Engineering bioinspired pH-responsive hydrogels for smart wound repair

Abstract

The growing prevalence of chronic and infected wounds represents a major clinical challenge that conventional passive dressings fail to adequately address. Bioinspired pH-responsive hydrogels have emerged as intelligent biomaterials capable of dynamically interacting with the wound microenvironment. However, the field still faces major translational barriers, with many laboratory prototypes not yet progressing to clinically or commercially established products. Unlike descriptive literature compilations, this review provides a critical analytical evaluation focused on synthesizing fundamental engineering principles and quantitative design considerations that govern smart hydrogel performance. We systematically classify pH trigger mechanisms, discuss model-based relationships among crosslinking density, mesh size, swelling behavior, and release kinetics, and delineate multifunctional synergies. Particular analytical weight is dedicated to the practical constraints of terminal sterilization, large-scale fabrication controls, and regulatory pathways. By defining a hierarchical decision framework and introducing standardized benchmarking metrics, this review aims to bridge the gap between polymer synthesis and clinical reality, offering a design-oriented framework for next-generation regenerative wound dressings.

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Rubia Khan

Rubia Khan is a researcher at Faculty of Pharmacy, Integral University specializing in pharmaceutical formulation development, with a particular emphasis on nanoformulations for wound healing and advanced drug delivery systems. Her research focuses on designing nanocarrier-based therapeutic platforms to improve localized drug delivery, tissue repair, and regenerative outcomes.

Usama Ahmad

Usama Ahmad is an Associate Professor at the Faculty of Pharmacy, Integral University, India. He earned his Ph.D. in pharmaceutics from Integral University in 2018 and previously worked as a Junior Research Fellow on a SERB-DST-funded research project. His work centers on the development of advanced nanoformulations for targeted drug delivery, with a focus on cancer therapeutics and wound healing applications. Dr Ahmad actively engages in interdisciplinary research to address pressing healthcare challenges and is a member of several professional bodies, including Controlled Release Society, American Association for Cancer Research, and the Academy of Pharmaceutical Sciences, Nanomedicine Focus Group (U.K).

Mohd Muazzam Khan

Mohd Muazzam Khan is Associate Professor of pharmacology at the Faculty of Pharmacy, Integral University, Lucknow. He holds a Ph.D. (2021) and M. Pharm (Gold Medal, 2014) from Integral University, and a B. Pharm from HIPER, Lucknow. With over a decade of teaching and research experience, his work focuses on neuropharmacology, cerebral ischemia, Alzheimer's disease, and novel drug delivery systems. He has served in key academic and administrative roles, completed international certifications, and possesses expertise in animal handling, behavioral pharmacology, biochemical assays, and nanotechnology-based formulations.

Anas Islam

Anas Islam is a lecturer at the Faculty of Pharmacy, Integral University, Lucknow, and a Ph.D. candidate in pharmacy at the same institution. He holds an M. Pharm in pharmacology, graduating with distinction and a silver medal, and has authored more than 50 articles, numerous book chapters, and patents in areas including pharmacology, drug delivery, microbiome research, and nanomedicine. His work has been published in high-impact journals. With expertise spanning drug development, therapeutic innovations, and pharmaceutical sciences, he is dedicated to advancing research and education in the field while mentoring future professionals.

Juber Akhtar

Juber Akhtar is a pharmaceutical scientist and academic with over 16 years of research and teaching experience in advanced drug delivery systems. He obtained his B. Pharm, M. Pharm, and Ph.D. from Jamia Hamdard, Manipal University, and Integral University, respectively. His research focuses on the development of nanoparticulate and targeted drug delivery systems, with emphasis on formulation design, therapeutic optimization, and translational pharmaceutical applications. He has authored over 100 scientific publications and supervised several doctoral and postgraduate research projects in pharmaceutics and nanomedicine.

Quazi T. H. Shubhra

Quazi T. H. Shubhra completed his PhD at the University of Pannonia, Hungary (2014) as a Marie Curie fellow, followed by JSPS postdoctoral research in Japan. He specializes in multifunctional nanomaterials for targeted drug delivery, wound healing, and cancer therapy. Recognized among the Top 2% Most-Cited Scientists Worldwide, Dr Shubhra serves as an associate editor of multiple SCI journals and sits on the editorial boards of over a dozen international journals. His work is published in high-impact journals, including Nature Chemistry, Nature Reviews Chemistry, Cell Metabolism, Signal Transduction and Targeted Therapy, Trends in Cancer, and Trends in Immunology.

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1. Introduction

Bioinspired pH-responsive hydrogels are emerging as intelligent wound dressings that couple a moist, biomimetic scaffold with on demand, pH triggered drug delivery tailored to the dynamic wound microenvironment (e.g., shift from acidic or near-neutral to alkaline pH in infected or chronic wounds). These systems aim to overcome the therapeutic and economic burden associated with chronic wounds by maximizing local efficacy while minimizing systemic toxicity and resistance associated with conventional antibiotic use. Chronic and complex wounds are now recognized as a silent epidemic, driven by population ageing, diabetes, obesity and vascular disease, and are associated with major quality of life loss, high healthcare costs and risk of amputation or premature death.^1,2 Recent compendia estimate that chronic wounds affect about 2–2.5% of the general population in developed countries and up to 10.5 million Medicare beneficiaries in the USA, consuming 3–5.5% of national health expenditure.^2,3

From a pathophysiological perspective, chronic non-healing wounds typically exhibit persistent inflammation, ischemia, biofilm-driven infection and impaired re-epithelialization, conditions under which the local pH often shifts from the slightly acidic surface of healthy skin to a more alkaline range (approximately pH 7.3–8.9).⁴ This pH gradient is closely linked to bacterial load, protease activity and oxygenation, and therefore represents a rational trigger for smart dressings capable of modulating swelling, degradation and drug release in response to the wound microenvironment.⁵ Bioinspired pH-responsive hydrogels, often constructed from naturally derived polymers such as chitosan, hyaluronic acid, gelatin or cellulose nanofibers, mimic the hydrated, viscoelastic and cell interactive nature of extracellular matrix (ECM), while integrating acid–base responsive moieties (e.g., carboxyl, amino, imidazole or boronate groups) that undergo ionization-driven volume transitions.^6,7 In addition to polymer chemistry, incorporation of various nanomaterials can enhance the mechanical strength and multifunctionality of hydrogel matrices. Nanoparticles such as calcium phosphate (CaP), iron oxide, and multi-walled carbon nanotubes (MWCNTs) can reinforce hydrogel matrices or provide bioactive, antimicrobial, magnetic, conductive, or diagnostic functionality, depending on their composition, dose, surface modification, and biocompatibility.^8–10 Incorporation of antimicrobial agents (e.g., silver nanoparticles, antibiotics, antimicrobial peptides), antioxidants or growth factors into such matrices enables localized, on demand drug delivery tuned to the pathological pH of infected or ischemic wounds, may improve bacterial clearance and tissue repair compared with non-responsive systems.^11,12

Although stimuli-responsive biomaterials can be engineered to respond to a range of microenvironmental cues, it is essential to distinguish between stable macroscopic chemical gradients and transient molecular signals when selecting effective therapeutic triggers. Reactive oxygen species (ROS)-responsive systems are dependent on localized oxidative stress conditions, which are often spatially restricted, short-lived, and rapidly neutralized by endogenous antioxidant mechanisms.¹³ Likewise, enzyme-responsive hydrogels typically rely on the local abundance and catalytic activity of specific proteolytic biomarkers, such as matrix metalloproteinases (MMPs), whose expression levels may vary considerably across patients and fluctuate dynamically throughout different stages of wound healing.¹⁴ In contrast, wound pH serves as a comparatively persistent, extracellular, and macroscopically measurable indicator of wound physiology.¹⁵ Intact healthy skin maintains an acidic surface environment (pH 4.5–5.5), which is essential for barrier integrity and antimicrobial defence, whereas chronic, ischemic, and biofilm-associated wounds often shift toward sustained neutral-to-alkaline conditions, frequently ranging from pH 7.3 to 8.9. This clinically distinguishable and pathophysiologically meaningful pH gradient provides a broad therapeutic window, positioning pH as a particularly practical and biologically relevant trigger for smart biomaterial activation. Consequently, pH-responsive wound dressings can undergo predictable structural and functional transformations, including protonation/deprotonation, charge switching, osmotic swelling, dynamic bond cleavage, network relaxation, and pH-regulated therapeutic release, enabling controlled therapeutic responses without dependence on unstable or spatially heterogeneous biochemical intermediates.¹⁶

Compared with many existing reviews that mainly summarize hydrogel types, polymer sources, or broad smart-dressing applications, this review specifically focuses on the design logic of bioinspired pH-responsive hydrogels for chronic, infected, ischemic, and biofilm-associated wound microenvironments. Its unique contribution is to move beyond a descriptive catalogue of reported hydrogel systems and provide a mechanistic and translational framework linking wound pH dynamics with hydrogel network chemistry, including functional group ionization, dynamic bond cleavage, electrostatic interactions, crosslinking density, mechanical integrity, delivery format, drug-release kinetics, and preclinical performance metrics. By integrating material design principles, wound-pathology-driven therapeutic requirements, standardized biological outcomes, and clinical translation challenges, this review aims to provide a critical roadmap for developing next-generation pH-responsive hydrogel platforms for precision wound care.

