The team, led by researchers including Tianhao Wang and Xiaoxiang Ren, defines its constructs as scaffold-guided engineered bone organoids, meaning the biomaterial establishes the initial three-dimensional architecture while the encapsulated cells progressively take over, depositing bone-specific extracellular matrix and driving mineralization. This dynamic remodeling is what separates a true organoid from a passive cell-laden scaffold. Conventional bone organoid platforms are largely built to push stem cells toward osteogenic differentiation, but they rarely incorporate immune components, a significant drawback given that macrophages must typically shift from a pro-inflammatory M1 state to a pro-regenerative M2 state to resolve inflammation, induce new vessel formation, and facilitate matrix remodeling during healing.

The new bioink blends three components in a carefully optimized ratio of 10 percent gelatin methacryloyl (GelMA), 1 percent Laponite synthetic nanoclay, and 40 percent aloe vera gel. Each ingredient earns its place through a defined function. GelMA, a photocrosslinkable derivative of gelatin, carries the arginine-glycine-aspartic acid cell-adhesion motif and offers tunable mechanics through rapid UV cross-linking. Laponite forms what materials scientists describe as a house-of-cards microstructure, imparting strong shear-thinning behavior that makes the ink extrusion-printable while boosting elastic modulus and toughness; its degradation products, magnesium and silicon ions, have independently been shown to foster a pro-regenerative microenvironment. Aloe vera serves as the immunologically active component, delivering bioactive polysaccharides such as acemannan along with phytosphingosine- and polyphenol-related metabolites identified by liquid chromatography-mass spectrometry.

Reaching that sweet-spot formulation required systematic trade-off analysis. Lower GelMA concentrations produced weak mechanical support and structural collapse, while higher levels restricted cell migration and matrix remodeling. Laponite at 1 percent elevated shape fidelity to a printability coefficient near 1.0, but higher loadings clogged nozzles and pushed cell viability below 80 percent through elevated shear stress. Aloe vera below the optimal threshold weakened immunomodulatory efficacy, whereas excess diluted the precursor and compromised cross-linking. The final formulation, seeded with rat bone marrow mesenchymal stem cells at one million cells per milliliter, yielded continuous filament deposition, precise architecture, and post-printing viability exceeding 90 percent, all without a single exogenous cytokine such as IL-4.

The printing parameters themselves are a study in delicacy. Constructs were extruded at 8 degrees Celsius to preserve gel consistency and prevent filament deformation, under pneumatic pressure of 0.2 to 0.3 megapascals at a speed of 4 millimeters per second, using a 21-gauge metal nozzle. A rectangular, eight-layer porous grid of 5 by 5 millimeters was built with 1.5-millimeter infill spacing and 90-degree interlayer rotation. Cross-linking used 365-nanometer UV light at just 5 percent intensity, applied for 10 seconds per layer with brief post-curing, enough to lock in shape without damaging the stem cells. Printed precursors then spent 24 hours in growth medium before switching to osteogenic induction medium supplemented with beta-glycerophosphate, ascorbic acid, and dexamethasone for up to 28 days.

In vitro, the organoids behaved as hoped. Alkaline phosphatase and Alizarin Red S staining documented progressive osteogenic differentiation and mineral deposition, confirmed by elevated expression of the master osteogenic markers OCN, RUNX2, and OPN and by micro-computed tomography detection of mineralized matrix. On the immune side, the constructs increased macrophage recruitment, invasion, and adhesion, and shifted the cells toward a CD206-positive, iNOS-low phenotype characteristic of pro-regenerative M2 macrophages, accompanied by reduced IL-1beta and increased IL-10 expression. Bulk RNA sequencing of implanted constructs revealed broad immune remodeling across Th1/Th2/Th17-related pathways and alterations in STAT6, NF-kappaB, PI3K/AKT, and RANKL-related signaling, consistent with enhanced pro-regenerative responses and dampened inflammation, though the authors caution these associations do not yet establish direct causality.

The in vivo results are where the platform becomes genuinely striking. When implanted subcutaneously into nude mice, the organoid precursors matured into bone-like tissue, organizing type 1 collagen and periostin into structured extracellular matrix, forming vinculin-positive focal adhesions, and sprouting prominent surface capillaries alongside internal CD31-positive microvascular networks. The team then moved to the decisive test: bilateral 5-millimeter critical-sized calvarial defects in rats, wounds too large to heal on their own. By eight weeks, the aloe-containing organoids had promoted more robust bone regeneration than GelMA-only or GelMA/Laponite control scaffolds, with improved mineralized bone formation, closer integration with host tissue, and CD206-positive macrophages populating the repair site. Histology of major organs and routine blood biochemistry revealed no obvious systemic toxicity.

The authors are candid about the platform’s limits. The protocol models macrophage-mediated regulation only; neutrophils, osteoclasts, T cells, and other stromal populations were not systematically incorporated, and the use of immunodeficient nude mice precludes assessment of adaptive immunity. Late-stage osteocyte maturation and lacuno-canalicular network organization remain uncharacterized, and the eight-week observation window captures only early-to-intermediate regeneration, leaving scaffold degradation kinetics, vascular stabilization, and biomechanical load-bearing integration for future studies extending to 12 to 24 weeks and, ultimately, large-animal models. Batch-to-batch consistency of aloe vera gel also emerges as a critical quality-control point, since variability in its bioactive constituents could weaken macrophage polarization.

Even so, the implications extend well beyond the skull. The researchers envision adapting the bioink to model immune-dysregulated orthopedic diseases such as rheumatoid arthritis and osteoporosis by incorporating patient-derived macrophages, synovial fibroblasts, or osteoclast precursors. Adding chondrogenic factors like TGF-beta3 could generate cartilage organoids, while the same immunoregulatory chemistry might improve wound repair and reduce scarring in skin models. Because the constructs simultaneously promoted bone formation and vascularization in vivo, the system could also help solve the vascularization bottleneck that plagues the engineering of many other tissues. Multi-nozzle bioprinting and microfluidic culture could eventually arrange bone-forming, vascular, and marrow-like compartments in spatially organized, immunocompetent constructs. For a field long tethered to an ill-defined gel extracted from mouse tumors, a printable, plant-powered alternative that teaches immune cells to heal rather than inflame marks a genuinely consequential turn in the organoid revolution.

Subject of Research: Fabrication of immune-regulatory bone organoids using a plant-based GelMA/Laponite/Aloe vera bioink

Article Title: Protocol for fabricating immune-regulatory bone organoids via plant-based bioinks

Article References: Wang, T., Gao, G., Zhang, X., Huo, K., Liu, C., Geng, Z., Bai, L., Zhang, H., Liu, H., Xu, K., Lai, Y., Wang, J., Jing, Y., He, C., Wang, G., Su, J., & Ren, X. (2026). Protocol for fabricating immune-regulatory bone organoids via plant-based bioinks. iScience, 29(11), Article 117866. https://doi.org/10.1016/j.isci.2026.117866

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117866

Keywords: bone organoids, bioink, Aloe vera, GelMA, Laponite, 3D bioprinting, macrophage polarization, osteoimmunology, bone regeneration, Matrigel-free, tissue engineering, calvarial defect

The study, published in Materials Today Bio, was led by Wenbi Wu and Maling Gou and centers on a modified form of gelatin known as gelatin methacryloyl, or GelMA. Rather than using conventional GelMA, which forms a relatively static network once crosslinked, the researchers devised a way to make the material dynamic. GelMA was first self-assembled into nanodroplets dispersed within a Pluronic F68 solution, and then locked into a solid hydrogel through rapid photopolymerization under visible light. The result is a scaffold built from interconnected GelMA nanoparticles, roughly 500 to 700 nanometers across, separated by continuous micron-sized pores. Under the microscope, the network looks open and sponge-like, an architecture that supports cell infiltration and the transport of nutrients and oxygen deep within the matrix.

The key innovation lies in how the team tuned the material’s behavior. By blending GelMA with two different degrees of methacrylate substitution, one highly crosslinked at 98 percent and one lightly crosslinked at 50 percent, they produced three formulations with progressively looser networks. Rheological testing revealed that the loss modulus of these hydrogels showed pronounced frequency dependence, a signature of dynamic, rearrangeable networks. The loosest formulation, Nano-GelMA3, proved the most permissive: it had the highest porosity and swelling capacity, the lowest stiffness, and the fastest enzymatic degradation in collagenase solution. In other words, it behaved less like a rigid barrier and more like a temporary, yielding matrix that cells could push through and remodel.

Laboratory experiments demonstrated just how responsive the material is. When Schwann cells, the glial cells that act as first responders after nerve injury, were embedded in the hydrogels, they spread rapidly, proliferated vigorously, and in time-lapse imaging were seen physically deforming the surrounding nanostructure as they moved. In conventional GelMA gels, cells remained largely spherical and the matrix barely changed. In the nanostructured gels, cells and matrix engaged in a visible dialogue: the cells pulled, the network yielded, and the local architecture reorganized to accommodate them. Schwann cells seeded on the surface of a three-millimeter-thick Nano-GelMA3 block migrated through its entire depth within 72 hours, a net displacement of roughly one millimeter per day, even under a gradient of nerve growth factor mimicking the physiological cue at an injury site.

