Diabetic wounds fail to progress normally through overlapping phases of hemostasis, inflammation, proliferation, and remodeling. Persistent hyperglycemia, oxidative stress, vascular and neural injury, infection, and immune dysregulation can keep wounds in an inflammatory state. NF-κB is central to this transition because it regulates cytokines, chemokines, extracellular-matrix remodeling, and other processes needed for early immune defense and repair. Its activity normally rises after injury and then declines as pathogens and damaged tissue are cleared. In diabetic wounds, repeated metabolic and inflammatory signals can prevent that decline, sustaining expression of mediators such as TNF-α, IL-1β, and IL-6 while disrupting keratinocytes, fibroblasts, endothelial cells, and tissue reconstruction.

The distinction between pathway activation and related measurements is crucial. At rest, IκBα inhibits the RelA/p65–p50 complex in the cytoplasm. Receptor signals activate the IKK complex, which phosphorylates IκBα and promotes its degradation, allowing p65 to enter the nucleus and activate inflammatory and repair-related genes. Changes in NF-κB messenger RNA, total p65 protein, reactive oxygen species, or cytokine concentrations may indicate that the inflammatory environment has shifted, but they do not by themselves establish inhibition of the core cascade. More direct evidence comes from measurements of IκBα phosphorylation or degradation, p65 phosphorylation, nuclear translocation, DNA binding, or transcriptional activity. The review therefore separated studies with such readouts from those reporting only expression, pathway-associated proteins, or downstream inflammation.

Engineered systems have addressed several barriers that limit direct topical use of herbal-derived compounds. Berberine, an isoquinoline alkaloid with antibacterial, anti-inflammatory, antioxidant, and metabolic-regulatory activities, has been encapsulated in lecithin–chitosan nanoparticles measuring 168.4 nanometres on average, dispersed in calcium-crosslinked hydrogels, and incorporated into radially aligned fibers designed to guide fibroblast migration. These studies reported reduced inflammatory-cell infiltration or macrophage cytokines, along with faster closure, angiogenesis, collagen deposition, or tissue remodeling in diabetic wound models. Their evidence differed, however: one measured total NF-κB expression, while others primarily reported antioxidant or inflammatory outcomes. None directly quantified berberine exposure within wound tissue.

Polyphenols have been engineered for similar purposes, with poor water solubility and chemical stability presenting major formulation constraints. Curcumin loaded into chitosan nanoparticles showed slower in vitro release and increased macrophage uptake, while curcumin in heparin-grafted aligned PLGA fibers produced sustained release, supported cell migration, and retained endogenous growth factors at the wound interface. Quercetin nanoparticles embedded in a gelatin methacryloyl hydrogel released the compound for about 48 hours, compared with complete release of free quercetin within 8 hours. The composite reduced RAGE, total NF-κB protein, reactive oxygen species, and inflammatory mediators while favoring a reparative macrophage state. Taxifolin incorporated into alginate/PVA electrospun fibers was associated with lower TLR4/NF-κB/NLRP3-associated proteins and improved repair. Yet these studies did not measure IκBα degradation or p65 nuclear movement, leaving their pathway evidence at the expression or associated-protein level.

Some herbal compounds serve as active cargoes and structural components at once. Glycyrrhizic acid can form supramolecular networks with zinc ions, while oxidized Ganoderma lucidum polysaccharides can crosslink with carboxymethyl chitosan through Schiff-base bonds to create a stable double-network hydrogel. Such systems promoted shifts from inflammatory toward reparative macrophage states, reduced reactive oxygen species or TNF-α, and improved re-epithelialization, angiogenesis, collagen deposition, and restoration of skin architecture. Rhein from rhubarb was assembled into fibers and placed in a ferrocene–β-cyclodextrin hydrogel that weakened under oxidative conditions, triggering release while preserving the assembled therapeutic. More complex formulations combined responsive release, antibacterial particles, peptides, or additional vesicles. When component-specific controls were missing, the review attributed biological effects to the complete formulation rather than to the herbal ingredient alone.

Chinese herbal polysaccharides, multi-component extracts, and plant-derived nanovesicles have expanded the range of available delivery architectures. An Astragalus membranaceus polysaccharide and baicalein carrier carrying berberine was incorporated into dissolving microneedles for biofilm-covered diabetic wounds. The needles penetrated the wound surface, dissolved, and released cargo in response to high reactive oxygen species. Treatment reduced p65 phosphorylation, TNF-α, IL-6, and reactive oxygen species while improving closure, angiogenesis, and collagen deposition. Houttuynia cordata extracellular vesicles released from a glucose- and reactive-oxygen-responsive collagen hydrogel produced more direct evidence: investigators detected reduced IκBα and p65 phosphorylation, restored total IκBα, lower inflammatory mediators, and increased angiogenesis and collagen deposition. A Ginkgo biloba vesicle system and a bitter melon vesicle–mesenchymal stromal cell vesicle hydrogel likewise improved repair, although their broader effects were evaluated mainly through inflammation, oxidative stress, macrophage state, or associated pathways.

These findings are encouraging, but two linked gaps prevent a firm conclusion that engineering specifically strengthens NF-κB modulation. First, slow release in a buffer does not demonstrate prolonged residence in a wound, and a persistent carrier or fluorescent signal cannot substitute for measuring the therapeutic itself. Most studies characterize particle size, encapsulation, release, or cellular uptake, but relatively few quantify local therapeutic concentrations, tissue distribution, and intracellular exposure in the same experiment. Second, most biological findings concern upstream signals such as TLR4/MyD88, antioxidant pathways, reactive oxygen species, or downstream cytokines. These endpoints are compatible with improved NF-κB control but do not prove that the core cascade mediates healing. The review’s conclusion is that current evidence more consistently supports better formulation performance and wound repair than a proven delivery-dependent enhancement of NF-κB activity.

Timing and cellular context add another layer of uncertainty. Moderate NF-κB activation during the early phase of injury contributes to macrophage recruitment, bacterial clearance, and the initiation of repair, so the therapeutic aim should be to limit persistent pathological activation rather than suppress the pathway continuously. A lower p65 signal measured at one late endpoint cannot reveal whether a formulation has selectively dampened prolonged activation or also blocked useful early responses. Whole-wound measurements likewise cannot distinguish altered signaling within a cell type from changes in the wound’s cellular composition. The authors argue that future studies should measure local exposure and NF-κB activity together across healing phases and relevant cell populations, while using blank-carrier, free-therapeutic, and component-specific controls to separate the effects of engineering, carrier, and added bioactive ingredients.

Translation also requires stronger quality control and safety testing of complete products. Extracts, polysaccharides, and biological nanoparticles can vary in composition, molecular weight, structure, stability, and preparation method, and those differences can alter encapsulation, crosslinking, release, and biological activity. Sterilization, storage, and scale-up may further change particle states and material networks. Final formulations also require biocompatibility assessment because zinc oxide, copper ions, photoinitiators, crosslinking reactions, and degradation products can introduce effects absent from testing individual components. Animal models remain another boundary: conventional diabetic skin-defect models do not reproduce the combined neuropathy, ischemia, infection, and mechanical loading of a human diabetic foot. Faster closure therefore shows efficacy within a selected model, not clinical effectiveness. The review’s proposed next step is not simply longer release, but experimentally aligned systems that demonstrate where a therapeutic is present, how it changes NF-κB activity over time, which cells are affected, and whether those changes causally contribute to repair.

Subject of Research: Review of engineered Chinese herbal medicine delivery for modulating NF-κB in diabetic wound models

Article Title: Engineered delivery of Chinese herbal medicine-derived therapeutics for diabetic wound healing: a focus on NF-κB cascade modulation

Article References: Chen, B., Wang, Q., Zhang, J., Li, X., Wang, N., Zou, M., Huang, Z., Feng, J., Zhang, G., & Ju, S. (2026). Engineered delivery of Chinese herbal medicine-derived therapeutics for diabetic wound healing: a focus on NF-κB cascade modulation. Frontiers in Bioengineering and Biotechnology, 14, 1977317. https://doi.org/10.3389/fbioe.2026.1977317

Image Credits: AI Generated

DOI: 10.3389/fbioe.2026.1977317

Keywords: diabetic wounds, NF-κB signaling, engineered delivery, Chinese herbal medicine, hydrogels, nanoparticles, microneedles, nanovesicles, wound healing, tissue repair, Engineered, delivery

These structures have been used to encapsulate and release hydrophobic and hydrophilic pharmaceutical compounds, as well as to co-deliver multiple drugs. Unlike another Pluronic type, F68, F127 can form micelles below body temperature. The review identifies low stability, degradation associated with solubilization in the bloodstream and poor mechanical robustness as continuing challenges for F127-based materials.

