Wound healing is a dynamic and highly coordinated process involving inflammatory responses, extracellular matrix remodeling, cellular signaling, oxidative stress, and microbial activity. Healthy skin maintains an acidic surface pH, typically around 4 to 6, which supports barrier function and limits the growth of harmful microbes. When skin is injured, the wound environment shifts, and in chronic wounds—such as diabetic foot ulcers, venous leg ulcers, and pressure sores—the pH is frequently dysregulated, often drifting toward alkaline values. A recent prospective multicenter cohort study cited in the review found progressive acidification of wounds as they healed and persistently higher pH in chronic non-healing wounds, underscoring pH as a clinically meaningful biomarker rather than a passive chemical detail.

The consequences of altered wound pH ripple through nearly every stage of repair. Elevated pH promotes bacterial colonization and biofilm formation, the slimy microbial communities that shield pathogens from antibiotics and immune cells. It also modulates the activity of matrix metalloproteinases, enzymes that degrade the extracellular matrix; in chronic wounds, an imbalance between these enzymes and their natural inhibitors, the tissue inhibitors of metalloproteinases, leads to excessive destruction of newly formed tissue. Altered pH further influences reactive oxygen species generation, inflammatory signaling pathways, the migration of keratinocytes and fibroblasts, angiogenesis, and the assembly of collagen and other matrix components. In short, the review argues, pH is not merely a symptom of a troubled wound—it is an active driver of healing failure.

At the molecular level, pH responsiveness in polymers arises from protonation and deprotonation reactions. Weak acid groups, such as the carboxyl groups in polyacrylic acid and alginate, shed protons and become negatively charged as pH rises, while weak base groups, such as the amine groups in chitosan, poly(N,N-dimethylaminoethyl methacrylate), and polyhistidine, gain protons and become positively charged as pH falls. The review is careful to distinguish these ionization processes from their downstream physicochemical consequences: changes in charge density alter electrostatic repulsion within the polymer network, driving swelling or collapse; changes in ionization state alter solubility, permeability, and degradation kinetics; and all of these together govern when and how fast a loaded drug is released. Sulfonamide-containing polymers, for example, undergo sharp solubility transitions near physiological pH, a property that has been exploited for on-demand delivery.

Translating this chemistry into clinical tools, researchers have built pH-responsive systems across an impressive range of formats. Hydrogels—water-swollen polymer networks—are the workhorse platform, with formulations based on natural polymers such as chitosan, alginate, hyaluronic acid, and gelatin, often cross-linked through dynamic Schiff base bonds that form and break depending on acidity. Nanoparticles, nanofibers, microspheres, injectable systems, microneedle arrays, and multifunctional wound dressings round out the arsenal. In one cited example, a pH-responsive calcium alginate hydrogel laden with protamine nanoparticles and hyaluronan oligosaccharides promoted diabetic wound healing by enhancing both angiogenesis and antibacterial activity. In another, a chitosan and protocatechualdehyde hydrogel formed via Schiff base chemistry delivered antioxidant and antibacterial effects precisely where the wound environment triggered it.

Some of the most striking recent work combines pH responsiveness with other therapeutic modalities. The review highlights dual- and multi-responsive hydrogels that react simultaneously to pH, reactive oxygen species, glucose, temperature, or near-infrared light. A near-infrared and pH dual-responsive chitosan hydrogel containing epigallocatechin gallate and hollow copper sulfide nanoparticles was reported to reprogram ROS dynamics for infected wound healing, while a triple-responsive supramolecular hydrogel with a synergistic photothermal effect regulated inflammatory signaling to remodel the diabetic wound microenvironment. These systems embody the concept of microenvironment-feedback regulation: the material senses pathological conditions and releases its therapeutic payload only when and where it is needed, reducing off-target exposure and drug waste.