The molecular basis of this behavior points to mechanotransduction, the process by which cells convert physical cues into biochemical signals. Immunostaining showed that Schwann cells in the nanostructured gels formed far more focal adhesions, the molecular anchors connecting cells to their surroundings. Levels of paxillin, phosphorylated focal adhesion kinase, and vinculin, all core components of the adhesion machinery, were significantly elevated compared with cells in conventional gels. Quantitative PCR revealed upregulation of integrin beta, Rac1, and Cdc42, regulators of cytoskeletal dynamics and cell-matrix signaling. The cells also expressed higher levels of nerve growth factor, myelin basic protein, and myelin protein zero, suggesting a phenotype primed for supporting axons and rebuilding myelin sheaths. The authors are careful to note that these findings are associative rather than proof of a single causal signaling pathway, but the pattern is consistent with a matrix that actively coaches cells into a regenerative state.

To turn the hydrogel into an implantable device, the team built a dual-layer conduit. The inner wall is an electrospun polycaprolactone tube about 300 micrometers thick, providing tensile strength, while the outer layer is a roughly 100-micrometer F127DA hydrogel shell printed directly onto the tube by digital light processing. The resulting conduit withstood a two-newton compressive force and sprang back to its original shape, while suture retention tests confirmed it could survive surgical handling. Filled with Nano-GelMA3, the complete device, dubbed PFNC, was biocompatible with Schwann cells in extraction assays and maintained its channel structure throughout the study period.

The decisive test came in rats with ten-millimeter sciatic nerve defects. Seven days after implantation, longitudinal sections of the regenerated tissue told a striking story. In conduits filled with the adaptive hydrogel, Schwann cells had infiltrated and occupied the entire luminal matrix, forming organized cellular populations from the proximal stump deep into the conduit. In hollow control conduits, cells clustered sparsely near the proximal end, waiting for a fibrin network to form before they could advance. By 24 days, the hydrogel-filled conduits contained continuous, aligned bridges of axons and Schwann cells spanning the gap, with significantly greater NF200-positive axonal extension and bridge coverage than the hollow controls. Histology at 14 days showed regenerating neural tissue growing within the residual hydrogel, confirming that the material facilitated rather than blocked tissue ingrowth, and the loosest formulation degraded progressively in vivo, clearing space as the new tissue took over.

Twelve weeks after surgery, the functional results were remarkable. Electrophysiological recordings showed that the compound muscle action potential latency in the hydrogel-filled conduit group, at 1.32 milliseconds, was significantly better than the hollow conduit group and statistically indistinguishable from the autograft group. Nerve conduction velocity reached 36.42 meters per second, again approaching the autograft benchmark of 41 meters per second. The gastrocnemius muscles served by the repaired nerves regained wet weight and fiber diameter comparable to the autograft group, evidence that the regenerated nerves were genuinely re-innervating their targets. Under the transmission electron microscope, regenerated myelinated fibers in the hydrogel group averaged 3.79 micrometers in diameter with myelin sheaths 0.55 micrometers thick, both essentially matching the autograft values. Histological examination found no necrosis, no severe inflammatory accumulation around the implant, and no pathological abnormalities in major organs.

What distinguishes this work from earlier attempts at nerve-filling hydrogels is the mechanism of adaptation. Most dynamic hydrogels respond to cell forces through the breaking and reforming of reversible molecular crosslinks, a process that allows gradual rearrangement at the molecular scale. The Nano-GelMA system instead adapts through wholesale reorganization of its nanoparticle network, permitting rapid, large deformations that open space for migrating cells, while the interconnected pores provide room for infiltration and nutrient flow. Notably, all of this was achieved without loading the material with exogenous growth factors or drugs; the physical architecture of the matrix alone was sufficient to recruit and activate the body’s own repair cells.

The road to the clinic still has checkpoints. The authors acknowledge that scalable manufacturing, batch-to-batch quality control of nanostructure and degradation, sterilization and storage protocols, and long-term assessment of residual material clearance and fibrosis all require further work. The precise mechanotransduction pathways engaged by the matrix also await confirmation through integrin-blocking and pathway-inhibition studies. Nevertheless, the central lesson of the study is already clear: a regenerative implant does not need to be a passive scaffold. By designing materials that yield, deform, and remodel in response to the cells they host, engineers can create an environment that meets the nervous system on its own terms, and in this rat model, that meeting produced recovery on par with the body’s best self-donated tissue.

Subject of Research: A cell-adaptive nanostructured GelMA hydrogel for engineering early regenerative microenvironments in peripheral nerve repair

Article Title: A cell-adaptive nanostructured hydrogel enables an early regenerative microenvironment for peripheral nerve repair

Article References: Wu, W., Zhu, Q., Dong, Y., Zhao, W., Peng, M., Zhang, Y., Zhang, J., Liu, H., Li, L., Liu, J., Zhang, L., Ren, Y., Luo, X., Li, B., Du, T., & Gou, M. (2026). A cell-adaptive nanostructured hydrogel enables an early regenerative microenvironment for peripheral nerve repair. Materials Today Bio, 41, Article 103725. https://doi.org/10.1016/j.mtbio.2026.103725

Image Credits: AI Generated

DOI: Not provided

Keywords: peripheral nerve repair, hydrogel, GelMA, Schwann cells, nerve guidance conduit, mechanotransduction, focal adhesion, nanotechnology, tissue engineering, 3D bioprinting, nerve regeneration, biomaterials

The robot, which the researchers call an aquabot, is built around a skeleton made from a film of gel roughly the length and width of a stick of chewing gum. The two halves of the gel serve as the robot’s fins, and each fin is coated with a layer of live skeletal muscle cells far thinner than a single strand of human hair. These cells are genetically engineered to contract when illuminated, which means the robot can be steered entirely with light. When the team shines light on one fin, the muscle cells on its surface twitch in unison, causing the whole fin to flap with enough force to pull the robot through the water. By flashing light on one fin or the other, and by varying the timing of those flashes, the researchers can control both the direction and the speed of the swimming robot.

In demonstrations, the paper-thin bot swam and swiveled its way through a simple watery maze set inside a large petri dish, following a light source that the researchers maneuvered manually over the surface of the water. At its fastest, the aquabot covered a distance of about four times its body length in one minute. That pace is admittedly modest compared with elite human swimmers, who can cover up to sixty-five body lengths per minute, but it is competitive with more leisurely swimmers in the animal kingdom. The cow shark, for instance, explores the ocean at roughly the same rate relative to its body size. For a robot whose entire propulsion system is a film of muscle cells thinner than a hair, the performance is a striking proof of concept.

It takes a lot of force to move through water versus air, notes study author Ritu Raman, associate professor of mechanical engineering at MIT. The robot’s quite strong, given its size, she says. That strength did not come by accident. It was the product of a deliberate engineering campaign to optimize every parameter of the platform on which the living muscle grows, a process the researchers describe as tuning the robot’s skeleton. The lesson of the work is that in biohybrid robotics, the artificial scaffold matters just as much as the biological engine that sits on top of it.

The new aquabot builds directly on a milestone the same group achieved the previous year. In that earlier effort, Raman’s laboratory created an iris-inspired disk of artificial muscle tissue by stamping a disk of gel with a pattern of concentric and radial grooves and then depositing live muscle cells onto the gel’s surface. The cells grew along the grooves, forming a thin layer, and when stimulated with light they moved in patterns that stretched and squeezed the disk much as a human iris dilates and constricts the pupil of the eye. That work was the first to show that muscle cells could be grown in a very thin layer and in complex patterns that, when stimulated, could move in multiple controllable directions. People hadn’t seen this muscle architecture engineered from scratch before, Raman says, and the cells were moving in multiple directions. But they only moved about one hundred microns. From a robotics perspective, their movements were tiny.

The goal of the new study was to close that gap: to maximize muscle movement so that the tissue could produce enough force to do useful mechanical work, such as powering a swimming robot. The key, the team discovered, was the underlying gel. In the iris-inspired design, the muscle cells had been grown on fibrin, an ultrasoft gel that the researchers realized could quickly shrivel in response to the forces generated by the contracting muscles. A scaffold that deforms under load wastes the very force the cells are trying to deliver. To better support the cells and maximize their output, the engineers focused on tuning three properties of the gel: its composition, its stiffness, and the size and shape of the grooves stamped into its surface. For engineering any type of tissue, it’s known that these are knobs you can tune, Raman says. And we wanted to optimize all these parameters to support live muscle cells.