By contrast, physically crosslinked systems often display rapid structural recovery, including restoration of more than 80% of the storage modulus, or G′. Their potential limitation is long-term structural stability. Hybrid systems integrate physical and chemical mechanisms and are presented as emerging frameworks for next-generation hydrogels.

According to the review, these combined networks are intended to provide controlled rheology, sustained release and structural adaptability. The review also positions multifunctional Pluronic F127 platforms as relevant to drug delivery, regenerative medicine and bio-fabrication. The article is a review rather than a report of a new clinical study, and its scope is the design and evaluation of F127-based hydrogels through different crosslinking routes.

Its central contribution is a framework for comparing how physical interactions, chemical crosslinking and hybrid bonding influence rheology, mechanical integrity, injectability and degradation.

Subject of Research: Crosslinking strategies for improving the performance of Pluronic F127-based hydrogels

Article Title: Advanced crosslinking strategies in Pluronic F127-based hydrogels

Article References: Syed Ismail, S. N., Holilah, H., Suryanegara, L., Ramli, S. N., Mohd Noor, S. F., Bustami, Y., Ku Ishak, K. M., Azmi, N. N., & Abdul Hamid, Z. A. (2026). Advanced crosslinking strategies in Pluronic F127-based hydrogels. Journal of Materials Science, 61(40), 30435-30465. https://doi.org/10.1007/s10853-026-12720-0

Image Credits: AI Generated

DOI: 10.1007/s10853-026-12720-0

Keywords: Pluronic F127, hydrogels, crosslinking, micelles, drug delivery, rheology, injectability, mechanical properties, degradation, biomaterials, Advanced, strategies

The review considers collagen and gelatin, hyaluronic acid, silk fibroin, chitosan, alginate, fibrin and related matrices. That perspective shifts attention from a scaffold’s nominal composition alone to the physical and biological properties produced by crosslinking. It also supports treating crosslinking as a multidimensional regulator rather than a single measure of scaffold stability.

Different crosslinking methods used in these materials include covalent, photoinduced, enzymatic, ionic, physical and dynamic covalent approaches. The review organizes these approaches around the distinct biological microenvironments they can generate. This comparison matters because the choice of network chemistry is linked to several outcomes at once, including how a material behaves mechanically, how molecules move through it and how its structure changes over time.

A material therefore cannot be characterized adequately through one property when several coupled characteristics may influence its biological performance. Crosslinking is also closely connected to how a scaffold is fabricated. The review examines extrusion bioprinting, electrospinning, freeze-drying, injectable hydrogel formation and porous-scaffold fabrication, emphasizing the coupling between processing routes and network formation.

It further argues that the timing of network creation can be as important as the nominal polymer composition. The central analytical point is that a material’s processing history must be considered when relating its chemistry to its eventual biological environment. Preclinical studies summarized in the review indicate that regenerative performance cannot be inferred from stiffness alone.

Stress relaxation, degradation, transport, interfacial chemistry, immune modulation and preservation of matrix-remodeling capacity are identified as additional considerations. The cited findings are preclinical and therefore do not establish clinical benefit or demonstrate outcomes in patients. The review proposes a mechanistically informed evidence chain to connect the design of a material with its observed behavior.

The sequence begins with material definition, proceeds to properties measured in the hydrated state and then to cellular responses. It extends from those responses to ex vivo or in vivo behavior and, finally, to tissue-specific regenerative outcomes. Reproducibility is another major focus of the proposed validation approach.

The review highlights sterilization, storage and aging-related property drift as factors that may affect a material after fabrication. It calls for controls capable of distinguishing genuine network effects from formulation confounders. Such controls are essential when comparing materials, because an observed difference cannot be assigned to network design if other changes in processing or handling are not adequately addressed.

The review’s final conclusion is that crosslinking should be designed and reported as a multidimensional regulator of the regenerative microenvironment. Its effects on network mechanics, viscoelastic behavior, swelling, transport, degradation, ligand accessibility and cell interactions should be evaluated together with the processing route used to create the material. For regenerative biomaterials, the review argues, crosslinking is not merely a manufacturing operation or a shorthand for stability; it is a central variable linking material chemistry, fabrication and preclinical biological validation.

Subject of Research: Crosslinking, processing and preclinical validation of biopolymer scaffolds for tissue engineering and regenerative medicine

Article Title: Crosslinking-controlled biopolymer biomaterials for tissue engineering and regenerative medicine: network chemistry, processing, and mechanistically informed validation

Article References: Bellucci, S. (2026). Crosslinking-controlled biopolymer biomaterials for tissue engineering and regenerative medicine: network chemistry, processing, and mechanistically informed validation. Frontiers in Bioengineering and Biotechnology, 14, Article 1962375. https://doi.org/10.3389/fbioe.2026.1962375

Image Credits: AI Generated

DOI: 10.3389/fbioe.2026.1962375

Keywords: crosslinking, biopolymer scaffolds, tissue engineering, regenerative medicine, hydrogels, biofabrication, mechanobiology, matrix remodeling, biomaterials, network chemistry, Crosslinking-controlled, biopolymer

Hydrogels are water-rich polymer materials whose mechanical properties can be tuned through composition, crosslinking, processing and environmental conditions. In additive manufacturing, small changes in polymer concentration, crosslinker content, ionic environment or processing can lead to nonlinear changes in viscoelastic behavior, as expressed by storage and loss moduli. The design of such polymers often depends on iterative experiments, which can be time-consuming, expensive and difficult to generalize across material systems. Machine learning can learn relationships among structure, process and measured properties, while conditional generative models address the reverse design problem: identifying formulations that may satisfy a specified performance condition. Agentic Hydrogel brings these activities into one traceable sequence rather than introducing a new algorithm for any single task.

The system is organized around four specialized software components. A Planner Agent identifies the dataset, task type, regression or classification targets, and the conditioning and output variables needed for conditional generation. An Analysis Agent performs preprocessing, visualization and prediction. A Generation Agent trains generative models, produces probable material compositions and process parameters, and evaluates the synthetic data. An Orchestrator Agent coordinates the complete workflow, records states, manages communication among the agents and produces human-readable reports. Here, an “agent” is a software component that receives workflow information, applies task-specific rules, invokes assigned tools, updates the workflow state and passes structured outputs onward. Conventional algorithms perform data loading, schema discovery, model training, validation, evaluation and workflow management; a language model has no authority over these scientific decisions.

Human oversight is built into the command-line interface. Before execution, users must specify the dataset, task type, target variables for regression or classification, conditioning and output variables for generation, and any optional model settings. The framework then presents a summary listing the selected dataset, cleaned feature set, targets or conditions, analysis mode and planned computational steps. Users can approve, modify or terminate the workflow before processing begins. This confirmation is intended to prevent silent errors in consequential assignments, because treating a variable as an outcome or a target condition represents a scientific assumption that may not be inferable from data statistics alone. An optional large language model, available through a local deployment or cloud service, can summarize procedures and results, but it does not select data, define targets or control the analysis.

For regression and classification, Agentic Hydrogel uses adaptive multilayer perceptrons with rectified linear unit activation functions and optional dropout. Models are optimized with Adam, and validation-based early stopping is used during training. The base network in the reported experiments had two hidden layers with 64 neurons each, and the user-defined performance threshold was 0.60. If a model did not reach that threshold, network capacity could be increased and training repeated up to a user-set maximum, after which the model with the highest evaluation score was retained. This is a capacity-adjustment mechanism tied to a chosen threshold, not an exhaustive search for an optimal architecture. The authors selected multilayer perceptrons because they provide a unified nonlinear model for regression, classification and multi-output prediction within the same PyTorch workflow; they do not claim that this approach outperforms linear or tree-based models.