The review also surveys an emerging convergence between responsive biomaterials and diagnostics. Optical and electrochemical biosensing, wearable monitoring devices, and intelligent therapeutic approaches are being integrated directly into dressings. Carbon quantum dot-entrapped hydrogels with sensitive pH response and photodynamic antibacterial properties have been developed for visual, intelligent wound monitoring, allowing clinicians to read wound status by color change. Dual-responsive surface-enhanced Raman scattering nanoprobes have been used for real-time imaging of pH and ROS dynamics during healing. Electrochemical immunosensing platforms can now measure matrix metalloproteinases MMP-2 and MMP-9 directly from chronic wound exudates without labels, and hyaluronic acid hydrogel-based biosensors paired with artificial intelligence are being explored for continuous monitoring of chronic wound healing. Wireless, closed-loop smart bandages with integrated sensors and stimulators, described in Nature Biotechnology, point toward a future in which the dressing both diagnoses and treats.

The clinical stakes are enormous. Chronic wounds affect millions of patients worldwide and impose a substantial burden on health systems, particularly among people with diabetes, vascular disease, and immobility. Conventional dressings are largely passive, delivering drugs at fixed rates regardless of the wound’s state. pH-responsive platforms promise something fundamentally different: dressings that act as closed-loop therapeutic agents, releasing antimicrobials when bacterial alkalization signals infection, scavenging excess reactive oxygen species when oxidative stress spikes, and modulating protease activity when matrix destruction runs out of control. Because the trigger is the wound’s own chemistry, the same material can behave differently in a healing wound versus a stalled one, matching therapy to need.

The authors are candid about the obstacles standing between laboratory promise and clinical reality. Response specificity remains a challenge, since pH changes in wounds are gradual and can overlap with other chemical shifts, making it difficult to design materials that respond only within the desired window. Stability in the harsh, enzyme-rich, and microbe-laden wound fluid is another concern, as is biosafety, particularly for cationic polymers and nanoparticle components whose long-term toxicity profiles require careful evaluation. Scalability of manufacturing—especially for microfluidically synthesized particles and precisely engineered multilayer systems—and the cost and regulatory hurdles of clinical translation add further friction. The review also notes that wound pH depends on factors such as wound size and measurement technique, complicating the standardization needed for regulatory approval.

What emerges from the analysis is a call for rational, mechanism-driven design rather than trial-and-error formulation. By integrating wound microenvironmental biology—cellular crosstalk, inflammatory pathways, redox balance, protease dynamics, and biofilm behavior—with the molecular physics of ionizable polymers, the authors propose a framework for developing next-generation pH-responsive platforms for precision wound management and tissue regeneration. If that framework succeeds, the humble bandage could evolve from a passive covering into an active, sensing, self-regulating therapeutic system—one that reads the chemistry of the wound beneath it and responds in real time, bringing a genuinely intelligent layer to one of medicine’s oldest challenges.

Subject of Research: pH-responsive biomaterials for wound healing and their molecular mechanisms

Article Title: pH-responsive biomaterials for wound healing: molecular mechanisms, therapeutic applications, and future perspectives

Article References: Rattan, D., Kumar, D., Awasthi, A., Singh, T. G., & Kumar, M. (2026). pH-responsive biomaterials for wound healing: molecular mechanisms, therapeutic applications, and future perspectives. Journal of Materials Science. https://doi.org/10.1007/s10853-026-13780-y

Image Credits: AI Generated

DOI: 10.1007/s10853-026-13780-y

Keywords: pH-responsive biomaterials, wound healing, chronic wounds, hydrogels, drug delivery, chitosan, alginate, hyaluronic acid, biofilms, reactive oxygen species, smart dressings, biosensors

The research team, led by Gaoquan Zheng, Dianqing Li, and colleagues, set out to test whether a deliberate local pH signal built into the implant interface could guide neutrophil behavior and strengthen host antibacterial defense without adding any exogenous bactericidal agent. Neutrophils are among the first innate immune cells recruited to infected sites, and beyond phagocytosis and degranulation they can release neutrophil extracellular traps, or NETs, which are extracellular chromatin-based networks that capture pathogens and limit their spread. Prior work had hinted that extracellular pH regulates this process: bicarbonate-rich pancreatic fluid has been shown to promote PADI4-dependent aggregated NET formation, a high bicarbonate-to-CO2 ratio and moderately alkaline pH favor NET release, and extracellular acidosis suppresses ROS-dependent NETosis. What remained poorly understood was how such a physicochemical cue is converted into functional changes inside the neutrophil, and whether it could be harnessed at a biomaterial surface.