The optimization process was systematic. The team experimented with multiple formulations of gel at different stiffnesses, each stamped with grooves of different geometries. One groove type resembled a skinny square trough, while another was more of a long curved valley. When muscle cells were deposited onto each type of grooved gel, the researchers found that the cells settled into alignment most effectively in grooves that were more square than curved. This matters because alignment is everything in engineered muscle: cells that line up in the same direction tend to fuse into fibers, and those fibers form a stronger, more coordinated muscle tissue capable of generating useful force in a single direction. Square grooves, the team concluded, were the way to go.

Composition and stiffness proved equally consequential. Instead of fibrin, the researchers switched to gelatin methacrylate, or GelMA, a material widely used in tissue engineering. By preparing different recipes of GelMA, they created skeletons of varying stiffness and observed how muscle cells grew on each. The cells grew in better alignment and produced the most force on stiffer gels, a finding that runs counter to the intuition that softer scaffolds are always gentler on living tissue. The team also varied the thickness of the gel and found that a film just half a millimeter thin offered good support for a single layer of muscle cells while remaining light enough that the cells stayed anchored to the gel when they contracted, rather than peeling away. As a final step, the researchers exercised the muscles, subjecting them to a training routine of flashing lights that strengthened the tissue over time, much as workouts build strength in an athlete.

With the pumped-up cells and the optimized gel in hand, the team assembled a thin, two-finned robot: the gel, stamped on both sides with square-bottomed grooves and lined with muscle cells that fused into fibers and eventually formed a strong, aligned muscle tissue. You can think of the robot as having two independent muscles, Raman says. If we shine a light on just one, only that muscle moves. If shining on both, they both flap. This independent control of each fin is what gives the aquabot its maneuverability, allowing it to turn and navigate obstacles rather than simply drifting forward in a straight line.

The researchers acknowledge that the current design is relatively basic in form; their first aim was simply to show that the bot could produce enough force to swim at all. Their next goal is to optimize the body design to enable faster swimming. But even at slow swim speeds, the possibilities are intriguing. One could imagine a muscle-powered swimmer being used for purposes like environmental monitoring in aquatic environments, Raman says. Biohybrid robots powered by living muscle could one day perform delicate jobs like exploring environments too fragile or unpredictable for conventional hardware, because living tissue is soft, responsive to its surroundings, and can heal itself. The approach also promises practical advantages over existing biohybrid designs, which are typically built from bulky, three-dimensional chunks of lab-grown skeletal muscle that require millions of cells to fabricate. Thinner, less bulky designs like the aquabot could be cheaper to build and could move more efficiently, bringing soft, light-driven, self-healing machines a step closer to real-world duty beneath the water’s surface.

Subject of Research: Biohybrid robotics using engineered skeletal muscle thin films to power light-controlled swimming robots

Article Title: Powered by muscle cells, a paper-thin robot swims through watery maze

Article References: Powered by muscle cells, a paper-thin robot swims through watery maze. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: biohybrid robots, muscle cells, soft robotics, aquabot, MIT, light-activated actuators, GelMA, tissue engineering, swimming robot, skeletal muscle, environmental monitoring, Advanced Functional Materials

The material, called GelMA–nHA–PEGDA, is built from three components that each play a distinct role. Gelatin methacryloyl, or GelMA, is derived from partially hydrolyzed collagen and retains the cell-interactive motifs and enzyme-cleavable sites of the body’s own structural protein. Polyethylene glycol diacrylate, or PEGDA, is a hydrophilic, biocompatible polymer whose internal architecture resembles the natural extracellular matrix. The third ingredient is nanoscale hydroxyapatite, the calcium phosphate mineral that gives real bone its hardness. Rather than simply mixing mineral powder into a polymer, the team coaxed hydroxyapatite to grow directly onto the GelMA–PEGDA network — a process called biomineralization that imitates how osteoblasts, the bone-forming cells, deposit mineral onto collagen templates during natural osteogenesis.

The chemistry of that mineralization is elegantly simple. Before photocuring, the researchers added calcium nitrate, diammonium hydrogen phosphate, citric acid, and sodium hydroxide directly into the liquid precursor. The negatively charged carboxyl groups on GelMA attract positively charged calcium ions, which in turn neutralize phosphate ions and create nucleation sites on the hydrogel surface. Calcium and phosphate then migrate toward the surface and precipitate as hydroxyapatite, completing the mineralization. Electron microscopy confirmed the result: the original hydrogel’s smooth, porous structure — pores between 10 and 100 micrometers — became denser, with hydroxyapatite nanorods roughly 100 nanometers long and 15 nanometers wide uniformly coating the pore walls. Energy-dispersive X-ray analysis measured a calcium-to-phosphorus ratio of 1.48, closely matching the 1.50 expected for true hydroxyapatite, and X-ray diffraction showed sharp crystalline peaks replacing the amorphous signature of the unmineralized gel.

What makes the material genuinely practical for the operating room is its photosensitivity. The precursor is a warm, molten liquid that can be injected into a fracture gap in a minimally invasive fashion. A patented delivery system then threads an optical fiber through a guiding sleeve to the fracture site and floods it with 405-nanometer light for just 20 seconds. That exposure triggers radical polymerization of the carbon–carbon double bonds in both GelMA and PEGDA, crosslinking the network in place. In tests on fresh chicken femur fragments preconditioned at body temperature, the cured adhesive bonded the two fracture ends strongly enough to support a 500-gram weight in a vertical orientation, and the bond remained stable while submerged in warm saline for 72 hours. The adhesive also stuck to wood, metal, glass, polymers, and other organic surfaces, a versatility that reflects the abundance of hydrogen-bonding groups — hydroxyl, amide, carbonyl, and ether — that grip complementary chemical features on tissue surfaces.

Mechanical testing showed that biomineralization and photocuring work synergistically. In uniaxial compression, the mineralized, cured adhesive tolerated significantly higher maximum pressure before failure than unmineralized material, with elevated modulus and toughness. Three-point bending and lap-shear tests, which probe resistance to vertical and shear stresses respectively, likewise showed substantially higher maximum loads after photocuring. The team reports immediate tensile strength of 0.08 megapascals and lap-shear strength of 0.15 megapascals — figures that exceed representative fibrin-based surgical sealants, though they remain below some experimental polyethylene glycol glues and polymethyl methacrylate bone interfaces. The researchers argue that the combination of rapid application, adequate strength, and regenerative activity could still support standalone use in selected fractures where traditional internal fixation is impractical.

Swelling and degradation behavior matters as much as strength, because an adhesive that lingers too long can block tissue ingrowth. Over 40 days of immersion in body-temperature saline, the material swelled rapidly — more than 50 percent within three days as water penetrated the hydrophilic network — before reaching equilibrium around day 25, when hydrogen bonds among carbonyl groups tightened the crosslinked structure. Degradation proceeded gradually over the same period and accelerated noticeably in the presence of collagenase type II, the enzyme that cleaves the GelMA component. That enzyme-sensitivity is a feature, not a flaw: it means the adhesive should break down in step with the body’s own remodeling machinery, yielding space for new tissue rather than persisting as a permanent barrier the way slow-degrading cyanoacrylate glues can.

Biocompatibility assays with mouse bone marrow-derived mesenchymal stem cells were encouraging. Cells cultured with material extracts showed dose-dependent growth that peaked at 75 percent extract concentration, and adhesion tests at 1, 4, and 7 hours found significantly more cells attached to GelMA–nHA–PEGDA-coated surfaces than to uncoated wells. Live/dead staining revealed predominantly living cells and a higher relative growth rate than either blank controls or plain GelMA. The mineralized adhesive then demonstrated true osteogenic power: Alizarin red staining showed abundant calcium nodules after three weeks of culture, alkaline phosphatase staining — a marker of early osteoblast differentiation — was strongest in the adhesive group, and western blot, quantitative PCR, and immunocytochemistry all confirmed upregulation of the master osteogenic regulators ALP, RUNX2, osteopontin, and collagen 1A1.

The decisive test came in living animals. In a mouse femoral fracture model, 63 animals were randomly assigned to three groups: untreated fractures, conventional Kirschner-wire fixation, and adhesive-only repair with a 20-second light cure. X-ray imaging scored by the Lane–Sandhu system showed that the adhesive group healed significantly better than untreated fractures at both two and four weeks, and by four weeks both the adhesive and pin groups had achieved radiographic union. Histology told an even stronger story: the adhesive group earned the highest callus maturity scores and produced the largest area of new bone, exceeding even the metal-pin group. Three-point bending tests confirmed that adhesive-repaired femurs bore higher maximal loads and stresses than unrepaired bones, and footprint gait analysis showed that mice treated with the adhesive walked with a wide, confident hindlimb stance while untreated and pinned animals dragged their injured limbs.