The polyacrylamide dataset contained 2,336 samples and nine variables and was used for multi-output regression of storage and loss moduli from material composition and additive-manufacturing parameters. In shuffled five-fold cross-validation, the multilayer perceptron achieved an R² of 0.782 ± 0.026, a mean absolute error of 247.079 ± 7.783 pascals, a root mean square error of 424.342 ± 16.857 pascals and a mean absolute percentage error of 19.25% ± 0.19%. The base network did not require capacity expansion. Because storage and loss moduli differed substantially in numerical scale, the authors caution against interpreting the metrics as a state-of-the-art benchmark or as evidence that the model learned the physical mechanisms governing rheology. The result instead demonstrates that the framework can configure, execute and document a pipeline for predicting continuous properties. The analysis was also repeated with five-fold cross-validation independent of the standard execution path, with preprocessing, early stopping and capacity decisions confined to the training folds to reduce data leakage.

Classification was evaluated on two granular hydrogel subsets, each containing 3,969 samples and ten variables. One subset used oscillation strain and the other oscillation stress as the differing experimental input, while both were used to predict a binary resuspension state. The two classes were approximately balanced. In stratified five-fold cross-validation, the oscillation-strain subset achieved an accuracy of 0.940 ± 0.017 and a macro-F1 score of 0.939 ± 0.017. The oscillation-stress subset achieved an accuracy of 0.937 ± 0.015 and a macro-F1 score of 0.937 ± 0.015. Neither base network required expansion. The closely matched results are consistent with the fact that the datasets share most formulations and rheological variables and differ in only one column. The authors present these scores as evidence that the workflow can perform discrete classification, not as state-of-the-art results or proof that the model captured the underlying intricacies of hydrogel formulation.

Conditional generation reverses the conventional direction of prediction: rather than estimating properties from a known recipe, the system searches for statistically probable composition and process variables associated with specified rheological conditions. Agentic Hydrogel implements a conditional variational autoencoder and a conditional denoising diffusion probabilistic model. The autoencoder receives paired output and conditioning vectors, maps them into a continuous latent distribution through mean and log-variance representations, samples latent values and decodes them with the conditions to reconstruct a material formulation. Its objective combines mean squared reconstruction error with a weighted Kullback–Leibler divergence term. The diffusion model uses a multilayer-perceptron denoising network that receives noisy output variables, rheological conditions and a sinusoidal embedding of the diffusion timestep. Its implementation adapts Gaussian diffusion and continuous-variable tabular diffusion ideas, but encoded discrete variables are handled numerically and restored during postprocessing rather than through a separate multinomial diffusion process.

Generated candidates were evaluated from distributional, structural and conditional perspectives. A Kolmogorov–Smirnov statistic was calculated separately for each output variable to compare real and synthetic marginal distributions, with lower values indicating closer agreement. The Frobenius norm of the difference between real and synthetic Pearson correlation matrices assessed preservation of multivariable relationships. Conditional fidelity was measured by finding the nearest experimental sample in scaled conditioning space for each generated sample and comparing the associated output variables with root mean square error and mean absolute error. A final range analysis flagged values outside the experimentally observed ranges. For the polyacrylamide data, the conditional autoencoder generated samples with a mean KS statistic of 0.406, a correlation Frobenius norm of 0.693, a conditional nearest-neighbor RMSE of 1.147 and a conditional nearest-neighbor MAE of 0.667 in standardized units. For the granular oscillation-strain subset, the diffusion model produced corresponding values of 0.291, 0.373, 1.041 and 0.651; for oscillation stress, they were 0.290, 0.390, 1.013 and 0.624. These measurements indicate partial agreement, but they do not establish a ranking of the two models because the hydrogel families, sample sizes, variables and architectures differ.

Postprocessing makes generated values more interpretable through optional clipping, non-negativity constraints, rounding of encoded categories and user-defined parameter bounds. These operations keep a candidate within the numerical domain represented by the source datasets, but they do not establish mechanical or chemical feasibility. Every execution produces model checkpoints, generated datasets, evaluation metrics, figures, workflow logs and Markdown reports, allowing the analysis to be inspected and documented. The study analyzed existing datasets and did not perform closed-loop fabrication or rheological testing of the generated candidates. It also did not provide systematic benchmarking of alternative predictive and generative models, uncertainty estimates, reinforcement learning or physics-informed constraints. Agentic Hydrogel therefore offers an auditable, human-bounded way to organize hydrogel machine-learning work, while leaving physical and chemical validation as a separate step before any computational candidate could be regarded as a working material.

Subject of Research: Human-supervised computational workflow for hydrogel analysis and conditional candidate generation

Article Title: Agentic hydrogel: a human-in-the-loop computational workflow for hydrogel analysis and conditional candidate generation

Article References: Mohammad, S., & Hossain, M. S. (2026). Agentic hydrogel: a human-in-the-loop computational workflow for hydrogel analysis and conditional candidate generation. Frontiers in Soft Matter, 6, 1936657. https://doi.org/10.3389/frsfm.2026.1936657

Image Credits: AI Generated

DOI: 10.3389/frsfm.2026.1936657

Keywords: hydrogels, agentic AI, machine learning, generative AI, rheology, conditional generation, materials informatics, additive manufacturing, polyacrylamide, granular hydrogels, Agentic, hydrogel

The study began from an observation made during earlier work on cultivating L. plantarum in calcium alginate materials. The researchers noticed that bacteria grown in MRS broth containing 1% sodium alginate at 25 °C became a gel after subsequent storage at 4 °C, even though no external crosslinker had been added. Fresh alginate solution exposed to the same low temperature remained fluid. That contrast suggested that the bacteria were altering the polymer environment during growth, but it did not establish whether the cells, their metabolites or some combination of the two were responsible. The present experiment was therefore designed as an initial characterization of a previously unreported biological gelation process rather than as a fully optimized material formulation.

To test the requirements for gel formation, the team varied sodium alginate concentration, bacterial cultivation time and post-cultivation temperature. Gelation was judged macroscopically with a standardized calcium alginate bead: in a liquid sample the bead sank, whereas a newly formed gel matrix supported it near the surface. This indicator was not used to measure gel strength or other mechanical properties. At an alginate concentration of 0.5%, gel formation occurred only under limited conditions. A concentration of 1% consistently produced stable gels after the bacteria had been cultivated, while 2% supported gelation across a broader set of conditions. The results indicate that bacterial growth and a sufficient density of polymer chains are both required for the process. The standard preparation used for subsequent experiments was 1% alginate, 24 hours of bacterial cultivation and one hour at 4 °C.

Fractionating the culture provided the central mechanistic clue. The researchers prepared whole bacterial cultures, washed bacterial cells resuspended in water, and cell-free supernatants obtained by centrifuging and filtering the culture. Whole cultures and cell-free supernatants induced visible gel formation after low-temperature incubation, whereas the resuspended bacterial cells did not. This separation points to extracellular products of L. plantarum, rather than the physical presence of intact cells, as the active fraction under the tested conditions. The finding does not yet identify the relevant product, and the authors emphasize that the supernatant could contain several candidate contributors, including organic acids, exopolysaccharides, proteins, extracellular DNA and other metabolites.

Acification was the next focus of the investigation. L. plantarum primarily produces lactic acid during carbohydrate fermentation, and the bacterial cultures used for gelation reached a pH of approximately 4.3. The researchers separately acidified alginate-containing medium with lactic acid, a mixture of lactic and acetic acids, or hydrochloric acid, bringing each solution to the same approximate pH rather than matching a predetermined acid concentration. All of these chemically acidified samples underwent visible gelation after incubation at 4 °C. The result shows that a sufficiently acidic environment can initiate gel formation under the experimental conditions; it does not establish that lactic acid alone is responsible. Lowering the pH would be expected to protonate alginate carboxylate groups, reducing electrostatic repulsion between negatively charged chains and promoting intermolecular association.

Scanning electron microscopy nevertheless revealed a difference between simple acidification and biological gelation. Alginate cultured with L. plantarum had a dense appearance before cold incubation and developed a porous three-dimensional network afterward. A similar network appeared in gels formed by cell-free supernatant. By contrast, the gels produced with defined acids had comparatively compact morphologies. The authors therefore interpret acidification as a major trigger of gel formation, while additional extracellular products appear to influence the extent of association and the architecture of the resulting network. The molecular basis of the need for low-temperature incubation remains unresolved. One possibility discussed by the researchers is that acidification creates a state permissive for gelation, after which cooling promotes physical rearrangement or association among protonated alginate chains.