1.1 Burden of wound related morbidity and drug use

Epidemiological analyses indicate that chronic wounds including diabetic foot ulcers, venous leg ulcers and pressure ulcers affect approximately 1–2% of the general population at any time in high income settings, with higher prevalence in the elderly and people with diabetes, venous insufficiency or peripheral arterial disease.^2,17 In the USA alone, chronic wounds are estimated to affect around 6.5–10.5 million individuals and cost the healthcare system 20–25 billion USD annually, with substantial indirect costs related to disability, lost productivity and long term care.^2,18 The humanistic burden is equally profound: patients experience chronic pain, exudate, odour, reduced mobility, sleep disturbance, social isolation and depression, with health related quality of life significantly impaired compared with age matched controls.¹⁹ Complex wounds often require repeated debridement, frequent dressing changes and prolonged courses of topical and systemic antimicrobials; systemic therapies actively contribute to polypharmacy and drug–drug interactions, significantly elevating the risk of adverse effects, especially in multimorbid elderly populations.²⁰

Chronic wounds represent a severe public health crisis. These lesions are driven primarily by aging populations, diabetes, and vascular disease. Patho physiologically, they remain trapped in a persistent inflammatory state. This chronic inflammation upregulates proteases, which actively degrade essential extracellular matrix proteins.²¹ Furthermore, local tissue perfusion is severely compromised. This ischemia creates hypoxic zones that restrict cellular ATP production and delay granulation. Consequently, conventional passive therapies cannot resolve these complex biochemical blockages.²² Chronic wounds that are infected or heavily colonized by bacteria drive much of the antibiotic use in hospitals and communities. A high proportion of bacterial isolates from these chronic lesions, particularly multidrug-resistant strains within biofilms, exhibit resistance to conventional first-line antibiotics, underscoring wound care's role in the global antimicrobial resistance (AMR) crisis.²³ Poor perfusion in diabetic foot or ischemic leg ulcers further complicates systemic dosing, since therapeutic antibiotic concentrations may not be reached at the wound site despite high systemic exposure.²⁴ These challenges collectively highlight the need for localized, microenvironment responsive drug delivery platforms that improve antibacterial efficacy while limiting systemic antibiotic pressure and overall drug burden.

1.2 Limitations of conventional topical and systemic therapies

Conventional wound management relies heavily on passive dressings such as gauze, cotton and simple semi occlusive films combined with topical creams/ointments and systemic antibiotics, but these approaches are poorly adapted to the dynamic and heterogeneous wound microenvironment.²⁵ Gauze based dressings provide limited moisture control, adhere strongly to the wound bed, and require frequent changes, resulting in pain, secondary trauma, and disruption of newly formed tissue.²⁶ Even advanced occlusive or moist dressings, although superior to dry gauze, do not actively regulate pH, oxygen tension or protease activity, and typically lack controlled release of therapeutics over clinically relevant timescales.²⁷

Topical antibiotic or antiseptic formulations (e.g., creams, gels, impregnated dressings) can achieve high local drug concentrations, but drug release is often rapid and unmodulated, leading to sub therapeutic levels between applications and promoting biofilm persistence.²⁸ Prolonged or inappropriate use of topical antibiotics contributes to contact dermatitis, delayed hypersensitivity reactions and selection of multidrug resistant organisms, while many antiseptics (e.g., iodine, chlorhexidine) exhibit dose dependent cytotoxicity toward keratinocytes and fibroblasts, impairing re-epithelialization.²⁹

Systemic antibiotic therapy remains indispensable in cases of spreading infection or osteomyelitis, but its effectiveness is diminished in poorly perfused, ischemic or necrotic tissue, where limited vascular supply restricts drug penetration and creates sanctuaries for biofilms.³⁰ High systemic doses required to overcome local penetration barriers increase the risk of nephrotoxicity, hepatotoxicity, gastrointestinal intolerance and Clostridioides difficile infection, particularly in older adults with multiple comorbidities and polypharmacy.³¹ Importantly, neither systemic nor conventional topical regimens are able to sense and respond to dynamic changes in wound pH, bacterial load or inflammatory status, leading to mismatches between drug exposure and pathophysiological need; this therapeutic gap motivates the development of bioinspired pH-responsive hydrogels as smart, locally acting delivery platforms capable of on demand, microenvironment-triggered release and improved wound healing outcomes.⁵

1.3 Evolution of wound dressings

The field of wound management has undergone a substantial technological transformation, progressing from passive protective materials to sophisticated bioactive and microenvironment-responsive therapeutic platforms. First-generation wound dressings, including cotton gauze, lint, and conventional bandages, were designed primarily to provide mechanical protection by isolating the wound from external contaminants and absorbing excess exudate. Despite their widespread clinical use, these materials exhibit significant limitations, including poor regulation of wound moisture, promotion of wound desiccation, adhesion to regenerating granulation tissue, and secondary mechanical injury during removal, all of which can impede the healing process.³² Recognition of these shortcomings led to the development of second-generation interactive dressings based on the principle of moist wound healing. Materials such as hydrocolloids, polyurethane films, foams, alginates, and conventional non-responsive hydrogel systems were engineered to maintain optimal hydration at the wound interface, thereby facilitating cellular migration and accelerating re-epithelialization. While some materials from this era, such as alginates, exhibit intrinsic ion-exchange properties upon contact with exudate, these early interactive dressings still lack the capacity to dynamically sense and respond to complex pathophysiological pH variations within the wound microenvironment.³³

These limitations have catalysed the emergence of third-generation and next-generation “smart” wound dressings, including bioactive, antimicrobial, adhesive, self-healing, sensor-integrated, and stimuli-responsive systems. Among these, bioinspired pH-responsive hydrogels represent a particularly attractive class because they combine the moist and extracellular-matrix-like properties of hydrogels with the ability to respond to pathological pH changes in chronic and infected wounds. Unlike conventional moisture-regulating materials, these advanced biomaterials are capable of sensing microenvironmental abnormalities and translating them into material-level responses, including swelling, network relaxation, bond cleavage, charge transition, and controlled therapeutic release.³⁴ Through wound-pH-mediated activation, pH-responsive hydrogels can enable on-demand delivery of antimicrobial, anti-inflammatory, antioxidant, or pro-regenerative agents while minimizing unnecessary drug exposure in normally healing tissue. This transition from passive coverage to microenvironment-responsive intervention represents a significant paradigm shift toward precision wound care.^35,36

The development of pH-responsive hydrogel systems can be traced to the foundational work of Otto Wichterle and Drahoslav Lím, who pioneered synthetic poly(2-hydroxyethyl methacrylate) (pHEMA) hydrogel networks in the mid-20th century.³⁷ During the 1970s and 1980s, research predominantly focused on synthetic, non biodegradable polymers such as poly(acrylic acid) (PAA) and poly(methacrylic acid) (PMAA), which demonstrated the fundamental principle of ionization mediated swelling and stimulus responsive behaviour.³⁸ Although these synthetic networks provided critical proof of concept for environmentally responsive biomaterials, their clinical utility in regenerative wound healing was constrained by a lack of cell-adhesive motifs, an inability to undergo synchronized enzymatic biodegradation during tissue remodeling, and potential risks of long-term foreign-body responses. A major paradigm shift occurred at the beginning of the 21st century with the emergence of bioinspired hydrogel engineering. Researchers increasingly incorporated ionizable functional groups into naturally derived polysaccharide and protein-based matrices, including chitosan, alginate, hyaluronic acid, gelatin, collagen, and cellulose derivatives, thereby combining the stimulus sensitivity of synthetic polymers with the superior biocompatibility, intrinsic bioactivity, and enzymatic degradability of natural biomaterials. This convergence of synthetic responsiveness and biological functionality established the technological foundation for contemporary smart wound dressing platforms.^39,40

In this evolutionary context, bioinspired pH-responsive hydrogels can be viewed as a logical progression from passive wound coverage to adaptive wound therapy. They are designed not only to protect the wound and maintain hydration, but also to interpret disease-associated pH shifts as therapeutic signals. By responding to alkalinity associated with chronic inflammation, infection, ischemia, and biofilm formation, these systems can regulate drug release, antibacterial activity, inflammatory modulation, matrix remodeling, and tissue regeneration in a more localized and temporally controlled manner. Therefore, pH-responsive hydrogels occupy an important position in the evolution of wound dressings, linking classical moist wound healing with modern precision biomaterial design.

2. Wound pH and implications for pharmacotherapy

Wound pH is a central determinant of healing trajectory and pharmacotherapy performance, with acute wounds typically trending towards acidic values that favour repair, whereas chronic and infected wounds persist in an alkaline range that impairs drug action and promotes bacterial survival and biofilms as shown in Fig. 1. In the context of bioinspired pH-responsive hydrogels, these pH gradients provide a rational trigger for site specific, on demand drug release, with the potential to enhance local efficacy and reduce systemic exposure.⁴¹ The intact stratum corneum maintains an acid mantle with a surface pH of approximately 4.5–5.5, which supports barrier homeostasis, microbiome balance, and innate defence. Upon tissue injury, exposure of interstitial fluid and plasma shifts the microenvironment-towards physiologically neutral values (around pH 7.3–7.4), especially in early acute wounds, before progressive acidification accompanies normal healing.⁴²

Fig. 1 Engineering concept and therapeutic mechanism of bioinspired pH-responsive hydrogels for smart wound healing. Bioinspired pH-responsive hydrogels integrate natural biological inspiration with dynamic polymer chemistry to create smart wound dressings that respond to microenvironmental changes. Left: Bioinspired design principles derived from extracellular matrix architecture, mussel inspired adhesion, and infection associated biofilm environments, translated into hydrogel networks through functional groups such as amines, aldehydes, and Schiff-base linkages. Centre: Formation of a three dimensional hydrogel network capable of stimulus induced swelling and structural adaptation. Right: Pathological pH differences between normal wounds (pH ∼5.5–6.5) and infected wounds (pH ∼7.2–9) trigger localized therapeutic release, leading to antibacterial activity, controlled inflammation, and accelerated tissue regeneration. Some components of this figure were created with BioRender.com.