Micro-computed tomography revealed why the adhesive outperformed the metal pin. Reconstructed three-dimensional images showed complete fracture healing in both treated groups, but the adhesive group displayed significantly greater bone surface, bone volume, trabecular thickness, and trabecular number, with tighter trabecular spacing — a denser, better-organized repair. Immunofluorescent staining pointed to the mechanism: elevated alkaline phosphatase and osteocalcin confirmed active bone formation, while strong signal for paired related homeobox 1, a stem cell marker, showed that the biomineralized gel was actively recruiting bone marrow mesenchymal stem cells to the fracture site. Elevated type II collagen deposition indicated vigorous extracellular matrix assembly. In essence, the adhesive does not merely hold bone still — it behaves like a scaffold of newly forming bone, summoning the cells that build the real thing and switching on their genetic programs as it dissolves.

The implications reach beyond one material. By reproducing the composition and architecture of regenerating bone — collagen-derived polymer, hydroxyapatite mineral, and a degradable, cell-friendly matrix — the team has shown that a fracture fixation device can double as a regenerative medicine product. An all-in-one adhesive that flows into comminuted fracture gaps, cures in seconds under fiber-optic light, bonds to wet tissue, and then hands the job over to the patient’s own stem cells could reduce the burden of implant removal, lower infection risk, and make minimally invasive treatment feasible for injury patterns that currently demand extensive surgery. The reported strengths still fall short of the toughest load-bearing applications, and the work rests on mouse models with a 20-second cure window that will need refinement in larger animals and humans. But as a proof of concept, the study makes a compelling case that the fastest way to fix a broken bone may be to imitate the way bone builds itself.

Subject of Research: A biomineralized photocurable hydrogel bone adhesive for fracture fixation and skeletal regeneration

Article Title: An osteogenesis mimicking biomineralized bone adhesive for rapid skeletal regeneration

Article References: Liu, Y., Luo, H., Guo, B., Chen, X., Stoddart, M. J., Chen, W., Yang, X., Zhu, Y., & Zhu, J. (2026). An osteogenesis mimicking biomineralized bone adhesive for rapid skeletal regeneration. Bioengineering & Translational Medicine, Article e70182. https://doi.org/10.1002/btm2.70182

Image Credits: AI Generated

DOI: 10.1002/btm2.70182

Keywords: bone adhesive, biomineralization, hydroxyapatite, GelMA, PEGDA, photocuring, fracture repair, mesenchymal stem cells, osteogenesis, tissue engineering, regenerative medicine, hydrogel

The scaffold’s design reflects a growing recognition in biomaterials science that tumor removal and tissue reconstruction have traditionally been treated as separate clinical challenges. Surgeons excise the tumor, then wait—sometimes through multiple additional interventions—for the bone defect to heal, all while monitoring for local recurrence. The new scaffold attempts to collapse this timeline by embedding three complementary therapeutic functions into a single printed structure. Each component was chosen for a specific biochemical role, and together they form what the researchers describe as a catalytic-immune system working in concert with osteoinductive signaling.

At the heart of the antitumor function is a dopamine–manganese coordination nanozyme, abbreviated DM, which forms a mussel-inspired catalytic coating on the scaffold surface. The mussel-inspired chemistry is significant because polydopamine coatings adhere robustly to diverse substrates under mild aqueous conditions, allowing the nanozyme to be integrated without harsh coupling reagents that could damage the delicate biological cargo carried elsewhere in the scaffold. Nanozymes—engineered nanomaterials that mimic the catalytic activity of natural enzymes—have attracted intense interest because they combine enzyme-like reactivity with the stability, tunability, and manufacturability of synthetic materials.

The DM nanozyme behaves differently depending on the chemical environment it encounters, which is the key to its dual function. In the acidic milieu characteristic of tumor tissue, it exhibits peroxidase-like activity, catalyzing Fenton-type reactions that generate highly reactive hydroxyl radicals. These radicals attack tumor cells directly, while the nanozyme simultaneously depletes glutathione, the antioxidant molecule that cancer cells rely on to neutralize oxidative stress. The combined effect overwhelms the tumor cells’ redox defenses and induces oxidative stress–mediated cell death. This chemodynamic strategy exploits a vulnerability that is specific to the tumor microenvironment, so the lethal chemistry is triggered where the acidity marks malignant tissue rather than throughout the body.

Under physiological pH, however, the same nanozyme switches roles entirely. In the neutral conditions of healthy regenerating tissue, DM displays superoxide dismutase-like and catalase-like activities, the two enzymatic steps that together convert destructive superoxide radicals into water and oxygen. In this mode, the nanozyme scavenges reactive oxygen species and helps maintain redox homeostasis. That matters for bone repair because excessive reactive oxygen species are known to impair osteoblast function and drive the chronic inflammation that stalls fracture healing. By quenching oxidative stress at the defect site, the coating creates a biochemical environment in which bone-forming cells can operate, effectively turning the tumor-killing catalyst into a tissue-protective antioxidant once the malignant chemistry has been neutralized.

The second therapeutic arm of the scaffold is immunological. Encapsulated within the hydrogel are dendritic cell-derived exosomes loaded with a cyclic dinucleotide that acts as an agonist of STING, the stimulator of interferon genes pathway. STING signaling is a central hub of innate immunity: when activated, it prompts cells to produce type I interferons and other inflammatory mediators that recruit and activate cytotoxic T lymphocytes capable of hunting down tumor cells. Dendritic cells are the professional antigen-presenting cells of the immune system, and exosomes derived from them offer a natural delivery vehicle that can ferry their immunostimulatory cargo to target cells while evading rapid clearance. The scaffold’s hydrogel matrix provides sustained release of these Dex-CDN particles, prolonging the local immune activation window rather than delivering a single transient dose.

This local immune strategy addresses one of the most persistent fears after bone-metastatic tumor surgery: microscopic disease left behind at the resection margin. Catalytic therapy kills cells it can reach directly, but the STING agonist is intended to do something different—convert the surgical site itself into an immunological alert zone where the patient’s own adaptive immune system is primed against residual tumor cells. Combining chemodynamic cell killing with immune checkpoint-free immune activation is an increasingly popular concept in oncology research, because dying tumor cells release antigens that, in the presence of interferon signaling, can be presented to T cells to generate a systemic antitumor response.

The third arm of the scaffold is dedicated to rebuilding bone. The researchers crosslinked the hydrogel network with methacrylated osteogenic growth peptide, or OGP-MA. Osteogenic growth peptide is a naturally occurring short peptide found in bone and blood that stimulates osteoblast proliferation and bone formation. By modifying it with methacrylate groups, the team made it copolymerizable into the GelMA network, so the osteogenic signal is not simply adsorbed onto the surface where it would diffuse away quickly, but is covalently incorporated into the scaffold architecture. According to the study, OGP-MA triggers osteogenic differentiation through the BMP/Smad signaling pathway, one of the canonical cascades that drives mesenchymal stem cells toward the bone-forming lineage.

The choice of a 3D-printed sodium alginate/GelMA hydrogel as the carrier is itself a technical decision with clinical implications. Alginate contributes mechanical robustness and printability, while GelMA—a gelatin derivative bearing methacrylate groups that crosslink under light—offers cell-adhesive motifs and controllable degradation. Printing the scaffold allows its internal architecture and pore structure to be tailored to the geometry of the specific bone defect, an advantage over prefabricated implants when reconstructing irregular post-resection cavities. The hydrogel’s hydrated, soft matrix is also compatible with the encapsulated exosomes and peptide, protecting the biological cargo while allowing gradual release as the material degrades.

The integrated design—catalytic tumor ablation, STING-driven immunity, and OGP-driven osteogenesis within one printed implant—offers what the authors present as a promising strategy for localized tumor control and bone regeneration following resection of bone-metastatic tumors. The work was supported by funding from China’s National Key Research and Development Program, the National Science and Technology Major Project, the National Natural Science Foundation of China, and several regional research programs, and the animal experiments were approved by the Dongguan People’s Hospital Laboratory Animal Welfare and Ethics Committee. While the platform will require extensive further validation before clinical use, it illustrates a broader shift in biomaterials engineering: implants conceived not as inert scaffolds that merely occupy space, but as programmable microenvironments that sense where they are, choose their chemistry accordingly, and orchestrate the body’s own defenses and repair mechanisms in the critical weeks after surgery.