The newly formed material also retained useful processing characteristics. When extruded into distilled water, it formed a continuous filament before gradually dispersing. After being written or shaped, it could be sprayed with 1.5% calcium chloride and held for 20 minutes to produce a mechanically stabilized construct that retained its three-dimensional geometry. The researchers demonstrated extrusion, direct writing of patterned letters, and spreading onto skin; the skin coating could be rinsed away with running water. Compared with non-cultured alginate subjected to the same secondary calcium treatment, the bacteria-induced gel contracted less. These findings indicate that the spontaneous gelation changes how the polymer subsequently responds to calcium. They are qualitative processing observations, however, and the study did not systematically measure rheology, swelling, degradation, long-term mechanical stability or tensile strength.

Bacterial survival was assessed after the gels were stored for up to seven days at 4 °C, 25 °C or 37 °C. At 4 °C, L. plantarum remained highly viable throughout the storage period, with only a slight reduction in colony-forming units after seven days. Viability declined more gradually at 25 °C and more markedly at 37 °C. Indicator strips embedded in the gel changed little in color, suggesting that the acidic microenvironment created during cultivation remained broadly stable under the tested conditions. The authors interpret the temperature-dependent losses as possible consequences of continued metabolism, nutrient depletion and metabolic stress at warmer temperatures, while refrigeration slows those processes. The experiment establishes refrigerated viability for the tested period and conditions, not a validated shelf life or evidence that the gel can preserve bacteria during transport or long-term distribution.

The findings open several avenues for biofabrication while leaving important limitations. Because gel formation occurred while bacteria were present and viable, the approach could eventually inform live probiotic bioinks, living materials and gel systems that combine bacterial activity with a polysaccharide matrix. The spreadable material may also serve as a carrier for locally retained bacterial products, and the active gelation capacity of the cell-free supernatant suggests possible postbiotic gels that contain bacterial metabolites without living cells. These are proposed directions rather than demonstrated applications: the study did not test wound healing, tissue repair, drug delivery, printing performance in a controlled bioink system, or therapeutic efficacy. It examined only L. plantarum, used a complex MRS medium, and reported modest biological variation in final pH and extracellular composition. Quantitative material characterization was also limited, while the active gelation factor, the basis of temperature dependence, and whether other bacterial species produce similar or distinctive structures remain open questions. The study therefore provides a reproducible demonstration of bacteria-directed alginate gelation and a foundation for subsequent biochemical fractionation, controlled reconstruction and comparative testing.

Subject of Research: Bacteria-induced spontaneous gelation of sodium alginate using extracellular products of Lactiplantibacillus plantarum

Article Title: Biologically induced spontaneous alginate gelation mediated by extracellular products of Lactiplantibacillus plantarum

Article References: Gong, W., Cisterna-Vergara, S., Kanazawa, M., Villena, J., Nishiyama, K., & Kitazawa, H. (2026). Biologically induced spontaneous alginate gelation mediated by extracellular products of Lactiplantibacillus plantarum. Frontiers in Bioengineering and Biotechnology, 14, Article 1955981. https://doi.org/10.3389/fbioe.2026.1955981

Image Credits: AI Generated

DOI: 10.3389/fbioe.2026.1955981

Keywords: alginate, bacterial gelation, Lactiplantibacillus plantarum, extracellular products, biofabrication, living biomaterials, hydrogels, acidification, calcium crosslinking, bacterial viability, Biologically, induced

The research team, led by members of professor Eben Alsberg’s laboratory in UIC’s College of Engineering, set out to solve one of the most stubborn problems in tissue engineering. Human tissues are not flat. Cartilage curves around joints, blood vessels branch and bend, the trachea spirals in a series of horseshoe-shaped rings, and bone sweeps through the skeleton in arcs that no simple mold can reproduce. Conventional biofabrication approaches, which typically build tissues layer by layer or cast them in static scaffolds, have struggled to reproduce these intricate curvatures and fine surface features. The new strategy instead lets the material do the work, programming a flat construct to bend, fold, and curl itself into a target geometry as its internal structure swells at different rates.

Kirigami, the Japanese art of paper cutting, has already inspired engineers far beyond the classroom. Its techniques have informed deployable structures for spacecraft, flexible semiconductors, wearable technology, and optical devices. The appeal is straightforward: by introducing carefully placed cuts into a flat, stiff sheet, the material gains stretchability and flexibility it never had before, and it can be reshaped without any change to its chemical composition. What had been largely unexplored, according to Kaelyn L. Gasvoda, the paper’s lead author and a 2024 UIC PhD graduate now at the Mayo Clinic, was whether kirigami could be adapted to tissue engineering and, crucially, to soft, gel-like materials that can host living cells.

The challenge is that living hydrogels are nothing like paper. They are fragile, they swell in aqueous culture media, and any structural trick must remain cytocompatible, meaning it cannot harm the cells embedded within it. The UIC team’s solution was a hydrogel platform built from derivatives of gelatin and alginate, a natural polymer derived from seaweed. Both materials are well established in the biomaterials field: gelatin offers cell-friendly biochemical cues, while alginate provides a tunable structural backbone. By combining them, the researchers created a material system in which mechanical behavior and biological support could be engineered separately and then brought together.

The key to programming shape change lies in a technique called photolithography. Using patterned light, the team created regions of different crosslinking densities within the same hydrogel construct. Crosslinks are the molecular bridges that tie polymer chains together, and their density dictates how much a given region can swell when immersed in culture medium. Densely crosslinked areas resist expansion and hold their form, while lightly crosslinked areas absorb the medium and grow. By patterning these regions with kirigami-inspired precision, the researchers could dictate exactly which parts of a construct would stay rigid and which would expand, and by how much, producing controlled bending, folding, and self-patterning over time.

The design philosophy behind the platform reflects a deliberate division of labor within the material. Ding, a research associate professor on the team, explained that the researchers aimed to create structures with a rigid outer framework that would maintain its shape without expanding in the culture medium. In contrast, the inner regions needed to absorb the medium and expand while remaining compatible with long-term cell survival, growth, and differentiation. That combination, a stable skeleton paired with a growing, living interior, is what allows the constructs to transform autonomously while the cells inside them continue to develop into tissue-like structures with precisely defined geometries, all without additional manipulation by the researchers.

Gasvoda described the progression as an effort to push beyond the team’s earlier demonstrations. The initial achievement of constructs that changed shape over time was exciting, she said, but the goal was to create more complex shapes with controlled self-patterning and bending, designing structures where the researchers could precisely guide how they form and transform. That precision matters because, as Ding emphasized, complex geometries are central to tissue engineering: human tissues have intricate three-dimensional shapes that are closely linked to their functions. The Alsberg laboratory focuses on engineering tissues with complex architectures, including cartilage, bone, tracheal, and vascular tissues, with the aim of recreating their native structures and functions rather than approximations of them.

The implications extend to wound healing as well as tissue replacement. Repairing defects in curved anatomical surfaces, whether in cartilage, skin-adjacent structures, or tubular organs, requires implants or engineered constructs that match the geometry of the site they are meant to restore. A flat patch forced onto a curved wound bed fits poorly, integrates poorly, and functions poorly. A construct that can be fabricated flat, shipped and handled easily, and then programmed to assume the correct curvature as it matures offers a fundamentally different approach. The platform also enables the spatial organization of multiple cell types within a single construct, supporting their distinct functions in ways that uniform scaffolds cannot.

What makes the work particularly striking is its conceptual economy. No new chemistry was required, no exotic materials, and no external actuators. The shape change emerges from the interplay between patterned crosslinking, differential swelling, and time, the same interplay that turns a folded sheet of paper into a snowflake. Gasvoda summarized the demonstration succinctly: kirigami-patterned, cytocompatible hydrogels can be engineered to autonomously bend, fold, and transform into complex three-dimensional shapes. In doing so, the approach addresses a longstanding challenge in the field, opening the possibility of engineering tissues that more closely replicate the intricate architectures of the native tissues they are meant to replace or repair.