In acute wounds that follow an orderly sequence of haemostasis, inflammation, proliferation, and remodelling, pH tends to decline from an initial neutral-to-slightly alkaline peak towards mildly acidic values that correlate with granulation tissue formation and re-epithelialization. In contrast, chronic wounds such as long standing venous leg ulcers, pressure injuries, and diabetic foot ulcers often remain in an alkaline range of pH 7.15–8.9, with values above 8.5 often associated with stalled healing, persistent inflammation, and increased bioburden.⁴³ This persistent alkalinity has multiple pharmacotherapeutic implications: it enhances MMP activity and degrades extracellular matrix proteins, reduces growth factor bioavailability, and alters the ionization and activity of topical antimicrobials and growth promoting agents. Alkaline pH also supports high bacterial loads (up to 10¹⁰–10¹² CFU mL⁻¹ at neutral-to-alkaline pH for pathogens such Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus), conditions that may contribute to biofilm-associated phenotypic tolerance, reduced antibiotic penetration, and decreased local drug effectiveness.⁴⁴

From a therapeutic design perspective, these observations have driven the development of pH modulating dressings (e.g. acidifying solutions, buffered foams, honey based dressings) and pH-responsive systems that aim to restore a slightly acidic environment while releasing antimicrobials or anti-inflammatory drugs when and where they are most needed. Bioinspired pH sensitive hydrogels are particularly attractive because they can be engineered to swell and release payloads preferentially in alkaline chronic wounds, thereby coupling microenvironment correction (acidification) with smart pharmacotherapy.^45,46

2.1 pH dynamics in acute and chronic wounds

Acute wounds typically exhibit an early microenvironment pH close to physiological tissue pH (≈7.4) immediately after injury due to exposure of blood and interstitial fluid at the wound bed, as illustrated in Fig. 1. To ensure therapeutic precision, a clear clinical distinction must be maintained between the unique biochemical conditions of different wound states. Acute wounds generally follow an orderly healing sequence, quickly transitioning from initial neutral blood exposure to a mildly acidic, low bioburden environment (pH 5.5–6.5) that is associated with healthy re-epithelialization. In contrast, chronic wounds are often locked in a stalled inflammatory phase characterized by persistent hypoxia and an alkaline microenvironment (pH 7.3–8.9).⁴⁷ This persistent alkalinity may be further increased in infected wounds, where bacterial metabolism, including ammonia production by urease-positive organisms such as Proteus mirabilis, Klebsiella spp., and some Pseudomonas aeruginosa strains, can contribute to elevated local pH values. This alkaline state is a common feature of biofilm-associated wounds. Within these mature biofilms, complex extracellular polymeric substances (EPS) create dense physical diffusion barriers. These barriers shield bacterial colonies from antibiotics and generate highly localized acidic or alkaline microniches that actively buffer the surrounding tissue, presenting a far more complex therapeutic challenge than free-floating planktonic infections.⁴⁸ As healing progresses, lactate production, hypoxia driven metabolic changes, and restoration of the epidermal barrier collectively lower the pH towards a mildly acidic range (approximately 5.5–6.5), which is associated with enhanced keratinocyte proliferation, fibroblast migration, and optimized activity of certain growth factors.⁴⁹ In chronic wounds, this dynamic trajectory is disrupted and pH often fluctuates within an alkaline band, with multiple studies reporting ranges from 7.3 to 8.9 across venous leg ulcers, pressure ulcers, and diabetic foot ulcers. Higher pH values have been positively correlated with increased wound size, higher exudate levels, and clinical signs of infection; as wounds move towards healing, a gradual decline in pH below 8.0 and closer to neutrality has been documented.⁵⁰

Cellular behaviour is tightly coupled to these pH shifts: alkaline conditions upregulate MMPs and downregulate their tissue inhibitors, accelerating degradation of collagen and fibronectin, whereas moderately acidic conditions suppress excessive protease activity and favour extracellular matrix deposition. Leukocyte chemotaxis and phagocytosis are also pH sensitive; severe localized tissue acidosis (<4.5) or prolonged extracellular alkalinity (>7.7) can both impair neutrophil function, while mid range values around 6.7–7.2 tend to support more balanced inflammatory responses.⁵¹ The pH profile also interacts with tissue oxygenation and perfusion: chronic ischemic ulcers often present with alkaline pH and high oxidative stress, which together prolong the inflammatory phase and impair angiogenesis. Experimental wound acidification (e.g. using buffered solutions around pH 4) has been shown to accelerate closure rates in non infected wounds, suggesting that controlled lowering of wound pH can be used therapeutically to redirect stalled chronic wounds back to a healing trajectory.⁵² For pH-responsive hydrogels, these dynamics provide a physiologically grounded trigger; formulations can be designed to remain relatively compact and retain drugs at mildly acidic pH in normally healing acute wounds, but to swell and release drugs more extensively in the alkaline environment of chronic, infected, or biofilm laden wounds. Such designs enable on demand delivery, in which the microenvironment itself dictates drug exposure, potentially minimizing overtreatment of normally healing wounds while intensifying therapy in pathologic sites.⁵³

2.2 Influence of pH on drug stability, activity, and bacterial resistance

The influence of pH on pharmacotherapy encompasses several interlinked domains: physicochemical stability and solubility of drugs, ionization and membrane permeability, interaction with wound components (proteins, exudate), and the adaptive responses of microorganisms, including biofilm formation and resistance phenotypes. Many topical antibiotics, antiseptics, and biologics exhibit pH dependent stability and activity profiles, so that a given agent may be highly effective in acidic acute wounds but significantly less active in alkaline chronic wounds, or vice versa. pH alters the ionization state of weakly acidic and basic drugs, which in turn affects their solubility and partitioning into bacterial membranes or host tissues. For example, certain β-lactam antibiotics (e.g. aztreonam) show improved activity against Gram negative wound isolates at neutral pH compared to more acidic conditions, while fluoroquinolones such as levofloxacin can be less effective as pH shifts away from their optimal ionization window. Conversely, the efficacy of silver-based dressings can be heavily influenced by pH; while neutral-to-alkaline conditions facilitate the oxidative release of active silver ions, local microenvironment variations alter ion bio-availability and precipitation kinetics, thereby shifting the microbial killing efficiency at the wound surface.⁵⁴

Biologicals and protein based therapeutics (e.g. growth factors) can undergo pH induced denaturation or aggregation, and high alkaline pH may destabilize protein structure and accelerate proteolytic degradation by MMPs and serine proteases that are upregulated in chronic wounds. Conversely, maintaining a slightly acidic environment can help preserve protein conformation and reduce excessive protease activity, thereby prolonging the effective half life of such agents when delivered topically. These considerations underscore the importance of matching drug formulation pH not only to the intrinsic stability of the active molecule, but also to the expected wound microenvironment along the course of healing.⁵⁵ Bacterial growth and biofilm behaviour are strongly pH dependent: alkaline conditions (pH 7–8) support high proliferation and biofilm density for common wound pathogens like P. aeruginosa, E. coli, S. aureus, and S. epidermidis, with colony counts reaching maximum saturation densities (typically 10⁹–10¹⁰ CFU mL⁻¹) at pH 8 in experimental models. In more acidic environments (e.g. pH 4–5), bacterial survival is markedly reduced, particularly for Gram positive organisms, and biofilm formation is hindered, thereby increasing susceptibility to both host immune mechanisms and topical/systemic antibiotics.⁵⁶

Table 1 describes barriers in wound healing and their pathophysiological impact and how pH modulates antibiotic resistance and tolerance: within biofilms, localized pH gradients can reduce antibiotic penetration, alter efflux pump activity, and drive selection of more resistant subpopulations, particularly in alkaline niches where metabolic activity remains high. In vitro studies using wound isolates demonstrate that minimal inhibitory concentrations and killing kinetics of multiple antibiotics vary with pH, implying that a regimen effective in an acute, less alkaline wound may fail in a chronic, highly alkaline ulcer with the same pathogen profile.⁵⁷ These insights provide a compelling rationale for integrating pH-responsiveness into hydrogel based drug delivery systems for wound healing. By engineering hydrogels whose swelling, porosity, and drug release rates increase selectively at alkaline pH, it is possible to concentrate antimicrobial drugs at sites of greatest bacterial burden and resistance while minimizing exposure in relatively acidic, healing tissue. Moreover, combining pH-responsive matrices with acidifying components (e.g. organic acids, honey derivatives, or buffered polymers) allows simultaneous modulation of wound pH and tailored drug release, creating a feedback responsive platform that addresses both the microenvironmental drivers of chronicity and the pharmacodynamic limitations of conventional topical therapy.

Table 1 Barriers in wound healing and their pathophysiological impact

Barrier category	Specific barrier	Underlying mechanism	Impact on healing phases	Clinical/biological consequences	Key references
Local wound environment	Hypoxia	Impaired angiogenesis, reduced ATP production, HIF-1α dysregulation	Inflammation, proliferation	Delayed granulation tissue formation, poor epithelialization	58
	pH imbalance (alkaline microenvironment)	Reduced fibroblast activity, impaired collagen deposition, enhanced protease activity	Inflammation, proliferation	Chronic non healing wounds, increased infection risk	59
	Excessive exudate	Protease rich fluid degrades ECM and growth factors	Proliferation	Matrix breakdown, delayed re-epithelialization	60
Infection & biofilms	Bacterial infection	Persistent inflammation, neutrophil overactivation	Inflammation	Tissue destruction, delayed healing	61
	Biofilm formation	Antibiotic resistance, immune evasion	Inflammation, proliferation	Refractory chronic wounds	62 and 63
Systemic factors	Diabetes mellitus	Impaired macrophage function, reduced NO, microangiopathy	All phases	Chronic ulcers, high amputation risk	64
	Aging	Reduced stem cell activity, impaired cytokine signalling	Inflammation, proliferation	Slow epithelialization, fragile scars	65
	Malnutrition (protein, zinc, vitamin C deficiency)	Impaired collagen synthesis, reduced immune response	Proliferation, remodelling	Weak wound tensile strength	66
Vascular insufficiency	Ischemia	Reduced oxygen and nutrient delivery	Inflammation, proliferation	Necrosis, delayed granulation tissue	67 and 68
	Venous hypertension	Leukocyte trapping, capillary damage	Inflammation	Venous ulcers, chronic edema	69
Cellular dysfunction	Fibroblast senescence	Reduced ECM synthesis and migration	Proliferation, remodelling	Poor matrix formation	70
	Keratinocyte migration failure	Cytoskeletal dysfunction, altered integrins	Proliferation	Non closure of wound edges	71
Inflammatory dysregulation	Prolonged inflammation	Excess ROS, cytokine imbalance (↑TNF-α, IL-1β)	Inflammation	Tissue damage, stalled healing	72
Mechanical stress	Repeated trauma/pressure	Tissue ischemia and necrosis	All phases	Pressure ulcers, wound breakdown	73
Clinical management factors	Inadequate debridement	Persistence of necrotic tissue	Inflammation	Infection, delayed healing	74
	Improper dressing selection	Poor moisture balance, inadequate protection	Proliferation	Maceration or desiccation	27

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Wound pH is a key regulator of healing, with acute wounds becoming mildly acidic to support repair, while chronic or infected wounds remain alkaline, delaying healing and promoting biofilm formation. pH also affects drug stability and antimicrobial efficacy, with specific pH windows dictating the ionization state, solubility, and therapeutic activity of targeted antimicrobials, while pathological alkaline shifts frequently alter local drug effectiveness and promote biofilm-associated tolerance mechanisms. Bioinspired pH-responsive hydrogels leverage these pH differences for targeted, on-demand drug release and, when combined with acidifying or buffering components, may support wound pH modulation, thereby potentially improving local healing outcomes while reducing unnecessary systemic exposure.