Subject of Research: A 3D-printed hydrogel scaffold combining catalytic antitumor therapy, STING-mediated immunity, and osteogenic peptide signaling for bone repair after tumor resection

Article Title: A catalytic-immune OGP peptide-crosslinked 3D-printed hydrogel scaffold for concurrent antitumor therapy and bone regeneration

Article References: He, J., Wu, J., Wang, L., Yin, S., Yu, K., Liu, Y., Xu, D., Ji, T., Gao, Y., Du, Y., Gao, X., Cai, L., Xie, C., & Lu, X. (2026). A catalytic-immune OGP peptide-crosslinked 3D-printed hydrogel scaffold for concurrent antitumor therapy and bone regeneration. Advanced Composites and Hybrid Materials. https://doi.org/10.1007/s42114-026-02048-3

Image Credits: AI Generated

DOI: 10.1007/s42114-026-02048-3

Keywords: 3D-printed hydrogel scaffold, bone metastasis, nanozymes, Fenton reaction, STING agonist, dendritic cell exosomes, osteogenic growth peptide, bone regeneration, chemodynamic therapy, GelMA, tumor microenvironment, BMP/Smad signaling

The clinical problem is formidable. Bone defects caused by trauma, infection, tumour resection and congenital abnormalities are common, and while small injuries heal spontaneously, defects exceeding the local regenerative capacity, so-called critical-sized defects, often fail to close on their own. Autologous bone grafting remains the gold standard because it delivers osteogenic cells, inductive growth factors and a conductive matrix simultaneously, but it is limited by donor-site morbidity and restricted availability. Allografts are more available yet carry risks of immune rejection, infection and variable efficacy. What is needed, the review contends, are regenerative strategies that remain stable and reproducible inside the messy, inflamed microenvironment of a real defect.

Bioprinting offers an unusual degree of control over that environment. Unlike conventional fabrication, printing allows multiple materials, cells and bioactive signals to be arranged in three dimensions with defined pore architecture, compositional gradients and localised mechanical properties. Composite bioinks built from printable hydrogels such as gelatin methacryloyl (GelMA), alginate and hyaluronic acid methacrylate can be blended with inorganic phases including calcium phosphate, hydroxyapatite, beta-tricalcium phosphate and bioactive glass, balancing printability with an osteogenic milieu. Crucially, these same components release ions and present surface chemistry that shape the earliest host immune recognition of the implant, making the printer a tool for immunology as much as for structural engineering.

The biological rationale comes from the now well-established field of osteoimmunology. Bone repair unfolds in overlapping phases: an inflammatory phase dominated by neutrophils and pro-inflammatory M1-like macrophages that clear debris and pathogens; a proliferative phase in which macrophages shift toward reparative M2-like states, releasing factors such as TGF-beta and VEGF that recruit mesenchymal stem cells and drive angiogenesis; and a remodeling phase in which osteoblasts and osteoclasts, governed by the RANKL/OPG axis, convert woven bone into mechanically adapted lamellar bone. Simply suppressing the early inflammatory burst, the review stresses, can starve the repair process of the very signals that initiate cell recruitment and vascularisation. The goal instead is controlled, resolvable inflammation.

Material composition is one of the three main levers the authors identify. Strontium-substituted calcium silicate hydrate nanowires incorporated into a GelMA bioink, for example, released Sr, Ca and Si ions that nudged macrophages toward a repair-associated phenotype while supporting bone marrow stromal cell differentiation, producing substantial regeneration in rat critical-sized calvarial defects. Silicon-substituted calcium phosphate combined with methacrylated bone-derived extracellular matrix showed a striking temporal immune transition in vivo, from early pro-inflammatory activation to later anti-inflammatory resolution, linked to suppression of p38 MAPK signalling. Zinc-releasing ZIF-8 metal-organic framework particles delivered the anti-inflammatory polyphenol luteolin alongside Zn2+ ions, integrating immunomodulation, antioxidation and antibacterial action in a single printed construct.

Geometry itself can be immunologically active. Using digital light processing, researchers fabricated hydroxyapatite scaffolds identical in composition but differing only in pore size, and found that 600-micrometre pores best regulated macrophage behaviour through IFN-beta and HIF-1alpha-related signalling while improving vascularisation and bone formation. Even curvature matters: beta-tricalcium phosphate scaffolds engineered with negative Gaussian curvature suppressed macrophage Ras-MAPK/HIF-1alpha signalling and increased secretion of BMP-2 and VEGF, promoting vascularised bone ingrowth in a rabbit segmental defect model. Melt electrowriting adds another dimension, with ordered PCL microfibres and calcium phosphate coatings steering macrophages toward repair-associated states via PI3K/AKT and cAMP-PKA signalling, demonstrating that physical microarchitecture can substitute for exogenous drugs.

The most sophisticated strategies deliver bioactive cargo in stage-matched sequences. One printed system used coaxial bioprinting with sequential crosslinking to release interferon-gamma first, preserving the early inflammatory activation needed for repair initiation, before Laponite-derived magnesium and silicon ions gradually drove macrophages toward a reparative state, ultimately enhancing vascularised bone regeneration in calvarial defects. Interleukin-4 delivered from graphene oxide/black phosphorus nanointerfaces promoted CD206-positive macrophages while the materials themselves supported angiogenesis and osteogenesis. Exosome-based approaches add further nuance: macrophage-derived vesicles from mixed functional states outperformed those from purely M2-like macrophages in stimulating osteogenic signalling, underscoring the review’s warning that the simplified M1/M2 dichotomy cannot capture the continuum of immune states that real healing involves.

The authors are candid about translational hurdles. Every added component, whether living cells, recombinant cytokines, exosomes or decellularised matrix, increases batch variability, manufacturing complexity and regulatory burden. Sterilisation methods can silently alter hydrogel mechanics and even macrophage gene expression, while endotoxin contamination at low levels can confound the interpretation of a material’s intrinsic immunological effects. Degradation kinetics must be synchronised with tissue ingrowth: too fast and the scaffold loses support prematurely, too slow and the foreign-body response persists. The review advocates defining critical quality attributes that reflect immunomodulatory potency, not just scaffold geometry and compressive strength, and pursuing standardised platforms with patient-specific variation confined to a validated design space.

Looking forward, the field is moving toward spatiotemporal and even intelligent regulation. Microenvironment-responsive hydrogels that release therapeutic ions only under pathological acidity or oxidative stress, four-dimensional printing that changes scaffold architecture over time, and machine-learning frameworks that optimise bioink composition against immune as well as mechanical endpoints all feature in the review’s roadmap. Pathology-specific design receives particular emphasis: infected defects need preserved antimicrobial inflammation before resolution, diabetic defects require correction of hyperglycaemia-driven oxidative stress, and aged or osteoporotic bone demands restoration of senescence-impaired immune function rather than generic osteogenic stimulation. The overarching message is that the next generation of bone scaffolds should not simply contain more ingredients, but should speak the immune system’s own temporal language, guiding inflammation, vascularisation and remodeling in the order that nature intended.

Subject of Research: Immunoregulatory biomaterials and 3D bioprinting strategies for bone regeneration

Article Title: Advances in 3D bioprinting of immunoregulatory biomaterials for bone regeneration

Article References: Wang, X., & Zhang, A. (2026). Advances in 3D bioprinting of immunoregulatory biomaterials for bone regeneration. Materials Today Bio, 41, Article 103714. https://doi.org/10.1016/j.mtbio.2026.103714

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103714

Keywords: 3D bioprinting, bone regeneration, osteoimmunology, macrophage polarization, bioinks, GelMA, biomaterials, critical-sized bone defects, exosomes, cytokine delivery, scaffold architecture, tissue engineering

The raw material for the new models is malignant ascites, the fluid that accumulates in the peritoneal cavity when cancer cells seed the abdominal lining. Ascites is clinically accessible through routine paracentesis, and it is rich in viable tumor cells shed from peritoneal deposits, making it an attractive biopsy surrogate for patients who are too advanced for surgery. Conventional two-dimensional cell cultures, however, strip away the architecture and cell-cell interactions that define how tumors behave, and patient-derived xenografts take months to establish in mice, far too slow to inform a first-line treatment decision. The researchers set out to bridge that gap with extrusion-based three-dimensional bioprinting, a technique that deposits living cells suspended in a soft hydrogel in precise, layered patterns.

The bioink at the heart of the system combines two photo-crosslinkable materials: gelatin methacryloyl, known as GelMA, and hyaluronic acid methacryloyl, or HAMA. GelMA is derived from gelatin and carries methacrylate groups that polymerize under light, giving the printed construct mechanical stability while its cell-adhesive motifs, inherited from native collagen, allow tumor cells to attach, migrate and organize. HAMA contributes a hydrated, hyaluronic-acid-rich matrix that mimics components of the tumor microenvironment and helps regulate stiffness and porosity. A photoinitiator called lithium phenyl-2,4,6-trimethylbenzoylphosphinate triggers crosslinking under visible light during printing, so the structure solidifies gently enough to keep cells alive. Ascites-derived cells were mixed directly into this hydrogel blend, and the resulting ink was printed into small constructs in a process the authors report took less than six hours from sample processing to finished model.

Speed matters because the clinical window for treatment decisions in metastatic gastric cancer is narrow. The printed constructs proved remarkably self-organizing: within seven to ten days in culture, the embedded malignant cells reconstituted organized glandular-like structures or solid tumor architectures, echoing the histological patterns of the parent tumors. The models remained viable for at least two weeks, a sufficient window to run full dose-response experiments. In 13 of 14 patient cases, or 92.9 percent, the team successfully established a bioprinted model, a success rate that compares favorably with organoid cultures and far exceeds the yield of xenograft approaches for this disease stage.

