producing distributed antioxidant, immune and tissue-remodeling effects. The authors conclude that progress depends less on discovering additional agents than on standardizing potency, manufacturing, storage and validation, while testing constructs in aged, comorbid models and human-relevant microphysiological systems. The central proposal is that future regenerative matrices for pathologically stressed organs should sense and modify their surroundings rather than simply endure them.

Subject of Research: Biohybrid biomaterials that regulate oxidative stress and inflammation during organ repair

Article Title: Engineering antioxidant and anti-inflammatory biohybrid matrices for organ repair: from redox-immune design principles to clinical translation

Article References: Singaravelu, S., Jayaprakash, J., Balu, R., & Paramanathan, B. (2026). Engineering antioxidant and anti-inflammatory biohybrid matrices for organ repair: from redox-immune design principles to clinical translation. Frontiers in Biomaterials Science, 5, Article 1953249. https://doi.org/10.3389/fbiom.2026.1953249

Image Credits: AI Generated

DOI: 10.3389/fbiom.2026.1953249

Keywords: regenerative biomaterials, biohybrid matrices, oxidative stress, inflammation, extracellular vesicles, nanozymes, plant polyphenols, Nrf2 signaling, organ repair, clinical translation, Engineering, antioxidant