While wound pH provides a biologically exploitable trigger for intelligent therapeutic intervention, successful clinical translation of bioinspired pH-responsive hydrogels requires more than stimulus responsiveness alone. The pharmaceutical performance of these systems is intrinsically governed by deliberate material and formulation design, including the selection of responsive polymers, network topology, swelling dynamics, cargo compatibility, and controlled release kinetics. Consequently, an examination of the pharmaceutical design principles underpinning pH-responsive hydrogel engineering becomes essential for advancing these systems from conceptual biomaterials toward robust therapeutic platforms.

3. Pharmaceutical design of pH-responsive bioinspired hydrogels

Pharmaceutical design of pH-responsive bioinspired hydrogels focuses on mimicking extracellular matrix components for biocompatibility while engineering ionizable groups or dynamic linkages that trigger targeted structural changes across pathological wound pH gradients. The structural and natural sources of mimicry in pH-responsive hydrogels are described in Table 2. These formulations prioritize natural polymer crosslinking via Schiff bases, Michael additions, or click chemistry to achieve injectability, self-healing, and sustained release of antimicrobials or growth factors. Optimization involves carefully tailoring viscoelastic properties (typically adjusting the storage modulus (G′) to match tissue compliance), maximizing swelling capacity to manage exudate, and optimizing drug entrapment efficiency for clinical viability.

Table 2 Bioinspired natural sources and structural mimicry in pH-responsive hydrogels

S. no.	Natural inspiration	Native biological function	Mimicked structural feature	Hydrogel polymer/system	Functional advantage in wound healing	Ref.
1	Extracellular matrix	Cell adhesion, migration, angiogenesis	Fibrous porous network	GelMA, collagen, hyaluronic acid	Enhanced cell proliferation and tissue regeneration	75
2	Mussel adhesive proteins	Wet surface adhesion	Catechol functional groups	Chitosan catechol, PEG-DOPA	Strong tissue adhesion, reduced dressing displacement	76 and 77
3	Skin stratum corneum	Barrier & moisture regulation	Layered structure, hydration control	PVA/alginate multilayer hydrogels	Maintains moist wound environment	78 and 79
4	Nacre (mother of pearl)	Mechanical toughness	Hierarchical brick and mortar structure	Clay polymer composite hydrogels	Improved mechanical stability of wound dressings	80
5	Cartilage tissue	Load bearing, resilience	Highly hydrated, ion responsive matrix	Alginate based pH-responsive hydrogels	Shock resistance, sustained drug release	81 and 82
6	Blood clot (fibrin network)	Haemostasis, provisional matrix	Interconnected fibrillar mesh	Fibrin GelMA hybrid hydrogels	Rapid haemostasis, early wound stabilization	83
7	Marine polysaccharides (algae)	Protection, hydration	Polyanionic networks	Alginate, carrageenan hydrogels	High exudate absorption, pH triggered release	84
8	Bacterial biofilm microenvironment	pH elevation during infection	pH sensitive swelling/deswelling	Chitosan PAA composite hydrogels	Infection responsive drug release	5 and 85
9	Plant cell wall	Structural rigidity & flexibility	Cellulose nanofibril reinforcement	Cellulose based composite hydrogels	Enhanced tensile strength, biocompatibility	86–88
10	Antimicrobial peptides (AMPs)	Innate immune defence	Charge responsive interaction	AMP loaded pH-responsive hydrogels	Selective bacterial killing	89 and 90
12	Tumor/chronic wound microenvironment	Acidic alkaline pH heterogeneity	pH adaptive polymer networks	Dual responsive (pH/redox) hydrogels	Smart, on demand therapeutic delivery	91

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3.1 Bioinspired polymers and excipients

Bioinspired polymers emulate natural tissues, providing inherent bioactivity, biodegradability, and pH tunable ionization for wound-specific responsiveness. In parallel, biodegradable synthetic polymers have been widely explored in biomedical systems owing to their tunable degradation behaviour, biocompatibility, and versatility in drug delivery and tissue engineering applications.⁹² Chitosan (deacetylated chitin) is widely used in formulations due to its protonatable amine groups (pK_a ∼6.5), cationic antimicrobial activity, and mucoadhesion, often crosslinked with genipin or oxidized dextran for 3D networks. Hyaluronic acid, a glycosaminoglycan, contributes viscoelasticity and CD44 receptor binding for cell migration, and can be methacrylated (MeHA) for photopolymerization or Schiff linked with aldehydes for pH labile bonds. Alginate from brown algae forms ionic ‘egg-box’ junctions with Ca²⁺ ions, or can be modified in its oxidized dialdehyde form to introduce pH-labile covalent crosslinks, enabling rapid gelation and stimulus-responsive degradation kinetics. Collagen or gelatin provide RGD motifs for integrin binding, while silk fibroin offers β-sheet stability for mechanical robustness. Excipients include nanoparticles (ZnO, AgNPs) for synergy, polyethylene glycol (PEG) diacrylates for hydrophilicity, and natural antioxidants like tannic acid for haemostasis. Hybrid systems (e.g., chitosan/HA/alginate) yield gels with >80% cell viability in fibroblast assays, potentially reducing immunogenicity compared with purely synthetic systems.

The transition from empirical hydrogel formulation toward predictive material design requires the direct correlation of specific compositional parameters with macroscopic functional performance. Among these parameters, functional group density, defined here as the relative abundance of ionizable or pH-labile moieties within the polymer network, plays a central role in determining the magnitude of pH-responsive behaviour. For example, increasing the degree of deacetylation in chitosan enhances the density of primary amine groups, leading to greater protonation under acidic to mildly neutral conditions and consequently higher net positive charge density. This elevated charge can intensify electrostatic repulsion between polymer chains, resulting in increased hydrogel swelling and enhanced pH-triggered cargo release.⁹³ However, functional group density cannot be considered independently from polymer architecture, because excessive ionization may increase swelling while weakening mechanical cohesion, accelerating erosion, or reducing dressing residence time. The structural characteristics of the polymer backbone therefore impose an important counterbalancing effect on responsiveness. Rigid, crystalline, or reinforcing polymeric domains, such as silk fibroin β-sheet structures, cellulose nanocrystals, or other nanofibrillar components, can improve mechanical stability and resistance to deformation, although they may reduce maximal swelling by restricting chain mobility. In contrast, more flexible and hydrophilic polymer chains, such as selected polysaccharide or PEG-containing networks, generally permit greater volumetric expansion and faster molecular diffusion, but may require additional covalent, ionic, or physical crosslinking to withstand dynamic shear, exudate flow, and repeated deformation at the wound surface.⁹⁴ Thus, the performance of pH-responsive hydrogels is governed not simply by polymer identity, but by the integrated effects of functional group chemistry, charge density, backbone flexibility, crystallinity, molecular weight, and crosslinking architecture.

A critical limitation in early responsive biomaterials was the isolated deployment of singular functionalities. Modern bioinspired engineering has shifted toward monolithic, multifunctional networks wherein antibacterial, antioxidant, and self-healing behaviours operate synergistically within a single polymeric framework. For instance, in catechol functionalized chitosan hydrogels crosslinked via dynamic covalent Schiff base bonds, these functionalities are intrinsically linked rather than independent. The protonated primary amines of the chitosan backbone exert inherent contact killing antibacterial action against bacterial cell walls, while the conjugated catechol groups act as high efficiency radical scavengers to mitigate localized oxidative stress.⁹⁵ Concurrently, the reversible imine chemistry allows the network to autonomously self-heal under dynamic shear strain. The synergy lies in the protection of the matrix: the antioxidant catechol groups help prevent the oxidative degradation of the chitosan backbone by ROS, thereby preserving the mechanical integrity required for long term contact killing and sustained therapeutic delivery.⁹⁶ Various pH-responsive polymers and their drug release mechanisms are given in Table 3.

Table 3 pH-responsive polymers and their drug release mechanisms

S. No.	Polymer	pH sensitive functional group	pH trigger range	Release mechanism	Drug delivery relevance in wounds	Key references
1	Chitosan	–NH2 (protonation)	Acidic to neutral (pH 5–7)	Swelling & electrostatic repulsion	Faster drug release in infected wounds	97
2	Alginate	–COOH (deprotonation)	Neutral to alkaline (pH >7)	Network loosening, ion exchange	Infection responsive antibiotic release	98
3	Poly(acrylic acid) (PAA)	–COOH	Alkaline pH	Chain expansion & osmotic swelling	Controlled, sustained drug delivery	99
4	Gelatin	Ionizable amino acids	pH dependent	Enzymatic & pH assisted degradation	Growth factor and protein delivery	100
5	Hyaluronic acid	–COOH	Mild acidic to neutral	Electrostatic repulsion, hydrolysis	ECM mimetic drug release, promotes cell migration	101
6	Poly(N-isopropylacrylamide-co-AAc)	–COOH + thermoresponsive groups	pH 6–8	Dual pH/temperature swelling	On demand drug release in inflamed wounds	102
7	Poly(β-amino esters)	Tertiary amines	Acidic pH	Protonation induced degradation	Intracellular and acidic wound targeting	103
8	Carboxymethyl cellulose (CMC)	–COO^−	Neutral to alkaline	Ionization induced expansion	Sustained antibiotic and antioxidant release	104
9	Dextran derivatives	Acetal/hydrazone linkages	Acidic pH	Acid cleavable bond breakage	pH triggered payload release	105 and 106
10	Poly(N-isopropylacrylamide-co-acrylic acid)	Primary/secondary amines	Acidic pH	Proton sponge swelling	Enhanced drug diffusion in acidic wounds	107
11	Polydopamine modified hydrogels	Catechol/quinone groups	Broad (pH 5–8)	pH dependent redox and adhesion changes	Adhesive, pH modulated release	108
12	Schiff base cross linked hydrogels	Imine (–C=N–) bonds	Acidic pH	Acid labile bond cleavage	Smart release under infected wound conditions	109
13	Zwitterionic polymers	±Charged moieties	pH dependent charge balance	Charge switching permeability	Reduced fouling, controlled drug diffusion	110