The team is candid about the road ahead. Having shown that the platform can generate complex geometries in concert with new tissue formation in the laboratory, the next step is to evaluate its performance in animal models, with the long-term goal of translating the technology toward clinical applications. That path will test whether the programmed transformations remain reliable in the messier environment of a living body, where mechanical loading, biochemical signaling, and immune responses all compete with the engineered design. But the underlying idea, that a flat sheet of living material can be taught to fold itself into the shape of the tissue it will become, offers a compelling glimpse of where biofabrication may be headed, and it began, fittingly, with a pair of scissors and a sheet of paper.

Subject of Research: A 4D bio-kirigami hydrogel platform for engineering complex tissue curvatures

Article Title: New 4D biofabrication technology holds promise for tissue engineering, wound healing

Article References: New 4D biofabrication technology holds promise for tissue engineering, wound healing. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: 4D biofabrication, kirigami, hydrogels, tissue engineering, wound healing, photolithography, alginate, gelatin, cell Biomaterials, University of Illinois Chicago, cartilage, regenerative medicine

The review, led by researchers surveying the state of the art in wearable, implantable, biodegradable and self-powered biosensing platforms, takes an unusually rigorous approach. Rather than simply cataloguing recent breakthroughs, the authors analysed 144 publications using a bibliometric method, building a quantitative map of the research landscape. The analysis reveals a field that has grown rapidly and become deeply multidisciplinary, drawing on electrochemistry, materials science, microfluidics, wireless engineering and data science. It also charts a decisive transition in ambition: from one-off or periodic measurements toward connected, autonomous sensors that operate reliably for weeks, months or even longer.

At the heart of this transformation lies a quiet revolution in materials. The review systematically examines how advanced functional materials are being engineered to overcome the classic weaknesses of biosensors, which historically traded sensitivity for stability and speed for selectivity. Carbon nanotubes and graphene quantum dots, with their extraordinary electrical conductivity and vast surface areas, enhance charge transfer between the biological recognition element and the electronic transducer, boosting signal strength. MXenes, a family of two-dimensional transition metal carbides and nitrides, and covalent organic frameworks, crystalline porous polymers with tunable chemistry, create pathways that improve analyte accessibility, allowing target molecules to reach the sensing surface more efficiently even in complex samples.

Perhaps most intriguing are the materials designed to solve the selectivity problem, arguably the hardest challenge in biosensing. Molecularly imprinted polymers act as artificial antibodies, with binding cavities sculpted around a template molecule during synthesis, giving them the ability to recognise specific targets amid a crowded biochemical background. Functional polymers and hydrogels add reversible recognition, meaning the sensor surface can release the analyte and be regenerated for the next measurement cycle, a property essential for any device intended to monitor continuously rather than be used once. Chiral composites exploit the handedness of molecules to discriminate between chemically identical mirror-image forms, a subtle but clinically important distinction, while engineered antifouling surfaces resist the protein and cell deposition that would otherwise blind the sensor within hours of deployment.

On the mechanical side, hydrogels and flexible polymers allow devices to conform to the curved, moving surfaces of the human body, maintaining stable contact with skin or tissue without irritation. This mechanical flexibility, combined with biocompatible encapsulation and, in some designs, fully biodegradable architectures, is what turns a laboratory curiosity into a device a patient can genuinely live with. Self-powered designs go further, harvesting energy from bodily motion or bioelectrochemical reactions to eliminate the need for battery replacement, a major barrier for implantables.

The review is careful to stress that materials alone do not make a continuous monitoring system. Electrochemical and optical transduction strategies are examined systematically, since the choice of how a molecular binding event is converted into an electrical or optical signal determines much of the device’s performance envelope. Around that core, the modern biosensor is increasingly a networked computing device. Microfluidic channels deliver and prepare samples at microscopic scales, wireless links transmit data from body or field, and artificial intelligence and machine learning algorithms interpret raw signals, compensate for drift and extract clinically meaningful trends. Edge and cloud computing architectures, tied together through the Internet of Things, are enabling multiplexed platforms that track many biomarkers simultaneously and even close the loop, adjusting a therapy automatically in response to what the sensor measures.

Yet the review’s most sobering contribution may be its honest assessment of the barriers standing between laboratory promise and real-world deployment. Sensor regeneration, the ability to reset the sensing surface without degrading it, remains difficult. Biofouling, the accumulation of biological material on the device, degrades signal quality over time. Signal drift means a sensor calibrated on day one may report falsely by day ten, and matrix interference from proteins, salts and other sample components can swamp the target signal entirely. Calibration strategies, energy demands, biocompatibility, device integration, manufacturing scalability, cybersecurity of connected health devices, regulatory compliance and the scarcity of genuine clinical and field validation all loom as obstacles that laboratory benchmarks routinely understate.

Indeed, one of the review’s most striking arguments is that the traditional figures of merit of analytical chemistry, sensitivity and limit of detection, are simply inadequate for judging whether a biosensor is ready for deployment. A device can post dazzling detection limits in a clean buffer solution and still fail within days in blood, sweat or river water. What matters instead, the authors contend, are long-term stability, tolerance of complex matrices, reproducibility between devices and validation under realistic conditions. Until the field adopts these deployment-oriented metrics alongside conventional ones, lab-to-life translation will remain the exception rather than the rule.

The path forward, as the review sketches it, is correspondingly holistic. Priority directions include regenerative and antifouling sensing interfaces that keep themselves clean and functional, multimodal and self-powered platforms that reduce dependency on external energy, physiomimetic and minimally invasive architectures that the body tolerates better, and AI-enabled signal interpretation that can distinguish true biological trends from artefacts. Equally critical are unglamorous but essential steps: standardized performance metrics that allow honest comparison between devices, scalable manufacturing routes that can bring costs down, and rigorous clinical and environmental validation studies that test devices where they will actually be used.

Taken together, the review’s message is that reliable continuous biosensing will not emerge from any single breakthrough in nanomaterials or transduction chemistry. It demands the coordinated advancement of advanced materials, biorecognition chemistry, device engineering, energy management, digital connectivity and data analytics as an integrated system. If that integration succeeds, the payoff is substantial: personalized healthcare that watches over patients continuously rather than at the discretion of a blood draw schedule, and environmental stewardship that detects contamination as it happens rather than after the fact. The sensors are getting closer to ready. The challenge now is everything around them.

Subject of Research: Continuous monitoring biosensors for healthcare and environmental applications

Article Title: Continuous monitoring biosensors for advanced healthcare and environmental applications: challenges, material innovations and future directions

Article References: Amireddy, K. K., Reddy, P. V. R. R., Reddy, C. N., & Reddy, P. P. (2026). Continuous monitoring biosensors for advanced healthcare and environmental applications: challenges, material innovations and future directions. Frontiers in Sensors, 7, Article 1968999. https://doi.org/10.3389/fsens.2026.1968999

Image Credits: AI Generated

DOI: 10.3389/fsens.2026.1968999

Keywords: biosensors, continuous monitoring, wearables, implantable sensors, MXenes, graphene quantum dots, molecularly imprinted polymers, hydrogels, electrochemical sensors, artificial intelligence, Internet of Things, environmental monitoring

Hydrogels are three-dimensional polymer networks with a water content typically ranging from 70 to 99 percent of their weight, making them naturally suited to mimic the hydrated environment of the extracellular matrix that surrounds living cells. Their intrinsic viscoelasticity and tunable stiffness allow them to replicate the biomechanical microenvironments of native tissues, which has made them staples of regenerative medicine, localized drug delivery and 3D bioprinting. But conventional hydrogels, once fabricated, keep the mechanical properties they were given. Mechanically adaptive hydrogels break that rule: they can dynamically alter their stiffness and viscoelasticity in response to stimuli such as temperature, pH, enzymatic activity and, crucially, the mechanical forces of daily loading.

The review, authored by Ioana-Cristina Băncilă of TU Wien, synthesizes 86 studies selected from an initial pool of 279 papers spanning 2011 to 2025. It organizes hydrogels into four broad classes. Natural hydrogels like collagen and hyaluronic acid offer excellent biocompatibility but lack the strength needed for load-bearing bone. Synthetic systems based on polyethylene glycol or polyvinyl alcohol deliver tunable, stable stiffness through covalent crosslinks. Hybrid materials attempt to balance bioactivity with mechanical robustness. And at the frontier sit mechanoresponsive hydrogels, which embed mechanosensitive elements that modulate stiffness in real time under physiological load.