Establishing that the models faithfully represent each patient’s cancer was the central analytical challenge. The researchers performed immunohistochemistry on the printed constructs and found preservation of core gastric cancer markers, including the intestinal lineage transcription factor CDX2 and the carcinoembryonic antigen CEA. More therapeutically important, the expression patterns of three clinically actionable biomarkers, HER2, PD-L1 and Claudin 18.2, were generally consistent between the bioprinted models and the parental tumors. These are the targets that determine eligibility for HER2-directed antibodies, immune checkpoint inhibitors and Claudin 18.2-directed therapies, so their retention in the model is a prerequisite for any claim that the platform can guide treatment selection.

Genomic fidelity was assessed with whole-exome sequencing. The team compared somatic single-nucleotide variants detected in the bioprinted models with those in the parental ascites samples and found that key genomic features were preserved. To quantify this, they correlated the variant allele frequencies of mutations shared between each model and its parent sample, obtaining a median Pearson correlation coefficient of 0.817, with values ranging from 0.679 to 0.921. Variant allele frequency reflects the proportion of sequencing reads carrying a mutation and serves as a proxy for the cellular composition of a sample, so a high correlation indicates that the printed construct recapitulates not just which mutations are present but in what proportions. For a model built from a heterogeneous fluid containing tumor cells, immune cells and stromal elements, that degree of concordance is a strong indicator of faithful representation.

With fidelity established, the platform was put to its intended use: drug sensitivity testing. The researchers exposed each patient’s model to the standard chemotherapeutic backbone for gastric cancer, including oxaliplatin, fluorouracil and paclitaxel, and measured viability across a range of concentrations. Dose-response curves were fitted with a four-parameter logistic model, and the area under the curve, or AUC, was calculated as a summary metric of drug response, with lower values indicating greater sensitivity. The results revealed marked inter-patient heterogeneity: models from different patients responded very differently to the same agents, mirroring the unpredictable treatment responses seen in the clinic and underscoring why one-size-fits-all regimens so often fail in peritoneal disease.

To translate continuous dose-response data into a clinically interpretable verdict, the team needed a decision boundary. They derived an exploratory normalized AUC threshold of 0.675 using the Jenks natural breaks method, a statistical classification technique that identifies natural groupings within a data distribution by minimizing within-class variance and maximizing between-class variance. Applying this threshold, each model’s response to each drug was classified as sensitive or resistant. When the researchers compared these in vitro classifications with the clinical outcomes of the corresponding patients, the results were generally consistent, suggesting that the printed models captured enough of each tumor’s drug biology to predict, at least in an exploratory sense, whether a given agent would help or fail.

The authors are careful to frame the threshold as exploratory rather than validated. A single-arm study of 14 patients cannot establish predictive accuracy with the statistical rigor required for clinical deployment, and the concordance between in vitro classification and clinical outcome will need to be confirmed in larger, prospective cohorts with predefined endpoints such as progression-free survival and overall survival. Questions also remain about how the ascites microenvironment, including immune and stromal cells that may or may not survive the printing process, influences drug responses, and whether the platform can be extended to targeted agents and immunotherapies beyond cytotoxic chemotherapy. The open-access study was conducted under approval from the Medical Ethics Committee of Peking Union Medical College Hospital with written informed consent from all participants, and the authors declare no competing interests.

Even with those caveats, the work represents a meaningful advance in translational cancer modeling. It demonstrates that a clinically obtainable fluid, processed within hours into a bioprinted three-dimensional construct, can reproduce the histological, biomarker and genomic identity of a patient’s gastric cancer and yield drug-response data on a timescale compatible with real treatment decisions. If validated at scale, ascites-derived bioprinted models could give oncologists caring for patients with peritoneal metastasis something they currently lack: a personalized, functional readout of which chemotherapy is likely to work before the first dose is given. The study was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the National High Level Hospital Clinical Research Funding, the Peking Union Medical College Hospital Talent Cultivation Program and the Ningbo Major Research and Development Plan Project.

Subject of Research: 3D bioprinted patient-derived ascites models for drug sensitivity testing in gastric cancer with peritoneal metastasis

Article Title: 3D bioprinted ascites-derived models for gastric cancer patients with peritoneal metastasis

Article References: Hua, Y., Du, L., Sun, H., Sun, M., Pang, M., Jiang, S., Zhang, K., Lu, Y., Mao, Y., Sun, Z., Ge, Y., Nie, M., Wang, C., Wang, X., Yao, G., Yang, D., Bai, C., Yang, H., & Zhao, L. (2026). 3D bioprinted ascites-derived models for gastric cancer patients with peritoneal metastasis. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08953-x

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08953-x

Keywords: 3D bioprinting, gastric cancer, peritoneal metastasis, malignant ascites, drug sensitivity testing, bioink, GelMA, HAMA, whole-exome sequencing, patient-derived models, precision oncology, hydrogels

The starting point for the study was a deceptively simple observation problem. Dental follicle stem cells, or DFSCs, are considered strong candidates for periodontal tissue engineering because they are accessible, expandable in culture, and naturally inclined toward the lineages needed to rebuild tooth-supporting structures. Yet like all adult stem cells, they accumulate damage with passaging and environmental stress. The team therefore asked a question that sits at the intersection of stem cell biology and regenerative dentistry: what molecular changes accompany DFSC senescence, and can any of them be reversed before the cells are transplanted into a patient?

To answer it, the researchers pushed human DFSCs into senescence in two distinct ways. One cohort was subjected to oxidative stress, mimicking the inflammatory environment of a diseased periodontal pocket, while another was driven into replicative senescence through repeated rounds of cell division. Gene-expression profiling and protein analyses then revealed a dramatic pattern: IGFBP5 expression collapsed in both models, falling by more than fivefold under oxidative stress and by a striking 69-fold during replicative senescence. The senescent cells simultaneously displayed elevated reactive oxygen species, impaired viability and migration, and weakened osteogenic differentiation, confirming that the aging process was compromising exactly the functions a therapeutic cell population would need.

What happened when the researchers restored IGFBP5 is the heart of the study. Reintroducing the protein counteracted several hallmarks of senescence at once: senescence-associated molecular changes diminished, reactive oxygen species levels dropped, cell-cycle activity improved, and markers of bone formation rebounded in the stressed cells. “We found that restoring IGFBP5 could counter several features of stem cell senescence,” says Prof. Liu. “Improvements in cell survival and bone-forming ability suggested that IGFBP5 may help preserve the regenerative function of DFSCs during aging.” In other words, a single binding protein appeared to act as a gatekeeper for the regenerative identity of these cells.

The mechanistic trail then led the team into Wnt signaling territory, one of the most consequential regulatory networks in developmental and stem cell biology. Gene-expression analysis pointed to the non-canonical Wnt pathway, rather than the classical Wnt/beta-catenin arm, as the relevant branch. IGFBP5 overexpression reduced levels of WNT5B and the transcription factor c-Jun, while canonical pathway components remained largely unchanged. Follow-up experiments sharpened the causal picture: adding WNT5B externally weakened the bone-forming benefits conferred by IGFBP5 and increased a cellular senescence marker, whereas blocking WNT5B partially rescued both the senescent phenotype and the osteogenic defects of replicatively aged cells. Together, the data suggest that IGFBP5 sustains the function of aging DFSCs at least partly by suppressing WNT5B-related signaling, positioning the IGFBP5-WNT5B axis as a regulatory circuit with real therapeutic leverage.

Translating a molecular discovery into a usable therapy requires more than a protein target; it requires a delivery vehicle that can keep engineered cells alive in the harsh environment of a periodontal defect. The Sichuan team addressed this with a composite scaffold called Gel-vHA@oe-DFSC. The system weaves three components together: a gelatin methacryloyl, or GelMA, hydrogel that provides a biocompatible three-dimensional matrix; vinyl-functionalized nanohydroxyapatite, a bone-mimetic mineral phase that supports osteoconductivity; and DFSCs genetically engineered to overexpress IGFBP5. In laboratory testing, the hydrogel supported cell survival under oxidative stress, promoted healthy cell spreading, and enhanced osteogenic activity, indicating that the material itself was actively contributing to the regenerative environment rather than merely holding cells in place.

The decisive test came in rats with experimentally induced periodontitis. When the IGFBP5-overexpressing cell-laden hydrogel was applied to periodontal defects, the treated animals showed improved alveolar bone quality, with measurable increases in bone mineral density and bone volume fraction. Histological examination of the regenerated tissue revealed less inflammation and better collagen organization than in controls, suggesting that the treatment did not simply deposit mineral but fostered structurally more faithful repair. “Our results suggest that rejuvenating therapeutic stem cells before delivery may be more effective than simply transplanting untreated cells,” says Prof. Liu. “The scaffold also provides a way to support these modified cells at the periodontal defect site while they promote local tissue repair.”