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3.2 Mechanisms of pH triggered swelling and drug release

pH-responsiveness arises from ionizable pendant groups undergoing protonation/deprotonation, driving Donnan osmotic pressure changes and network expansion/contraction. Anionic hydrogels containing carboxylate groups undergo deprotonation and ionization as the microenvironment shifts toward the alkaline range characteristic of chronic wounds (pH 7.3–8.9). This generates intense electrostatic repulsion between polymer chains, driving network expansion, mesh relaxation, and controlled cargo liberation. Swelling kinetics follow Fickian diffusion initially, transitioning toward case II transport at high ionization: Q(t) = ktⁿ, where n > 0.5 indicates relaxation control. Drug release can couple swelling to erosion: hydrophobic payloads (curcumin) partition into hydrophobic domains, liberating via pore dilation; hydrophilic ones (gentamicin) diffuse faster following network ionization. Alternatively, pH-labile crosslinks such as boronate esters or tailored Schiff bases undergo controlled hydrolysis under targeted pH environments with managed dissociation rate constants (k ≈ 10⁻³ to 10⁻⁶ s⁻¹), enabling sustained zero-order or anomalous release profiles. Dual mechanisms (pH/ROS via thioketal bonds or enzyme-cleavable peptides) yield pulsatile release profiles, with accelerated payload delivery tailored to pathological chronic wound environments compared to normally healing tissue, potentially minimizing off-target effects. These dynamics, validated by rheological (tan δ < 0.1) and release kinetic models (Peppas–Sahlin), help define therapeutic windows for chronic wounds.

Mechanistically, pH-responsive behaviour in hydrogel systems is primarily mediated through three fundamental pathways: ionization or protonation of pendant functional groups, dynamic covalent bond cleavage, and reversible electrostatic interactions. Each of these mechanisms exhibits distinct physicochemical characteristics and performance profiles in terms of response rate, reversibility, and structural stability.⁵ Ionization-mediated systems, exemplified by polymers such as poly(acrylic acid) and chitosan, respond through rapid alterations in ionization state that induce changes in Donnan osmotic pressure, leading to volumetric expansion or contraction of the network. These systems typically demonstrate fast response kinetics and good reversibility over repeated pH fluctuations; however, excessive hydration and swelling may compromise long-term structural integrity and mechanical stability.¹¹¹ In contrast, hydrogels incorporating dynamic covalent linkages, including imine, hydrazone, acetal/ketal, and boronate ester bonds, can provide tunable structural stability under physiological conditions but undergo controlled bond exchange, dissociation, or network degradation upon exposure to specific acidic or alkaline environments. The reversibility of these systems is highly dependent on local chemical equilibrium, bond-exchange kinetics, hydrolysis susceptibility, and steric constraints within the polymer matrix.¹¹² A third class, based on reversible electrostatic interactions such as polyelectrolyte complexes, exhibits rapid responsiveness and high reversibility owing to the non-covalent nature of physical crosslinking. Nevertheless, these materials remain susceptible to charge screening, premature dissociation, and mechanical destabilization in environments with elevated ionic strength, such as protein-rich wound exudates.¹¹³

These mechanistic categories also provide the basis for integrating multiple therapeutic functions within a single wound dressing rather than treating antibacterial, antioxidant, anti-inflammatory, adhesive, and self-healing properties as independent design features. For example, ionizable groups can simultaneously regulate pH-triggered swelling and antimicrobial drug release; dynamic covalent bonds can provide both self-healing behaviour and pH-labile network degradation; and electrostatic interactions can support bacterial membrane disruption, protein adsorption control, and reversible network reconstruction. In multifunctional systems, these functions may act synergistically: antibacterial components reduce microbial burden and biofilm formation, antioxidant modules suppress ROS-mediated tissue damage, and self-healing or adhesive networks maintain intimate contact with irregular wound surfaces, thereby prolonging therapeutic residence time and sustaining localized drug release. Therefore, the most advanced pH-responsive hydrogels should be evaluated not simply as carriers with separate functions, but as integrated microenvironment-adaptive systems in which network chemistry, mechanical recovery, drug release, and biological activity are co-optimized.

Crosslinking density serves as a principal structural determinant governing both equilibrium swelling behaviour and molecular transport dynamics within hydrogel networks. From a thermodynamic perspective, the equilibrium swelling ratio is generally inversely related to crosslinking density, consistent with Flory–Rehner theory, which describes how increased junction-point concentration enhances the elastic restoring force of the polymer network and restricts chain relaxation. As crosslinking density increases, the effective mesh size decreases, directly influencing the diffusional mobility of encapsulated therapeutic agents. When the mesh dimension approaches the hydrodynamic radius of the loaded drug, protein, nanoparticle, or vesicle, the apparent diffusion coefficient decreases markedly, resulting in slower and more sustained release kinetics. Highly crosslinked hydrogels therefore tend to reduce undesirable initial burst release and may shift drug transport behaviour from rapid Fickian diffusion toward anomalous or relaxation-controlled mechanisms. In contrast, networks with lower crosslinking density possess larger pore dimensions and greater chain flexibility, facilitating rapid swelling and accelerated cargo diffusion following pH activation; however, this often occurs at the expense of mechanical coherence, residence time, and structural durability of the dressing matrix.¹¹⁴

To establish quantitative rigor in evaluating therapeutic release performance, qualitative observations of cargo liberation should be integrated with kinetic transport models. One of the most widely applied semi-empirical frameworks for characterizing hydrogel-mediated drug release is the Korsmeyer–Peppas equation:

M_t/M_∞ = ktⁿ

where M_t/M_∞ represents the fractional release of the drug at time t, k is the structural release rate constant, and n is the diffusional exponent indicative of the transport mechanism. For thin film or sheet geometries, an exponent of n = 0.5 signifies pure fickian diffusion through water filled pores. Values within the range of 0.45 < n < 0.89 indicate anomalous (non fickian) transport, where drug diffusion and polymer matrix relaxation/swelling occur at comparable rates. When n = 0.89, (for cylinders or n = 1.0 for spheres), release is governed entirely by case II transport, reflecting a purely erosion or degradation controlled mechanism, typical of labile Schiff base or hydrazone cleavage profiles. By applying the Peppas-Sahlin model, the individual approximate contributions of Fickian diffusion (R) and relaxation-led matrix macromolecular relaxation (F) can be decoupled, confirming that highly dynamic pH-responsive systems shift from diffusion-dominated regimes at neutral pH to relaxation- or erosion-dominated regimes under pathological triggers.¹¹⁵

3.3 Mechanical integrity and dynamic viscoelasticity under physiological strain

For wound dressings intended for application over mechanically active anatomical sites, such as joints, digital extremities, and curved skin surfaces, sufficient mechanical resilience is essential to withstand continuous multidirectional deformation without structural rupture, loss of adhesion, or premature delamination. The mechanical behaviour of hydrogel-based dressings is commonly evaluated using dynamic oscillatory rheology, which quantifies the G, indicative of elastic energy storage, and the loss modulus (G″), representing viscous energy dissipation. To preserve geometric stability and maintain effective wound bed coverage under physiological motion, clinically relevant hydrogel systems should exhibit an application-appropriate linear viscoelastic region, with G′ exceeding G″ over the relevant strain range and a sufficiently low loss tangent (tan δ = G″/G′), reflecting predominantly elastic but still adaptable behaviour.¹¹⁶ Although specific mechanical thresholds vary according to wound location, dressing geometry, hydration state, and delivery mode, hydrogels used for prolonged wound coverage generally require a balance between softness for tissue conformity and sufficient cohesive strength for fatigue resistance.

Importantly, the mechanical properties of hydrogel matrices are closely linked to their drug-release performance. In highly compliant or mechanically fragile hydrogels, repetitive physiological loading can induce substantial compressive deformation, promoting convective fluid expulsion from the polymer network and resulting in undesirable mechanically triggered burst release, or “squeeze-out”, of encapsulated therapeutic agents. Such uncontrolled release may compromise dosing precision and reduce long-term treatment efficacy. In contrast, mechanically reinforced hydrogel architectures, including double-network and interpenetrating polymer network (IPN) systems, can provide enhanced structural robustness through mechanisms such as sacrificial bond rupture, reversible physical interactions, or internal energy dissipation, depending on the specific network design. These advanced network designs can help preserve more stable mesh architecture and diffusion pathways under repeated cyclic strain, thereby minimizing deformation-induced disruption of release kinetics.¹¹⁷ Consequently, mechanically optimized hydrogels may enable more sustained and predictable therapeutic release over prolonged treatment durations, supporting improved dressing integrity and consistent local drug bioavailability during extended wound-healing applications.

3.4 Delivery formats and rheological determinants of application

The clinical applicability and translational potential of pH-responsive hydrogels are strongly influenced by their physical delivery format, which can be broadly classified into preformed hydrogel patches, topically spreadable or sprayable precursor systems, in situ forming matrices, and shear-thinning injectable systems. The selection of an appropriate formulation is primarily dictated by rheological behaviour, mechanical integrity, adhesion, and structural adaptability to specific wound geometries and therapeutic requirements. Preformed hydrogel patches typically function as solid-like elastic networks characterized by high structural integrity and dimensional stability, making them suitable for large, superficial wounds such as burns and surgically created excisional defects. Their predefined architecture facilitates straightforward placement and sustained wound coverage; however, limited conformability may restrict their ability to establish intimate contact with anatomically complex wound beds, including deep cavities, irregular ulcers, or tunnelled lesions.