The biomechanical parameters that govern whether such scaffolds succeed are quantified in detail. Elastic moduli in the range of 0.1 to 5 megapascals can support osteogenic differentiation, though hydrogels at the low end cannot bear the full mechanical demands of a load-bearing defect. Swelling ratios of 10 to 60 times the dry weight influence stiffness and degradation, with swelling above 40-fold associated with a 20 to 30 percent reduction in scaffold stiffness. Porosity above 80 percent promotes cell infiltration and vascularization but can undermine tensile strength. Stress relaxation and creep — the time-dependent behaviors that let native tissue dissipate energy under repetitive loading — are highlighted as essential design targets rather than afterthoughts, because they directly shape how cells sense and respond to their surroundings.

One of the more striking findings synthesized in the review comes from studies comparing scaffold stiffness at the kilopascal scale: softer matrices of 0.66 kilopascals actually enhanced osteogenic differentiation and matrix mineralization compared with stiffer 5.4-kilopascal scaffolds, a counterintuitive result that underscores how mechanotransduction is not simply a matter of making materials harder. Stiffer microenvironments generally favor osteogenesis while softer ones steer cells toward chondrogenic pathways, and the timing and spatial distribution of these cues may matter as much as their magnitude. Hydrogels with programmable spatiotemporal mechanical cues have now been shown to improve stem cell differentiation and mineralization without relying exclusively on biochemical growth factors.

Standout examples illustrate the direction of travel. A dual-crosslinked, injectable hydrogel combining oxidized hyaluronic acid, gelatin, borax and Prussian blue nanoparticles exhibits self-healing behavior, scavenges reactive oxygen species, fights bacteria and maintains mechanical integrity under physiologically relevant loads. Gelatin methacryloyl hydrogels reinforced with polycaprolactone nanofibers and bioactive glass have promoted bone regeneration in critical-size cranial defects. Photocrosslinkable systems such as GelMA and PEGDA can be printed with spatial stiffness gradients that mimic the transition from trabecular to cortical bone, and composites loaded with hydroxyapatite nanoparticles emulate the mineralized matrix without sacrificing viscoelasticity.

Computation enters as the second pillar of the review. Finite element modeling, or FEM, has been used to simulate hydrogel scaffolds assigned Young’s moduli of 1 to 5 megapascals under compressive loads of roughly 1000 newtons, incorporating the properties of surrounding trabecular and cortical bone. Such models predict how scaffold stiffness, geometry and porosity distribution shape the local mechanical environment that governs osteogenic differentiation. But the review is blunt about the limitations: most FEM studies assume material homogeneity, ignore swelling, degradation and viscoelastic change over time, apply oversimplified axial loading, and lack experimental validation. Simulations that cannot capture these dynamics have limited power to predict what will happen inside a living patient.

The third pillar is the bone-on-chip, a microfluidic platform that recreates the bone microenvironment in vitro with far more physiological relevance than static cell cultures. Mechanically adaptive hydrogels are especially suited to these devices because they respond to compression, shear stress and cyclic deformation — the forces central to bone physiology. Recent platforms have demonstrated thermoresponsive hydrogels actuated by laser-based systems to stimulate osteogenesis in human mesenchymal stem cells without any biochemical factors, microporous biodegradable hydrogels supporting functional human bone cell networks under perfusion, and stiffness-gradient systems activating YAP/TAZ mechanotransduction pathways under dynamic compression. These chips can monitor cellular behavior, matrix remodeling and drug responses in real time under conditions that approximate the body.

The review does not shy away from the field’s fragmentation. Standards bodies including ASTM and ISO have published rigorous mechanical testing protocols for hydrogels, yet actual adoption remains sporadic, producing a literature that is difficult to compare or reproduce. Bulk tests like uniaxial compression average the response of an entire sample, masking the microscale stiffness gradients introduced by embedded cells, growth factors and nanoparticles — variations that profoundly influence cell fate. The author argues that spatially resolved techniques such as atomic force microscopy nanoindentation, Brillouin light scattering microscopy and scanning acoustic microscopy should be indispensable parts of the characterization pipeline, not optional extras, and that bone-on-chip data should feed directly into multiscale computational frameworks combining FEM with molecular dynamics.

The translational path forward links mechanical adaptability to specific clinical scenarios: craniofacial reconstruction, where scaffolds must withstand masticatory forces; spinal fusion, where compressive and cyclic loading dominate; and osteochondral repair, where stiffness gradients are inherent to the tissue. Regulatory hurdles, GMP-compliant manufacturing and long-term in vivo data gaps remain formidable, and candidates like the PEG-fibrinogen hydrogel GelrinC show promise while exposing challenges in scalability and vascularization. The convergence of adaptive materials, machine-learning-guided design, embedded biosensors and validated chip-model coupling offers, in the reviewer’s framing, a concise framework for rational scaffold design — one in which the material that heals your bone might one day adjust itself in step with your own skeleton.

Subject of Research: Mechanically adaptive hydrogels for bone tissue engineering

Article Title: Mechanically adaptive hydrogels for bone tissue engineering: from classification and biomechanics to modeling and translational applications

Article References: Băncilă, I.-C. (2025). Mechanically adaptive hydrogels for bone tissue engineering: from classification and biomechanics to modeling and translational applications. Frontiers in Medical Engineering, 3, Article 1703555. https://doi.org/10.3389/fmede.2025.1703555

Image Credits: AI Generated

DOI: 10.3389/fmede.2025.1703555

Keywords: hydrogels, bone tissue engineering, mechanically adaptive materials, finite element modeling, bone-on-chip, mechanobiology, stimuli-responsive biomaterials, stress relaxation, extracellular matrix, regenerative medicine, 3D bioprinting, vascularization

The gelling agents used to build oleogels are diverse, and each imparts distinct properties to the resulting network. Waxes, including candelilla, beeswax, and sunflower wax, form crystalline networks whose strength and thermal behavior depend on the chain length distribution of their hydrocarbon fractions and on the cooling history of the gel. Organogelators such as ethylcellulose build networks through polymer strand aggregation, while combinations of monoglycerides, phytosterols, and other small molecules can form tubular or fibrillar structures. Because the network architecture determines how oil is trapped, how the gel flows under shear, and how it melts or softens at elevated temperature, the choice of gelling agent is effectively a choice about the final food’s behavior during processing and consumption. This is why studies that systematically link gelator chemistry to functional performance in real foods, rather than in isolated gel systems, carry particular weight for the field.

Hydrogels operate on an analogous principle in the aqueous phase, using polysaccharides and proteins to build networks that hold water, modulate viscosity, and encapsulate hydrophilic compounds. Proteins such as whey, soy, and gelatin can form gels through heat-induced unfolding and aggregation, electrostatic complexation, or enzymatic crosslinking, while polysaccharides such as alginate, pectin, and carrageenan respond to ionic strength, pH, and hydration conditions. The stimulus-responsiveness highlighted in the review literature is especially relevant here: a hydrogel that remains intact in the acidic environment of the stomach but dissociates at intestinal pH can protect a sensitive cargo through gastric transit and release it where absorption is most favorable. Similar logic applies to temperature-triggered systems, which may remain stable during refrigerated storage but soften or release their payload at physiological temperature.

Bigels represent a further step in structural sophistication because they combine two gel phases that would normally be immiscible. In a typical bigel, an oleogel phase and a hydrogel phase are brought together under shear with the help of stabilizers and interfacial design, producing a material in which hydrophilic and lipophilic compounds can be compartmentalized separately. This compartmentalization matters for several reasons. It prevents reactive ingredients from contacting one another until the moment of consumption or digestion. It allows co-encapsulation of compounds with opposing solubility requirements. And it creates release profiles that can be tuned by adjusting which phase is continuous and which is dispersed, since a compound dissolved in the continuous phase will generally diffuse out faster than one sequestered in droplets of the dispersed phase. The phase ratio, droplet size distribution, and interfacial film composition therefore become design variables that food scientists can manipulate to achieve targeted delivery behavior.