To create the alkaline interface, the researchers subjected titanium plates to a hydrothermal reaction in a mixed sodium hydroxide and hydrogen peroxide solution at 80 degrees Celsius for 24 hours, followed by hydrochloric acid-mediated ion exchange to remove excess sodium-containing alkaline species and a thermal treatment ramping to 450 degrees Celsius. The resulting material, designated Ti-A, developed a uniform nanoscale porous architecture visible by scanning electron microscopy, in contrast to the relatively smooth pristine titanium surface. X-ray diffraction confirmed a mixed anatase and rutile TiO2 crystalline structure, and X-ray photoelectron spectroscopy detected a distinct sodium signal reflecting the incorporation of sodium-related species during alkali treatment. Critically, pH measurements taken approximately two millimeters above the surface showed that Ti-A maintained a local pH of roughly 7.88 in ultrapure water and, importantly, remained within a mildly alkaline range of about 7.49 to 7.78 even under physiological buffering conditions in PBS and cell culture medium over 48 hours.

The team then verified that this modified surface was compatible with the cells that matter. Rat bone marrow mesenchymal stem cells cultured on Ti-A retained well-organized F-actin cytoskeletons and intact nuclear morphology, with metabolic activity remaining approximately 92 percent of that observed on pristine titanium despite a modest but significant reduction. Neutrophils exposed to Ti-A for six hours retained roughly 89 percent of their CCK-8 metabolic signal, indicating that the interface did not cause extensive loss of neutrophil viability during the NET-induction period. With biocompatibility established, the researchers turned to the central question of whether Ti-A could trigger bona fide NET formation rather than nonspecific DNA leakage. SYTOX Green staining revealed more extracellular DNA-positive structures on Ti-A than on pristine Ti, and DNase I treatment markedly reduced these networks, confirming their dependence on a DNA scaffold.

Further molecular evidence strengthened the case. Ti-A markedly increased signals of citrullinated histone H3, a chromatin modification closely associated with NET formation, which colocalized with extracellular chromatin regions. Enzyme-linked immunosorbent assays showed higher levels of MPO-DNA complexes in the Ti-A group, indicating co-release of extracellular chromatin with neutrophil granule proteins, a biochemical hallmark of genuine NETs. When neutrophils and S. aureus were co-incubated on the surfaces for six hours, Ti-A achieved an antibacterial rate of approximately 86.67 percent compared with 47.50 percent on pristine titanium. Even without neutrophils present, Ti-A reduced bacterial survival, demonstrating intrinsic surface antibacterial activity, but the addition of neutrophils revealed a substantial host-mediated enhancement on top of that direct effect.

To dissect the mechanism, the researchers applied two pharmacological tools. DNase I, which degrades the extracellular DNA backbone of NETs, caused colony formation on Ti-A to rise sharply and the antibacterial rate to fall to a level close to that of Ti-A alone, indicating that NET-associated extracellular DNA structures were a major contributor to the enhanced killing. Cytochalasin D, which inhibits actin-dependent phagocytosis, also reduced the antibacterial rate, but it remained higher than that of Ti-A alone, suggesting that phagocytosis contributed without fully accounting for the neutrophil-mediated advantage. Together, these experiments established that beyond directly restricting bacterial survival, the alkaline interface amplified neutrophil extracellular killing as the dominant antibacterial mechanism.