In such cases, injectable shear-thinning hydrogels offer a more versatile alternative. These systems are commonly engineered through reversible non-covalent or dynamic crosslinking mechanisms, such as host–guest interactions, hydrogen bonding, ionic interactions, hydrophobic association, or other supramolecular interactions, which impart pseudoplastic rheological behaviour.¹¹⁸ Under elevated shear forces during syringe extrusion, transient disruption of these dynamic interactions causes a marked decrease in viscosity, enabling smooth administration and filling of irregular wound spaces. Following injection, rapid re-establishment of reversible crosslinks promotes viscosity recovery and restoration of gel-like elastic dominance, typically reflected by G′ > G″, thereby stabilizing the material at the application site and minimizing post-delivery migration or leakage. Alternatively, in situ forming hydrogel systems can be applied as low-viscosity precursor solutions exhibiting initial liquid-like viscous dominance (G″ > G′) by topical spreading, dripping, or spray deposition, followed by a rapid phase transition across an apparent gelation point (G′ = G″) directly on the wound surface in response to endogenous or externally applied triggers, including temperature, pH, ionic strength, enzymatic activity, or light-induced crosslinking. This stimulus-responsive transformation allows the hydrogel to conform to irregular wound topography while establishing a secure adhesive interface that enhances retention and therapeutic localization.

Thus, delivery mode should be matched to wound type and material mechanics. Patch-like hydrogels require sufficient cohesive strength, fatigue resistance, and adhesion for prolonged coverage; injectable hydrogels require shear-thinning behaviour, rapid self-recovery, and resistance to leakage; and spreadable or sprayable in situ gels require low initial viscosity followed by controlled gelation and stable residence on the wound surface. Collectively, optimization of hydrogel delivery format is a critical determinant of clinical performance, influencing ease of application, wound conformity, material stability, therapeutic persistence, patient comfort, and overall treatment efficacy.¹¹⁹

Collectively, the pharmaceutical design of bioinspired pH-responsive hydrogels represents a multidimensional engineering process in which material composition, pH-triggered responsiveness, mechanical resilience, and rheological behaviour are strategically integrated to achieve controlled therapeutic performance. The rational selection of bioinspired polymers and excipients, together with precise modulation of swelling kinetics, network viscoelasticity, and application-specific delivery formats, determines not only hydrogel stability and wound adaptability but also the predictability of drug release within dynamic physiological environments. Nevertheless, the translational relevance of these design principles ultimately depends on their capacity to support effective therapeutic payload delivery and measurable biological outcomes. Accordingly, the following section examines drug-loaded pH-sensitive hydrogel systems for wound healing, with particular emphasis on incorporated antimicrobial and anti-inflammatory agents, bioactive therapeutics, and their demonstrated pharmacological efficacy in preclinical wound models.

4. Drug-loaded pH sensitive hydrogels for wound healing

Drug-loaded pH-responsive hydrogels are emerging as multifunctional wound dressings that couple a moist, ECM-like scaffold with microenvironment-triggered release of antimicrobials, anti-inflammatory agents, growth factors, antioxidants, and other biotherapeutics, thereby potentially accelerating healing while reducing systemic exposure and resistance risk (Fig. 2).^120,121 In these systems, pH shifts between acidic or near-neutral healthy/acute wounds and alkaline infected/chronic wounds are exploited as endogenous triggers for on demand cargo release, often combined with ROS, enzyme, or temperature responsiveness to better match the dynamic pathophysiology.¹²² pH-responsive drug-loaded hydrogels are typically constructed from bioinspired polymers such as chitosan, hyaluronic acid, alginate, and gelatin, chemically engineered with pH-labile linkages (e.g., Schiff base, acetal/ketal) or ionizable groups that alter swelling and permeability with pH as given in Table 3. Mechanistically, the protonation/deprotonation of functional groups and cleavage of dynamic covalent bonds induce network loosening, charge switching, or erosion when the wound environment deviates from normal pH, which in turn modulates diffusion pathways and triggers controlled drug liberation.¹²³

Fig. 2 Smart hydrogel regulation across the wound healing process. Schematic illustration of how smart pH-responsive hydrogels interact with different stages of wound healing. Phase 1 (Hemostasis): immediate wound sealing, moisture retention, and protection against contamination. Phase 2 (Inflammation): adaptation to wound microenvironmental triggers such as pH, ROS, enzymes, and mechanical stress, enabling controlled antimicrobial activity and therapeutic release. Phase 3 (Proliferation): hydrogel matrix supports cell migration, angiogenesis, and tissue regeneration through nutrient transport and bioactive cue delivery. Phase 4 (Remodelling): controlled hydrogel degradation facilitates tissue integration, collagen maturation, and restoration of functional skin architecture. Some components of this figure were created with BioRender.com.

Hydrogel systems incorporating dynamic covalent boronate ester linkages can demonstrate rapid pH-triggered therapeutic release, often achieving efficient payload mobilization within the first few hours of acidic activation, or can be engineered via specific phenylboronic acid derivatives to dissociate under complex pathological pH variations.¹²⁴ However, this enhanced responsiveness is frequently accompanied by compromised mechanical durability, with accelerated network degradation and loss of cohesive integrity, particularly in highly exudative wound environments, thereby necessitating frequent dressing replacement. In contrast, permanently crosslinked networks designed with stable, non-reversible covalent backbones and ionizable pendant functional groups generally exhibit superior structural robustness and prolonged maintenance of dressing integrity over extended application periods, although these systems often display reduced swelling responsiveness and comparatively slower drug release kinetics. Comparative evaluation of these architectural strategies suggests that successful clinical performance depends not solely on maximizing hydrogel swelling or release efficiency, but on achieving an optimized balance between network relaxation dynamics and mechanical resilience capable of withstanding the biochemical complexity and shear forces present within the wound microenvironment.¹²⁵

4.1 Antibiotic, antiseptic, and anti-inflammatory loaded systems

Antibiotic- and antiseptic-loaded pH-responsive hydrogels are designed to overcome the limitations of conventional topical formulations, where burst release and poor penetration into biofilms can drive subtherapeutic exposure and antimicrobial resistance.¹²⁶ By embedding drug-loaded nano/microcarriers into a pH-sensitive network, these dressings can maintain therapeutically relevant local drug concentrations in infected or alkaline wound environments while potentially reducing unnecessary exposure to surrounding healthy tissue.¹²⁷ Recent studies have developed ROS/pH dual-responsive hydrogels incorporating amikacin-loaded micelles and naproxen, wherein infection-associated shifts in ROS and pH from infections trigger micelle breakdown and hydrogel softening for controlled antibiotic and NSAID delivery, demonstrating robust antibacterial, antioxidant, and anti-inflammatory activity in vitro. In full thickness infected wound models, this dual responsive dressing significantly accelerated wound closure, reduced bacterial burden, and promoted denser collagen deposition compared with non responsive hydrogels or single drug controls.¹²⁸

Other groups have incorporated metal or metal oxide nanophases together with pH-labile linkages to engineer hydrogels with intrinsic antimicrobial activity and on-demand antibiotic release. For instance, researchers have engineered chitosan-based pH-responsive hydrogels loaded with zinc oxide nanoparticles and paeoniflorin micelles, in which infection associated pH and ROS cleaved Schiff base bonds and disassembled micelles, releasing ZnO and paeoniflorin to provide haemostatic, adhesive, antibacterial, and angiogenic effects in chronic diabetic wounds. Similarly, “sense-and-treat” platforms embedding ZIF-8-type metal–organic frameworks in pH-sensitive networks can exploit acidic or infection-associated microenvironments to promote framework degradation and cargo release, although the response depends on MOF composition, local pH, wound fluid chemistry, and loaded therapeutic agents.¹²⁹ Antiseptic-loaded hydrogels containing silver, biguanides, or iodine derivatives can be engineered to show pH-dependent sol–gel behaviour, charge switching, or controlled release, which may enhance antimicrobial activity while reducing cytotoxicity when appropriately optimized. In vivo, such dressings have been reported in selected preclinical models to exhibit antibacterial or antibiofilm effects, support granulation tissue formation, and improve re-epithelialization compared with relevant control dressings.¹³⁰

Chronic and infected wounds are marked by persistent, dysregulated inflammation. pH-responsive hydrogels have been extensively studied for microenvironment-triggered delivery of NSAIDs, corticosteroids, and natural anti-inflammatory agents.¹⁴ The dual-responsive hydrogel co-loaded with amikacin and naproxen was reported to provide combined antibacterial and anti-inflammatory therapy, reducing pro-inflammatory markers and supporting pro-healing responses in infected wound models.¹³¹ Natural compounds such as curcumin and polyphenols, which provide combined antioxidant, anti-inflammatory, and antimicrobial actions, are frequently encapsulated within nano-carriers or covalently conjugated into pH-sensitive hydrogels to overcome their poor solubility and instability.¹³¹ In vivo studies of curcumin nano-formulations within hydrogels have reported faster wound closure, reduced oxidative stress and inflammatory cytokine levels, and improved angiogenesis or collagen deposition in diabetic and other experimental wound models.¹³²

In smart wound dressings, it is crucial to distinguish between intrinsic (contact mediated) and extrinsic (release mediated) antibacterial mechanisms, as each contributes differently to antimicrobial efficacy and clinical performance. Intrinsic antibacterial activity originates from the fixed chemical characteristics of the dressing matrix itself, enabling bacterial inactivation without the release of active compounds. For example, native or quaternized chitosan exhibits antibacterial activity largely through electrostatic interactions between protonated amine groups or permanently charged quaternary ammonium groups and negatively charged bacterial envelope components, such as lipopolysaccharides in Gram-negative bacteria and teichoic acids in Gram-positive bacteria, which can disrupt membrane integrity and promote leakage of intracellular contents.¹³³ In contrast, extrinsic antibacterial activity relies on the controlled diffusion and release of incorporated antimicrobial agents, including antibiotics such as levofloxacin, antimicrobial peptides, or ion-releasing/particle-based agents such as silver nanoparticles, which can establish broader antimicrobial zones and may be useful for managing heavily colonized, infected, or deeper wound regions when combined with appropriate clinical management. However, release-based systems may also introduce challenges such as localized cytotoxicity, unintended exposure of healthy tissue, burst release, and, in the case of conventional antibiotics, the potential development of microbial resistance. Therefore, achieving an optimal balance between these two strategies is essential for successful clinical translation, with intrinsic contact-active materials minimizing antimicrobial burden and extrinsic agents being selectively employed through stimuli-responsive mechanisms, such as pH-triggered release, to provide targeted therapy in wounds with elevated bacterial colonization or high bioburden.^134,135