The digestive fate of these systems deserves particular attention because the gastrointestinal tract subjects ingested materials to a sequence of environments that few laboratory tests replicate faithfully. In the mouth, shear forces and amylase begin to modify the matrix. In the stomach, acidic pH, pepsin activity, and mechanical churning act on the gel structure over periods ranging from minutes to hours. In the intestine, bile salts emulsify lipids, pancreatic lipase cleaves triglycerides, and the changing pH and ionic conditions continue to remodel whatever structure remains. A gel that appears stable in a beaker may disintegrate rapidly under gastric conditions, releasing its cargo prematurely, or conversely may resist digestion so effectively that its nutrients never become bioaccessible. Static in vitro digestion protocols that sequentially simulate oral, gastric, and intestinal phases have become standard tools for probing these transformations, and more advanced dynamic models that reproduce realistic transit times, pH profiles, and shear regimes are increasingly used to refine predictions.

Scattering and microscopy techniques underpin much of the structural insight in this field. Small-angle X-ray and neutron scattering can resolve features spanning from nanometers to hundreds of nanometers, revealing crystalline packing in wax networks, polymer mesh dimensions in hydrogels, and interfacial film thickness in emulsion gels. Confocal microscopy with selective fluorescent staining can map the spatial arrangement of oil and water phases in bigels, showing whether one phase forms connected channels or isolated domains. Rheology complements these methods by measuring how the network responds to deformation, distinguishing between elastic solids that hold their shape and viscous fluids that flow. When these measurements are collected at multiple stages of digestion rather than only on the freshly prepared gel, they allow researchers to construct a mechanistic narrative connecting formulation choices to structural evolution to nutrient release, which is precisely the framing that the current literature increasingly advocates.

The application of oleogels in baked goods illustrates how laboratory findings must confront the realities of industrial processing. Cookie production involves creaming of fat and sugar, which incorporates air bubbles that later expand during baking and set the final texture. A fat that does not cream properly will yield a dense, hard cookie regardless of its nutritional profile. During baking, the structuring fat must melt or soften at the right rate to allow expansion without collapse. After baking, it contributes to texture during chewing and to the migration of moisture during storage. Replacing conventional solid fat with a wax-based oleogel therefore requires that the gel network survive creaming shear, respond appropriately to oven temperatures, and deliver acceptable sensory properties, all while carrying functional compounds such as vitamin E that may themselves be heat-sensitive. Studies demonstrating complete replacement of solid fat in a real cookie formulation, with measurements of texture, color, and nutrient retention, thus provide evidence at a level of realism that model systems cannot.

High-temperature sterilization presents an even harsher challenge for gel-based systems. Retort processing, which is used to ensure the microbiological safety of shelf-stable meat products, exposes the food to temperatures well above those of normal cooking for extended periods. Proteins denature and aggregate further, polysaccharides may degrade, water held in gel networks can be expelled as the matrix contracts, and textures can shift from desirable to rubbery or mushy. Finding natural ingredients that help gels retain water and texture through such treatment is valuable both for product quality and for reducing the need for synthetic additives. Seaweed-derived ingredients are of particular interest in this context because they bring both water-holding polysaccharides and bioactive compounds, and their use in meat systems also aligns with efforts to reformulate processed meats toward improved nutritional profiles.

Bioaccessibility, the fraction of an ingested nutrient that is released from the matrix and made available for absorption, is the metric that ultimately connects delivery system design to nutritional benefit. A bioactive compound can be chemically intact in a food yet poorly bioaccessible if it remains trapped in an indigestible network or is degraded before release. Conversely, a gel that releases its cargo too early in the digestive tract may expose it to acidic conditions that promote degradation. The design goal is therefore not simply protection or simply release, but a controlled sequence in which the matrix survives processing and storage, resists premature disruption in the stomach, and disassembles at the appropriate point in the intestine. Achieving this requires that formulation studies measure bioaccessibility directly rather than inferring it from encapsulation efficiency alone, and the growing emphasis on digestion-coupled characterization reflects this recognition.

Several methodological themes emerge from the current body of work that will likely shape future research directions. First, the value of testing gels within finished foods under realistic processing conditions is now well established, and studies that bridge the gap between model gels and commercial products will continue to be needed. Second, the combination of structural characterization across length scales with digestion experiments offers a path toward predictive understanding, in which formulation changes can be anticipated to alter release behavior without exhaustive trial and error. Third, the use of plant-derived and food-grade gelators responds to consumer and regulatory pressure, and expanding the palette of such materials, including agricultural byproducts and underexploited seaweed species, broadens the options available to formulators. Fourth, the stability of bioactive compounds during processing, storage, and digestion must be tracked alongside structural performance, since a delivery system that protects structure but not payload fails its purpose.

The broader significance of this research area lies in its potential to reconcile nutritional goals with sensory expectations. Fat reduction, sugar reduction, and nutrient fortification all tend to compromise the textures that consumers enjoy, and the failure of many reformulated products in the marketplace reflects this tension. Gels that can be tuned independently in composition, structure, and responsiveness give formulators additional degrees of freedom, allowing fat to be restructured rather than removed, water to be bound rather than lost, and nutrients to be delivered rather than degraded. As the evidence base grows to encompass more food categories, more gelator combinations, and more complete digestive characterization, these systems will move from promising laboratory concepts toward practical tools for developing foods that are simultaneously healthier, stable, and enjoyable to eat.

Subject of Research: Next-generation oleogel and hydrogel systems for food structuring, digestion, and nutrient delivery

Article Title: Editorial: Next-generation oleogel and hydrogel systems: advances in structuring, digestion, and nutrient delivery in food matrices

Article References: Castelo-Branco, V. N. (2026). Editorial: Next-generation oleogel and hydrogel systems: advances in structuring, digestion, and nutrient delivery in food matrices. Frontiers in Soft Matter, 6, Article 2013976. https://doi.org/10.3389/frsfm.2026.2013976

Image Credits: AI Generated

DOI: 10.3389/frsfm.2026.2013976

Keywords: oleogels, hydrogels, bigels, food science, nutrient delivery, digestion, soft matter, food texture, bioactive compounds, stimuli-responsive materials, Editorial, Next-generation

The distinction between physically crosslinked and chemically crosslinked hydrogels deserves closer attention, because it shapes nearly every downstream decision in scaffold design. Physically crosslinked networks rely on reversible interactions such as hydrogen bonding, ionic bridging, hydrophobic association, or host-guest complexation. Alginate, for example, gels almost instantaneously when its guluronic acid blocks coordinate divalent calcium ions, a property that has made it a mainstay of cell encapsulation and bioprinting, since cells can be mixed into the precursor solution and entrapped gently as the network forms around them. The reversibility of these bonds, however, means the gel can erode, swell excessively, or exchange ions with the surrounding physiological fluid, which limits long-term mechanical stability. Chemically crosslinked networks, formed through covalent reactions such as radical polymerization, click chemistry, or enzymatic coupling, offer superior dimensional stability and tunable degradation, but the crosslinking chemistry must be chosen with care because reactive intermediates, residual monomers, or ultraviolet initiation can damage encapsulated cells. The most successful modern platforms often combine both modes, using rapid physical gelation to shape the material in situ and slower covalent crosslinking to lock in final properties.

Among natural polymers, each candidate brings a distinct biological personality. Collagen, the most abundant protein in the mammalian body, provides inherent cell-binding motifs such as the RGD sequence that synthetic materials must otherwise graft on artificially. Gelatin, its partially denatured derivative, retains many of these motifs while being easier to process and chemically modify, and its thermoreversible gelation near physiological temperatures underpins its use in injectable carriers and bioinks. Hyaluronic acid, a linear glycosaminoglycan, is not merely a passive structural component but an active signaling molecule: it interacts with cell surface receptors such as CD44 and RHAMM, influencing migration, proliferation, and inflammation resolution, which explains its prominence in wound healing and neural applications. Chitosan, derived from chitin, carries positive charges under physiological conditions, enabling electrostatic complexation with DNA, RNA, and negatively charged growth factors, a feature exploited in gene delivery and antimicrobial formulations. Alginate, by contrast, is relatively bioinert toward mammalian cells, which is a double-edged characteristic: it minimizes nonspecific immune activation but must be functionalized if specific cell adhesion is desired.