The implications of the study extend well beyond dentistry. Cellular senescence is a central obstacle in regenerative medicine generally, limiting the efficacy of stem cell therapies for bone, cartilage, skin, and other tissues in older patients. If IGFBP5 proves to be a generalizable marker and modulator of stem cell aging, it could serve a dual role: as a molecular indicator used to quality-control cell products before transplantation, and as a target for pre-treatment rejuvenation strategies. The findings also add momentum to the growing field of hydrogel-based cell delivery, where biomaterials are increasingly designed to do more than carry cargo, actively participating in the signaling dialogue that determines whether transplanted cells survive, integrate, and differentiate.

The authors are careful to frame the work as a foundation rather than a finished therapy. The experiments were conducted in human cell lines in vitro and in a rat model, and the researchers note that additional studies are needed in cells derived from older patients and in larger animal models before any clinical application can be contemplated. Questions about the long-term behavior of IGFBP5-overexpressing cells, the optimal dosing of the pathway modulation, and the safety of genetic engineering in therapeutic contexts all remain open. Still, the study is notable for the completeness of its arc, moving from a senescence phenotype, through gene-expression discovery and mechanistic validation, to a biomaterial delivery system and an in vivo demonstration of efficacy.

For the millions of people whose teeth are loosened by age-related periodontal bone loss, the prospect of regenerating the damaged foundation rather than merely slowing its decline remains a distant but increasingly credible goal. What this study contributes is a concrete molecular handle, IGFBP5 and its suppression of WNT5B signaling, and a practical delivery platform that pairs rejuvenated stem cells with a bone-mimetic hydrogel. By demonstrating that treating the cells before they are transplanted can outperform simply transplanting them, the Sichuan team has articulated a principle that could reshape how regenerative dentistry, and perhaps regenerative medicine more broadly, thinks about the aging of its most important raw material. The work was supported by the National Natural Science Foundation of China and the Sichuan Science and Technology Program, and the authors declare no competing interests.

Subject of Research: IGFBP5-mediated rejuvenation of dental follicle stem cells for periodontal bone regeneration

Article Title: A stem cell pathway offers a new route to periodontal bone regeneration

Article References: A stem cell pathway offers a new route to periodontal bone regeneration. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: periodontitis, dental follicle stem cells, IGFBP5, WNT5B, cellular senescence, bone regeneration, hydrogel, GelMA, nanohydroxyapatite, regenerative medicine, Sichuan University, non-canonical Wnt pathway

The challenge the researchers set out to solve is one of geometry and biology combined. Most laboratory studies of Kawasaki disease rely on flat, two-dimensional sheets of endothelial cells, the thin lining that coats the inside of blood vessels. Such cultures are easy to grow and easy to analyze, but they bear little resemblance to the real thing. A coronary artery is a hollow, curved, multilayered tube in which endothelial cells interface with blood on one side and smooth muscle cells wrap the exterior, providing structural support. Animal models, particularly mice, have been used for decades, but the differences between mouse and human vascular and immune biology often limit how well findings translate to the clinic. The team, led by Xuting Zhang and colleagues at Wenzhou Medical University and collaborating institutions, hypothesized that recreating the true three-dimensional, bilayered architecture of a coronary artery would yield a far more faithful model of the disease.

Their manufacturing method of choice was microfluidic coaxial bioprinting, an elegant technique that exploits the same principle as a pipe within a pipe. The researchers assembled a device from glass capillaries and injection needles, aligning an inner capillary concentrically inside an outer one. Two fluids were pumped through this coaxial nozzle: an outer bioink containing 10 percent gelatin methacryloyl, or GelMA, blended with polyethylene glycol diacrylate, or PEGDA, and an inner sacrificial stream of 10 percent polyvinyl alcohol. When the co-flowing streams emerged from the capillary tip, ultraviolet light at 405 nanometers triggered photopolymerization of the outer hydrogel, locking in a continuous tube. The uncrosslinked PVA core was then simply washed away, leaving behind a hollow hydrogel microfiber with an open lumen running its entire length.

The precision achievable with this setup is remarkable. By adjusting the relative flow rates of the inner and outer fluids, the team could dial in the dimensions of the fibers at will. Holding the inner flow at 15 milliliters per hour and raising the outer flow from 15 to 35 milliliters per hour shifted the ratio of inner to outer diameter from about 65.5 percent down to 58.4 percent, while the outer diameter swelled from roughly 712 to 911 micrometers. Reversing the adjustment, by accelerating the inner stream while holding the outer one constant, enlarged both the overall caliber and the relative lumen. Throughput was equally impressive: a single milliliter of bioink yielded between roughly 4 and 6.5 meters of continuous hollow fiber, depending on the diameter chosen, underscoring the scalability of the approach.

Mechanical tuning came from the PEGDA content. Three formulations containing 2.5, 5, and 7.5 percent PEGDA in 10 percent GelMA produced hydrogels with Young’s moduli of approximately 73, 153, and 221 kilopascals respectively, and rheological testing confirmed the same trend in storage modulus. Swelling behavior plateaued within 24 hours, and the matrices retained more than 95 percent of their mass after a day in culture medium, yet dissolved completely within 24 hours when exposed to the enzyme collagenase, showing that degradation is enzymatically controllable rather than a product of passive hydrolysis. Importantly, the softest formulation, 10 percent GelMA with 2.5 percent PEGDA, proved best for early cell attachment, because PEGDA, while excellent for structural strength, tends to resist cell adhesion. That formulation was selected for all subsequent vascular constructs.

With the scaffold optimized, the researchers populated it with human cells in a deliberate sequence. First, human umbilical vein endothelial cells, or HUVECs, at a density of 10 million cells per milliliter were injected into the lumen and allowed 72 hours to engraft, forming a continuous endothelial monolayer with uniform circumferential alignment. Then human coronary artery smooth muscle cells, at 100 million cells per milliliter, were applied to the outer surface, where they colonized the exterior and formed a distinct smooth muscle layer. Confocal microscopy of the cytoskeleton and immunostaining confirmed the architecture: the endothelial marker CD31 lined the luminal surface, while alpha-smooth muscle actin was confined to the outer layer, faithfully reproducing the bilayered organization of a native coronary artery.

Crucially, the model was more than a structural mimic. When the team perfused fluorescent dextran molecules of 4 and 70 kilodaltons through the lumen, the endothelialized constructs allowed far less leakage into the surrounding hydrogel than acellular controls, demonstrating that the engineered endothelium functioned as a selective barrier to both small solutes and large plasma proteins, just as a real vessel does. As a positive control, exposure to the inflammatory molecule TNF-alpha for six hours triggered a cascade of endothelial activation: elevated lactate dehydrogenase release signaling membrane injury, increased oxidative stress, upregulation of the adhesion molecules ICAM-1, VCAM-1, and E-selectin, a surge of inflammatory cytokines and chemokines including IL-1beta, IL-6, IL-8, CX3CL1, CCL5, and MCP-1, and clear activation of the NF-kappaB signaling pathway, traced by the phosphorylation of I-kappaB-alpha and the p65 subunit.

The decisive test came when the constructs were bathed in serum drawn from children during the acute phase of Kawasaki disease, before intravenous immunoglobulin therapy, mixed at a 10 percent volume ratio into the culture medium, with serum from age-matched healthy children as the control. Within six hours, the patient serum drove the engineered arteries into a state that mirrored the disease: heightened endothelial injury and oxidative stress, intensified expression of all three adhesion molecules, a broad transcriptional inflammatory response, and robust NF-kappaB activation. The serum also triggered pyroptosis, a fiery form of programmed cell death, evidenced by upregulation of the inflammasome sensor NLRP3, the executioner protein gasdermin D, and caspase-1. This finding aligns with growing evidence that pyroptotic endothelial death contributes to the coronary artery lesions that make Kawasaki disease dangerous, and it suggests that NF-kappaB signaling and the NLRP3 inflammasome operate in a reinforcing loop rather than as separate, sequential events.

The platform then proved its worth as a drug-testing instrument. Pretreating the constructs with atorvastatin, the widely used statin, at a non-toxic concentration of 10 micromolar significantly blunted the inflammatory response to Kawasaki serum, suppressing adhesion molecule and cytokine expression and dampening NF-kappaB phosphorylation, consistent with the statin’s known anti-inflammatory, lipid-independent pleiotropic effects and with early clinical trials of atorvastatin in Kawasaki patients with coronary aneurysms. The selective NLRP3 inhibitor MCC950, also tested at 10 micromolar, likewise reduced ICAM-1 expression and inflammatory mediator transcripts, and it specifically shut down the pyroptotic machinery, lowering NLRP3, gasdermin D, caspase-1, and IL-1beta. Because intravenous immunoglobulin resistance remains a major clinical problem, the ability to distinguish these two mechanistically distinct protective strategies within a single human tissue model is exactly the kind of preclinical capability the field has lacked.