4.2 Delivery of growth factors, antioxidants, and other biotherapeutics

Growth factors such as EGF, bFGF, VEGF, and PDGF promote fibroblast proliferation, keratinocyte migration, and angiogenesis but may suffer from rapid degradation and off target effects when applied freely. Encapsulating these proteins in nanoparticles, microparticles, or hydrogel matrices may enable sustained local delivery, partial protection from proteolysis, and more controlled release aligned with wound-healing requirements.¹³⁶ For instance, recent investigative efforts have developed a dual drug co-loaded nanoparticle/hydrogel system (EGF-Cur-NP/H), in which EGF and curcumin loaded nanoparticles are dispersed in an in situ gel forming hydrogel matrix designed for topical wound therapy. In a full thickness excisional wound model, EGF-Cur-NP/H was reported to enhance wound closure, granulation tissue formation, collagen deposition, and angiogenesis compared with saline, blank NP/H, Cur-NP/H, or EGF-NP/H, confirming the benefit of co-delivering a growth factor and antioxidant from a controlled release hydrogel depot.¹³⁷

Analogously, other researchers have used pH-responsive microcarrier composite hydrogels to deliver VEGF in response to local pH changes, thereby enhancing neovascularization and perfusion in bacterially infected wounds. Platelet rich plasma (PRP) encapsulated into ROS/pH dual responsive hydrogels has also shown prolonged release of platelet derived cytokines and growth factors, leading to improved re-epithelialization and collagen maturation in vivo compared with free PRP or non responsive matrices.¹³⁸ Excessive ROS and chronic oxidative stress impair all phases of wound repair, making antioxidants attractive cargos for pH and ROS-responsive hydrogels. Curcumin loaded nanocomposite hydrogels are the most extensively studied: nanoencapsulation improves its solubility and stability, while pH sensitive matrices provide triggered release, resulting in significant reductions in oxidative stress and inflammation and increased antioxidant enzyme levels and angiogenesis in diabetic and chemically injured wound models.¹³⁹

Peptide based hydrogels with inherent antibacterial and antioxidant activity have been engineered to respond to wound pH, showing rapid haemostasis, strong bactericidal effects, and accelerated wound closure in vivo. Nanozyme-containing hydrogels that exploit intrinsic enzyme-mimicking catalytic activities (such as superoxide dismutase- or catalase-like activities) to combine active ROS scavenging with pH-triggered release represent another promising direction, particularly for diabetic wounds where redox imbalance and alkaline pH coexist.¹⁴⁰ Additional biotherapeutics such as exosomes, nucleic acids, and engineered cells are being integrated into pH-responsive hydrogels to enable immunomodulation or gene regulation, although these remain largely at the preclinical proof-of-concept stage.¹⁶ The overall performance of various pH-responsive hydrogels in preclinical wound models is summarized in Table 4.

Table 4 Performance of pH-responsive hydrogels in preclinical wound models

Hydrogel system	Polymer type	Trigger pH	Payload	Release behaviour	Wound model	Healing outcome	Limitations	Ref.
Chitosan-based hydrogel	Natural polysaccharide (chitosan)	Alkaline pH (∼7.5–8.5)	Antibacterial drugs/growth factors	Swelling-mediated controlled release	Diabetic rat wound	∼40–50% faster wound closure	Limited mechanical strength; rapid degradation	141
Alginate–silver hydrogel	Alginate + silver nanoparticles	Broad alkaline-responsive	Silver ions (Ag^+)	Sustained antimicrobial ion release	Infected full-thickness wound	Significant bacterial reduction and faster healing	Cytotoxicity risk with prolonged silver exposure	142 and 143
GelMA pH-responsive hydrogel	Gelatin methacryloyl (GelMA)	Mild acidic-neutral shift	Cells/cytokines/bioactive molecules	Enzyme- and pH-mediated gradual release	Murine excisional wound	Enhanced angiogenesis and collagen deposition	Poor long-term mechanical stability	144
Composite bioinspired hydrogel	Hybrid polymer composite	High pH sensitivity	Multifactorial therapeutic agents	Smart adaptive release	Chronic ischemic wound	Complete epithelialization	Complex synthesis and scalability issues	145
Schiff-base cross-linked hydrogel	Dynamic imine-linked polymers	Acidic pH (<6.5)	Antibiotics/antimicrobial agents	Acid-labile bond cleavage → rapid release	MRSA-infected wound	Rapid bacterial clearance	Premature degradation in highly acidic environments	146 and 147
Zwitterionic pH-responsive hydrogel	Zwitterionic polymers	Charge switching (∼pH 6–7)	Anti-biofilm agents	Charge-triggered surface release	Biofilm-associated wound	Reduced biofilm formation	Limited drug-loading capacity	148
Dual-responsive (pH/redox) hydrogel	Synthetic multifunctional polymer	Acidic pH + oxidative stress	Antioxidants/drugs	Sequential smart release	Diabetic ischemic wound	Accelerated granulation tissue formation	Manufacturing complexity	149
Polydopamine-modified hydrogel	PDA-functionalized composite polymer	Broad pH (5–8)	Antioxidants/antimicrobials	Sustained responsive release	Infected excisional wound	Reduced inflammation and faster closure	Potential oxidative instability	150 and 151
Exosome-loaded pH hydrogel	Natural/synthetic hybrid hydrogel	Mild acidic sensitivity	Stem cell-derived exosomes	Triggered regenerative cargo release	Diabetic chronic ulcer model	Improved vascularization and remodelling	High production cost; exosome instability	152 and 153
Injectable self-healing hydrogel	Dynamic covalent polymer network	pH-adaptive	Drugs/biologics	Shear-responsive injectable release	Irregular deep wounds	Complete defect filling	Limited load-bearing strength	154 and 155
Nanocomposite pH-responsive hydrogel	Polymer + nanoparticles	Strong acidic response	Antibiotics/anti-inflammatory drugs	Sustained and targeted release	Infected deep tissue wound	Reduced inflammatory cytokines	Nanoparticle toxicity concerns	156 and 157
Carboxymethyl chitosan/oxidized dextran hydrogel	Modified polysaccharide composite	Acidic infection pH (<6.0)	Antimicrobial matrix (intrinsic)	Rapid initial matrix degradation	Full-thickness MRSA rat wound	Complete bioburden eradication; 92% wound closure by Day 10	Requires secondary protective securement film	158

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4.3 In vitro and in vivo pharmacological outcomes

Across antibiotic, antiseptic, anti-inflammatory, growth factor, and antioxidant loaded platforms, pH-responsive hydrogels have frequently shown improved pharmacological performance in preclinical studies compared with corresponding non-responsive matrices or conventional formulations, although outcomes remain highly dependent on formulation design, wound model, payload, and evaluation endpoint.¹⁵⁹ In vitro, they exhibit pH dependent swelling and drug release, high antibacterial and antibiofilm activity, ROS scavenging, and cytocompatibility with keratinocytes and fibroblasts, while helping preserve the bioactivity of selected encapsulated proteins or small molecules under formulation-specific conditions.¹⁶⁰ In vivo, studies using full-thickness, infected, and diabetic wound models have reported several recurring benefits, including faster wound closure, improved re-epithelialization, more organized granulation tissue and collagen deposition, and enhanced angiogenesis with increased VEGF expression or microvessel density.¹⁶¹ Many systems also achieve substantial reductions in bacterial load and biofilm formation, decreases in pro-inflammatory cytokines (e.g., TNF-α, IL-6), and normalization of oxidative stress markers, particularly when dual or multimodal responsiveness (pH + ROS, pH + temperature) is combined with rational drug or growth factor selection.¹⁶² These findings collectively support pH-responsive, drug-loaded hydrogels as next generation smart wound dressings that unify infection control, inflammation resolution, redox balance, and tissue regeneration within a single adaptable platform. For clinical translation, future research must standardize animal models and endpoints, directly compare smart hydrogels with guideline recommended dressings, and address manufacturing, sterilization, and regulatory issues; selected well-characterized candidates with strong safety, efficacy, and manufacturability data may then justify further translational development and early-phase clinical evaluation.¹⁶³

To improve cross-study comparability, descriptive in vivo performance data should be translated into standardized quantitative outcome metrics. The primary benchmark for macroscopic healing efficacy is the wound closure rate (WCR), calculated as:

WCR (%) = [(A₀ − A_t)/A₀] × 100

where A₀ is the initial wound area at day 0 and A_t is the remaining open wound area at evaluation day t. Because wound models, initial defect sizes, infection status, animal species, and evaluation time points differ substantially among studies, WCR values should be interpreted together with experimental context rather than compared as isolated percentages. Accordingly, in vivo assessment of pH-responsive hydrogels should report WCR at defined time points, such as day 7, 14, or 21, together with histological and biological indicators of repair. Critical analysis of literature datasets suggests that some bioinspired pH-responsive hydrogels can achieve high wound-closure rates in selected full-thickness murine wound models; however, universal mean values should not be stated unless derived from a formal meta-analysis with defined inclusion criteria, model stratification, and statistical methodology. Beyond macroscopic closure, translationally relevant in vivo evaluation requires standardized microscopic metrics, including collagen volume fraction (quantified via Masson's trichrome staining density), epithelial tongue length (μm), and microvascular density (MVD, quantified by the number of CD31⁺ vessels per unit area). Integrating these parameters enables a more rigorous comparison of whether pH-triggered hydrogel platforms merely accelerate superficial wound contraction or genuinely promote infection control, inflammation resolution, angiogenesis, extracellular matrix remodeling, and functional tissue repair. Some marketed bioinspired hydrogel wound dressings are given in Table 5.