Synthetic polymers answer a different set of needs. Polyethylene glycol remains the workhorse of synthetic hydrogel chemistry because it is highly hydrated, essentially protein-resistant in its unmodified form, and amenable to an extraordinary range of end-group functionalizations. This inertness allows researchers to build matrices from a blank slate, adding only the biochemical cues they deliberately choose, which is invaluable for systematically studying how matrix composition affects cell behavior. Polycaprolactone, with its slow degradation profile spanning months to years, suits applications requiring prolonged mechanical support, such as bone regeneration, while polylactic acid and its copolymers degrade faster and can be tuned through stereochemistry and molecular weight. Poly-N-isopropylacrylamide exhibits a lower critical solution temperature near thirty-two degrees Celsius, meaning it transitions from a hydrated coil to a collapsed globule as temperature rises through this threshold. Formulated appropriately, such thermoresponsive polymers remain soluble when handled cold and gel in place upon reaching body temperature, an elegant solution to the injectable delivery problem that avoids cytotoxic crosslinkers entirely.

The concept of mechanical tunability merits quantitative appreciation. Cells are remarkably sensitive mechanosensors: substrate stiffness in the kilopascal range can direct mesenchymal stem cells toward neurogenic, myogenic, or osteogenic lineages even in the absence of soluble differentiation factors, a finding that reshaped how the field thinks about stem cell culture. Brain tissue is on the order of a few hundred pascals in stiffness, muscle roughly ten to twenty kilopascals, and mineralized bone several gigapascals. A hydrogel intended to nurture neural progenitors must therefore be dramatically softer than one designed to support osteoblast maturation, and the ability to dial in elastic modulus through polymer concentration and crosslink density is among the most powerful levers in hydrogel engineering. Stress relaxation, the rate at which a matrix dissipates applied strain, has emerged as an equally important parameter, because dynamically remodeling matrices permit cells to spread, migrate, and deposit their own extracellular matrix in ways that purely elastic networks of identical stiffness do not.

Injectable hydrogel systems address one of the most practical constraints in regenerative surgery: the difficulty of pre-formed implants to conform to irregular defect geometries. A preformed scaffold requires invasive implantation, risks poor contact with surrounding tissue, and cannot easily fill complex cavities. In situ gelling systems, delivered as liquid precursors through minimally invasive injection, conform to the defect shape and polymerize under physiological triggers such as temperature, pH, ion concentration, or light exposure. Shear-thinning formulations add another layer of sophistication: they flow readily under the high shear of the injection needle yet recover their mechanical integrity immediately upon deposition, protecting encapsulated cells from the transient stresses of delivery. This property, borrowed from biological gels such as mucus and the cytoskeleton, has proven particularly valuable for bioprinting applications where the printed filament must hold its shape while remaining processable.

Nanocomposite hydrogels illustrate how inorganic phases can endow soft networks with capabilities they otherwise lack. Incorporating nanoscale hydroxyapatite into polymer matrices introduces mineral surfaces that promote osteoblast adhesion and osteogenic differentiation while simultaneously stiffening the network toward bone-like mechanics. Graphene oxide and carbon nanotubes confer electrical conductivity, which matters enormously for cardiac and neural engineering, since these tissues rely on synchronized electrical signaling that insulating hydrogels cannot support. Silica and clay nanoparticles can serve as physical crosslinking hubs, dramatically increasing toughness through sacrificial bond mechanisms in which nanoparticle-polymer interactions break and reform under load, dissipating energy that would otherwise fracture the network. The design challenge lies in ensuring that the reinforcing phase remains biocompatible, does not leach, and does not aggregate, since nanoparticle clustering creates stress concentrations that undermine the very toughness the fillers are meant to provide.

Stimuli-responsive behavior extends beyond temperature. pH-responsive systems exploit the acidic microenvironments of tumors, inflamed tissue, or infected wounds to trigger drug release precisely where it is needed. Redox-responsive networks disassemble in the reducing cytosol, enabling intracellular delivery of nucleic acids and proteins. Photo-responsive formulations allow spatiotemporally precise actuation, since light can be focused, patterned, and switched with exceptional control, and visible or near-infrared wavelengths penetrate tissue with minimal phototoxicity. Enzyme-responsive hydrogels represent perhaps the most biologically elegant category: by incorporating peptide sequences cleaved by matrix metalloproteinases, the scaffold degrades only where and when cells actively remodel it, mimicking the natural balance between matrix deposition and proteolytic turnover that governs tissue morphogenesis.

Self-healing hydrogels tackle a chronic failure mode of soft biomaterials: crack propagation under cyclic loading. Native tissues remodel continuously and repair microdamage; conventional synthetic gels accumulate defects until they fail catastrophically. Networks engineered with reversible crosslinks, dynamic covalent bonds such as boronate esters and imine linkages, or supramolecular host-guest interactions can autonomously re-form broken connections, restoring function after damage. In load-bearing cartilage applications, where joints experience millions of loading cycles annually, this resilience is not a luxury but a prerequisite for clinical durability.

The convergence of hydrogels with drug and gene delivery has produced some of the field’s most clinically near-term applications. Because hydrogels can entrap therapeutic molecules within their hydrated mesh and release them through diffusion, swelling, or degradation kinetics, they function as depot formulations that maintain therapeutic concentrations over days to months while avoiding the peaks and troughs of systemic administration. Growth factor delivery illustrates the principle: bone morphogenetic proteins, vascular endothelial growth factor, and transforming growth factor-beta each orchestrate distinct phases of tissue repair, and hydrogel carriers can be engineered to release them sequentially, mirroring the temporal choreography of natural healing. Affinity-based release, in which growth factors bind reversibly to polymer-bound heparin or other binding motifs, smooths release profiles far better than simple diffusion. Gene delivery from hydrogels, using plasmid DNA, messenger RNA, or viral vectors complexed with cationic polymers, aims to recruit resident cells into local production of therapeutic proteins, converting the scaffold from a passive carrier into an active instruction set.

Biosensing represents a frontier where hydrogels act as both transducer and interface. Their water content and softness minimize fouling and immune reaction at sensor-tissue interfaces, historically the limiting factor in continuous glucose monitoring and other implantable sensors. Conductive hydrogels incorporating PEDOT, polyaniline, or metallic nanostructures enable low-impedance recording and stimulation of electrogenic tissue, while responsive swelling or degradation can transduce biochemical signals into optical or electrical readouts. The same material that regenerates tissue can thus report on its progress, closing the loop for adaptive therapy.

The translational barriers documented in the recent literature deserve sober acknowledgment. Preclinical animal models frequently fail to predict human outcomes, a problem the FDA Modernization Act 2.0 partially addresses by permitting alternatives to animal testing for certain regulatory purposes, opening space for organoid platforms and advanced in vitro systems built on hydrogel matrices that better recapitulate human physiology. Scale-up introduces its own difficulties: laboratory syntheses relying on precise stoichiometry, sterile handling, and gentle crosslinking conditions do not always translate to good manufacturing practice environments. Sterilization poses a particular dilemma, since autoclaving, gamma irradiation, and ethylene oxide can each alter polymer molecular weight, crosslink density, or bioactivity. Regulatory classification adds further complexity, because combination products that merge device, drug, and biologic elements face overlapping review pathways. Progress will likely require not only better materials but better standardized characterization, reproducible manufacturing, and harmonized preclinical evaluation frameworks, so that the remarkable laboratory performance of next-generation hydrogels can be converted into dependable clinical benefit.

Subject of Research: Advanced hydrogels for tissue engineering and regenerative medicine: from material design to clinical translation

Article Title: Advanced hydrogels for tissue engineering and regenerative medicine: from material design to clinical translation

Article References: Vyas, J., Raytthatha, N., Vyas, P., Shah, N., & Modi, D. (2026). Advanced hydrogels for tissue engineering and regenerative medicine: from material design to clinical translation. Frontiers in Biomaterials Science, 5, Article 1861958. https://doi.org/10.3389/fbiom.2026.1861958

Image Credits: AI Generated

DOI: 10.3389/fbiom.2026.1861958

Keywords: hydrogels, tissue engineering, regenerative medicine, biomaterials, extracellular matrix, injectable hydrogels, stem cells, 3D bioprinting, drug delivery, clinical translation, Advanced, tissue