The authors are candid about the model’s current limits. The constructs were cultured under static conditions, without the fluid flow and shear stress that shape endothelial behavior in living arteries, and future versions will incorporate dynamic perfusion. The endothelial layer consists of HUVECs rather than coronary-specific endothelial cells, a pragmatic choice driven by the robust proliferation needed to form an intact barrier in a bioprinted scaffold. Even so, the achievement stands out. In a single platform, the team has combined tunable biofabrication, native-like multilayered architecture, functional barrier properties, patient-derived disease induction, and mechanistically resolved drug evaluation. For a disease that strikes young children, has no known cause, and can leave permanent cardiac damage, this bioprinted coronary artery equivalent offers a powerful new window into pathogenesis and a versatile testing ground for the therapies of tomorrow.

Subject of Research: Biomimetic 3D bioprinted coronary artery models for Kawasaki disease modeling and drug screening

Article Title: Engineering biomimetic coronary artery equivalents for Kawasaki disease modeling and drug screening

Article References: Zhang, X., Shao, C., Wang, Y., Liu, A., Rong, X., Jia, C., Yu, W., Zhang, H., Wu, R., Zhang, J., Zhang, L., Ye, F., & Chu, M. (2026). Engineering biomimetic coronary artery equivalents for Kawasaki disease modeling and drug screening. Materials Today Bio, 41, Article 103701. https://doi.org/10.1016/j.mtbio.2026.103701

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103701

Keywords: Kawasaki disease, coronary artery, bioprinting, microfluidics, GelMA, endothelial dysfunction, NF-kB, pyroptosis, NLRP3, atorvastatin, MCC950, drug screening

The study, published in the Journal of Cellular and Molecular Medicine, centres on exosomes—nanoscale vesicles that cells naturally secrete to communicate with one another. These vesicles ferry microRNAs, transcription factors and proteins between cells, and have become one of the most hotly pursued tools in regenerative medicine. Compared with transplanting living stem cells, exosomes are less immunogenic, more stable, and far easier to store and ship, making them an attractive cell-free therapy. The researchers sourced theirs from human umbilical cord blood, a material collected non-invasively after rigorous prenatal screening that is otherwise discarded as medical waste. Cord blood vesicles are known to be more concentrated and biologically active than those circulating in adult peripheral blood, and previous work has shown they can accelerate wound healing and bone repair.

But exosomes have an Achilles heel: injected alone, they are cleared from the body within hours, never maintaining a therapeutic concentration at the lesion. The team’s answer was a delivery vehicle built from two photocrosslinkable polymers—gelatin methacryloyl (GelMA) and sodium alginate methacryloyl (AlgMA)—mixed into a prepolymer solution with the vesicles and a photoinitiator called LAP. The mixture is fluid enough to inject into a periodontal pocket, then solidifies in 30 seconds under 405-nanometre blue light, forming a soft scaffold the authors call GA-Exos. Scanning electron microscopy revealed a loose, porous network with an average pore size of roughly 12 micrometres, while infrared spectroscopy confirmed the covalent crosslinking of both polymers.

Mechanical testing showed why the alginate component matters. Pure GelMA gels are biocompatible but floppy—poorly suited to the chewing forces of the mouth. The composite gel reached a peak compressive stress of 58.78 kilopascals at 60% strain, nearly double the 32.44 kilopascals of GelMA alone, and rheology confirmed a stable, elastic-dominant network after curing. Crucially, loading the exosomes did not disturb the gel’s water uptake or degradation kinetics: both GA and GA-Exos swelled to roughly 43% within about two days and lost around 46–47% of their dry mass over 21 days in physiological conditions. Release assays showed the vesicles trickling out gradually—48.1% of the payload by day 3 and 82.6% by day 21—exactly the sustained profile needed to keep regenerative signalling active through the weeks of healing.

In laboratory dishes, the material proved both safe and bioactive. Live/dead staining and CCK-8 assays found no cytotoxicity toward rat bone marrow mesenchymal stem cells (BMSCs), and the exosome-loaded gel actually boosted stem cell proliferation at 48 hours, while the bare gel did not. Fluorescently labelled vesicles were visibly internalised by the stem cells within 12 hours, accumulating around the nuclei. Scratch assays showed that exosome concentrations of 20 and 30 micrograms per millilitre significantly accelerated cell migration. Most strikingly, standard osteogenic assays—alkaline phosphatase staining at days 3 and 7, and Alizarin Red staining of mineralised nodules at days 14 and 21—showed that GA-Exos drove the stem cells firmly down the bone-forming pathway, with the genes RUNX2, ALP and OPN and their corresponding proteins all significantly upregulated.

The real test came in living animals. The team induced periodontitis in rats by tying silk ligatures around the first molars and injecting bacterial lipopolysaccharide (LPS) locally twice a week for four weeks, producing the classic signs of gum swelling, bleeding, loosened teeth and radiolucent bone loss on cone-beam CT scans. After debridement, the animals received injections of GA-Exos, bare GA gel, or saline into the periodontal pockets, cured in place with blue light. Four weeks later, the GA-Exos group showed markedly reduced gingival inflammation, with significantly lower expression of the pro-inflammatory cytokines TNF-α and IL-1β in gum tissue.

Bone imaging told an equally compelling story. Micro-computed tomography at 17-micrometre resolution revealed that the GA-Exos group had significantly higher bone volume fraction, greater mean CT values, thicker and more numerous trabeculae, and a shorter distance between the alveolar bone crest and the cementoenamel junction—the gold-standard measure of periodontal bone height. Histology backed this up: haematoxylin and eosin sections showed less inflammatory infiltration and clear evidence of newly formed periodontal tissue and blood vessels, while tartrate-resistant acid phosphatase (TRAP) staining revealed far fewer bone-resorbing osteoclasts than in the control groups. In other words, the treatment simultaneously rebuilt bone and shut down the cellular machinery that destroys it.

To find out how, the researchers turned to transcriptomics. Messenger RNA sequencing of exosome-treated versus untreated cells identified 1,381 differentially expressed genes—440 upregulated and 941 downregulated. Enrichment analysis pointed squarely at the Toll-like receptor and NF-κB signalling pathways, both significantly dampened, along with the LPS-sensing receptors LBP, CD14 and TLR4. Western blotting confirmed the mechanism at the protein level: LPS normally drives up TLR4 expression and phosphorylates the NF-κB subunit p65, igniting inflammation, but the cord blood exosomes reversed both effects without changing total p65 levels. Under inflammatory conditions, LPS alone suppressed mineral nodule formation, yet exosome treatment restored osteogenic differentiation—demonstrating that the vesicles protect bone formation precisely by disarming the bacterial sensor that would otherwise block it.

The implications reach beyond dentistry. Because TLR4/NF-κB signalling is a master regulator of inflammatory bone loss in many contexts, a cell-free, off-the-shelf vesicle therapy that suppresses it while delivering osteogenic cues could in principle be adapted to other defect types. The authors are careful about nomenclature, noting that under the MISEV2023 guidelines their ultracentrifugation-isolated particles are technically small extracellular vesicles, and that the active cargo—possibly exosomal microRNAs—remains to be pinned down. Limitations also include the usual gap between rat models and human periodontal pathology, unresolved donor variability and manufacturing standardisation, and the need for loss-of-function experiments with pathway inhibitors to confirm the mechanism rigorously.

Even so, the study offers a unusually complete proof of concept: a material that is injectable, sets in seconds under a dental-grade blue light, holds its mechanical ground in the mouth, releases its cargo over three weeks, quiets a destructive inflammatory pathway, and measurably regrows bone. If the results translate to larger animal models and eventually to patients, the humble contents of discarded cord blood, packaged in a photocured gel, could become a genuinely regenerative alternative to the drill-and-antibiotics cycle that currently defines periodontal care.

Subject of Research: Umbilical cord blood exosome-loaded hydrogel therapy for periodontal bone regeneration via TLR4/NF-κB signalling

Article Title: Injectable Hydrogel Loaded With Umbilical Cord Blood‐Derived Exosomes Promotes Periodontal Bone Regeneration via the TLR4/NF‐κB Signalling Pathway

Article References: Zhu, D., Liu, M., Fan, Y., Lang, L., Luo, X., Zhang, Z., Shen, Z., & Liu, H. (2026). Injectable Hydrogel Loaded With Umbilical Cord Blood‐Derived Exosomes Promotes Periodontal Bone Regeneration via the TLR4/NF‐κB Signalling Pathway. Journal of Cellular and Molecular Medicine, 30(19), Article e71347. https://doi.org/10.1111/jcmm.71347

Image Credits: AI Generated

DOI: 10.1111/jcmm.71347

Keywords: periodontitis, exosomes, umbilical cord blood, hydrogel, bone regeneration, TLR4, NF-κB, GelMA, alginate, mesenchymal stem cells, extracellular vesicles, inflammation