The deepest insight of the study came from untargeted metabolomic profiling of neutrophils stimulated on the two surfaces. Volcano plot analysis revealed 77 upregulated and 7 downregulated metabolites in the Ti-A group, with lipid metabolism dominating the differential profile. Sphingosine and N-palmitoyl-D-sphingosine were elevated and ranked among the most important metabolites distinguishing Ti-A-stimulated neutrophils from controls, while 6-phosphogluconic acid, a metabolite of the oxidative pentose phosphate pathway that supplies NADPH for reactive oxygen species generation, was also increased. KEGG enrichment analysis placed sphingolipid metabolism and sphingolipid signaling among the top enriched pathways. This metabolic signature pointed the investigators toward a specific signaling axis: sphingosine can be phosphorylated by sphingosine kinase 1, or SPHK1, to generate sphingosine-1-phosphate, which signals through receptors including S1PR2 and may engage calcium- and MAPK-related pathways linked to PAD4 activation, histone H3 citrullination, chromatin decondensation, and NET formation.

Subsequent molecular and pharmacological experiments supported this model. Neutrophils on Ti-A showed markedly stronger intracellular oxidative signals by DCFH-DA fluorescence and flow cytometry, and both SPHK1 and S1PR2 were significantly upregulated at the mRNA and protein levels. Notably, PMA, a standard positive NET-inducing stimulus, enhanced oxidative activity without inducing comparable SPHK1 or S1PR2 increases, indicating that this upregulation is not a generic consequence of NET induction but is more closely tied to the sphingolipid remodeling triggered by Ti-A. When the researchers blocked the pathway with PF-543, a selective SPHK1 inhibitor, or with DPI, which suppresses NADPH oxidase-derived ROS production, both the web-like extracellular DNA structures and the intracellular oxidative signal were significantly attenuated. Because neither inhibitor completely abolished NET formation, the authors conclude that the SPHK1-S1PR2/ROS axis makes a substantial contribution while operating alongside other signaling events initiated at the interface.

The strategy then faced its most demanding test in vivo. Titanium and Ti-A implants preloaded with S. aureus were inserted into femoral condyle defects in rats. At three days after surgery, fewer colonies were recovered from peri-implant bone tissues in the Ti-A group, accompanied by stronger Ly6G neutrophil staining, enhanced H3Cit signals indicating histone citrullination, and elevated SPHK1 and S1PR2 expression at the interface. At two months, bacterial burden remained significantly lower around Ti-A implants, and micro-CT reconstruction showed more newly formed bone with significantly higher bone volume fraction and bone mineral density. Histology revealed richer bone matrix and collagen deposition, stronger osteopontin staining, and milder inflammatory infiltration, while H&E staining of major organs showed no pathological damage, indicating no evident systemic toxicity.

Importantly, the modified interface did not trade immune-antibacterial activity for impaired osteogenic function. In vitro, Ti-A supported stronger alkaline phosphatase staining and activity, more extensive Alizarin Red S mineral deposition, and increased Runx2 and Col1a1 expression during osteogenic induction. The authors caution that the biological consequences of NET formation depend strongly on timing, magnitude, and clearance: early NETs can immobilize bacteria and assist macrophage-mediated killing, whereas persistent or excessive NETs may sustain inflammation and damage tissue. Their experiments did not track NET formation and clearance continuously, and serial measurements at intermediate time points will be needed to define how the response subsides as the interface shifts from infection control toward tissue repair. Nevertheless, the work positions mild interfacial alkalinity as a host-responsive design cue for anti-infective bone implants, offering a route to coordinate early infection control and subsequent bone regeneration that could hold particular translational value for patients facing infected bone defects where both problems must be solved concurrently.

Subject of Research: Mildly alkaline titanium implant interfaces regulating neutrophil sphingolipid immunometabolism and NET formation for antibacterial host defense and bone repair

Article Title: Interfacial mild alkalinity shapes Neutrophil immunometabolism through sphingolipid remodeling to enhance antibacterial host defense

Article References: Interfacial mild alkalinity shapes Neutrophil immunometabolism through sphingolipid remodeling to enhance antibacterial host defense. (n.d.). https://doi.org/10.1016/j.mtbio.2026.103691

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103691

Keywords: neutrophils, neutrophil extracellular traps, implant-associated infection, titanium implant, interfacial pH, sphingolipid metabolism, SPHK1, S1PR2, reactive oxygen species, Staphylococcus aureus, osseointegration, bone regeneration