Table 5 Marketed conventional and bioinspired hydrogel wound dressings: distinction from truly pH-responsive systems

S. no.	Product	Type/constituents	Primary function	Bioinspired or pH-related features/limitation	Typical indications
Most marketed products listed in this table are conventional moisture-regulating or bioinspired hydrogel dressings rather than true pH-responsive systems with programmed pH-triggered swelling, degradation, or therapeutic release.
1	Microdacyn wound care hydrogel	Sterile hydrogel dressing (hypochlorous acid based)	Maintains moist wound environment; supports autolytic debridement	Hydrogel interacts with exudate; acid base interaction can help microenvironment balance in wounds (pH of wound exudate influences swelling/absorption)	Acute & chronic wounds, burns, abrasions
2	Convatec sterile gel	Amorphous hydrogel (water based)	Moisture retention; promotes granulation	Hydrophilic polymer matrix that adapts to wound fluid pH/exudate volume (indirect pH adaptivity)	Chronic ulcers, pressure sores, burn wounds
3	Amerigel wound dressing tube	Advanced hydrogel dressing	Moisture balance; optimize healing	Polymer network interacts with wound pH/exudate to regulate fluid handling (general hydrogel behaviour)	Dry/necrotic wounds; rehydration needed
4	Lysil hydrogels medical dressing	Hydrogel matrix	Provides moist wound healing environment	Standard hydrogel physicochemical behaviour may respond to changes in wound fluid composition (including pH shifts)	Acute/chronic skin wounds
5	McKesson hydrogel amorphous dressing	Non sterile amorphous hydrogel	Moisture and cooling effect	Traditional hydrogel fluid interaction; supports moist wound environment influenced by wound pH dynamics	Minor burns, cuts, superficial wounds
6	DermaSyn	Water based hydrogel (with vitamin E)	Hydration & wound protection	Moisture retention; polymeric matrix interacts with wound fluid pH gradients in healing wounds (not explicitly pH-responsive)	Chronic wounds, partial thickness wounds
7	Neoheal hydrogel	Agar/PEG/PVP hydrogel	Moisture balance & soothing	Moist healing environment; polymers interact with wound fluid environments, including pH variations	Ulcers, burns, abrasions
8	Restore hydrogel (Hollister)	Hyaluronic acid + gauze	Moisture & ECM mimicry	HA mimics extracellular matrix and supports cell migration; interacts with pH shifts during healing phases	Chronic wounds, cavities
9	ActivHeal hydrogel	Water rich hydrogel	Moist healing & cushioning	Polymer hydrogel responding physically to wound fluid composition, indirectly influenced by wound pH/exudate changes	Leg ulcers, diabetic foot
10	NU-GEL (Systagenix)	Sodium alginate based hydrogel	Exudate management & moisture	Alginate hydrogels are known for ionic interactions that can be modulated by wound pH/exudate composition	Ulcers, leg wounds
11	Purilon (Coloplast)	Calcium alginate/carboxymethylcellulose hydrogel	Moisture balance, autolytic debridement	Alginate/CMC hydrogels interact with wound fluid pH & ions during gel formation and exudate absorption	Burns, chronic wounds

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Although most pH-responsive hydrogel wound dressings have been evaluated in rodent excisional, diabetic, infected, or full-thickness wound models, large-animal studies remain limited. This represents an important translational gap because porcine skin more closely resembles human skin in epidermal thickness, dermal architecture, collagen organization, hair follicle density, and wound contraction behaviour. Large-animal models also enable more realistic evaluation of dressing adhesion, mechanical durability, exudate handling, dosing frequency, safety, and therapeutic performance over clinically relevant wound sizes. Therefore, future studies should prioritize standardized large-animal wound models, where appropriate, before clinical translation to better predict performance in human chronic and infected wounds.

The growing evidence surrounding drug-loaded pH-sensitive hydrogels underscores their considerable therapeutic potential in wound healing, particularly through localized and stimuli-responsive delivery of antimicrobials, anti-inflammatory agents, growth factors, antioxidants, and other biotherapeutics. Collectively, in vitro and in vivo investigations have demonstrated improvements in infection control, inflammatory modulation, tissue regeneration, and wound closure kinetics, reinforcing the promise of these systems as multifunctional therapeutic platforms. Nevertheless, pharmacological efficacy alone is insufficient to ensure successful clinical translation. The transition from experimental formulations to clinically deployable wound therapeutics necessitates careful consideration of pharmaceutical development constraints, including formulation stability, sterilization compatibility, safety profiling, reproducible manufacturing, and regulatory compliance. Accordingly, the following section critically examines the developmental and regulatory challenges that shape the translational viability of pH-responsive bioinspired hydrogels for wound care.

5. Pharmaceutical development challenges and regulatory outlook

The translation of advanced hydrogel-based wound dressings from laboratory-scale innovation to industrial and clinical implementation is associated with significant challenges involving scalable manufacturing, terminal sterilization, long-term storage stability, functional stability under repeated pH cycling, and regulatory quality assurance. Large-scale production of natural polymer-based hydrogels is frequently constrained by inherent variability in raw material characteristics, including batch-to-batch differences in molecular weight, degree of functionalization, purity, viscosity, and rheological properties, which can hinder continuous manufacturing processes and compromise formulation reproducibility. For pH-responsive hydrogels, this variability is particularly important because small changes in functional group density, gelation kinetics, or crosslinking efficiency may shift the pH-transition threshold, swelling ratio, mechanical strength, and drug-release profile. In parallel, pharmaceutical development of these systems requires robust formulation control through systematic frameworks such as Quality by Design (QbD), alongside compliance with stringent safety, biocompatibility, and regulatory standards necessary for clinical translation.¹⁶⁴

In addition to manufacturing and stability considerations, the long-term safety profile of pH-responsive hydrogels requires careful evaluation because these materials may remain in contact with injured tissue for prolonged periods and undergo progressive swelling, erosion, or degradation. Particular attention should be given to the biological fate of degradation byproducts, residual monomers, unreacted crosslinkers, catalysts, and released nanomaterials or metal ions, as these components may induce cytotoxicity, irritation, delayed inflammation, sensitization, or impaired tissue remodeling. Therefore, future translational studies should assess not only acute cytocompatibility but also chronic local tissue responses, degradation-product clearance, hemocompatibility where relevant, local immune compatibility, and safety after repeated pH-triggered swelling–deswelling cycles.

Sterilization remains a particularly critical barrier for stimuli-responsive hydrogel platforms, as conventional methods may adversely affect their functional integrity. Steam autoclaving can induce thermal hydrolysis, polymer relaxation, or premature degradation of dynamic pH-sensitive covalent linkages, such as imine or hydrazone bonds, while gamma irradiation or high-dose electron beam treatment may generate free radicals that promote polymer chain scission, uncontrolled crosslinking, drug degradation, or reductions in mechanical properties, including G. Ethylene oxide sterilization may avoid thermal damage but introduces concerns regarding residual toxicity and prolonged degassing, whereas UV sterilization has limited penetration in opaque or thick hydrogel matrices. To address these limitations, alternative strategies, including aseptic manufacturing, sterile filtration of precursor solutions before gelation, terminal sterilization optimization, lyophilized sterile hydrogel precursors, and lower-dose radiation protocols, are being explored but require formulation-specific validation.¹⁶⁵

Furthermore, maintaining hydrogel stability during long-term storage presents additional formulation challenges, particularly for hydrated systems that are susceptible to syneresis, premature therapeutic payload leakage, microbial contamination, hydrolytic degradation, and oxidative deterioration under ambient conditions. For pH-responsive systems, stability must also be evaluated after repeated swelling–deswelling cycles because cyclic exposure to acidic and alkaline environments may cause network fatigue, irreversible bond cleavage, loss of mechanical recovery, reduced responsiveness, or unintended drug leakage. Consequently, optimization of downstream preservation methods, especially lyophilization protocols with appropriate cryoprotectants or lyoprotectants, is essential to preserve internal pore architecture, enable rapid rehydration, and maintain pH-responsive functionality upon clinical application. Collectively, overcoming these interconnected manufacturing, sterilization, stabilization, pH-cycling, and regulatory barriers is critical for the successful bench-to-bedside translation of next-generation smart hydrogel wound dressings.

5.1 Formulation stability challenges

Maintaining formulation stability demands comprehensive characterization of degradation kinetics under multifaceted stresses including thermal fluctuations, oxidative environments, pH shifts, and mechanical shear during processing or application.¹⁶⁶ For wound dressings incorporating bioactive agents like growth factors or antimicrobials, stability profiles often reveal accelerated hydrolysis in moist wound milieus, necessitating lyoprotectants such as trehalose or polymer matrices like chitosan for sustained release.¹⁶⁷ ICH Q1A(R2) mandates tiered stability protocols—real time (25 °C/60% RH), accelerated (40 °C/75% RH), and stress testing to delineate impurity profiles and establish retest periods, yet challenges persist in predicting long term performance for novel nano formulations where Arrhenius modelling falters due to non linear kinetics (ICH, 2009).

QbD addresses these by defining Critical Quality Attributes (CQAs) like assay potency (>95%), degradation products (<1%), and viscosity, then employing Failure Mode and Effects Analysis (FMEA) to prioritize risks from excipient API interactions.¹⁶⁸ Design of Experiments (DoE) elucidates design spaces, for instance, optimizing hydroxypropyl methylcellulose (HPMC) levels to balance mucoadhesion and erosion in hydrogel dressings, thereby minimizing batch to batch variability.¹⁶⁹ Persistent gaps include scalability from lab to pilot, where amorphous dispersions recrystallize, underscoring needs for in line PAT like Raman spectroscopy for real time monitoring.¹⁷⁰

Regulatory pathways for bioinspired pH sensitive hydrogels are evolving but stringent, and these systems may be regulated as combination products under FDA's Center for Drug Evaluation and Research (CDER) or EMA's centralized procedure, necessitating dual chemistry, manufacturing, and controls (CMC) dossiers.¹⁷¹ Classified as drug device combos (21 CFR 3.2(e)), they require master files for polymer excipients, with bioinspired elements scrutinized for immunogenicity via ICH S6(R1) guidelines. Pre-IND meetings emphasize QbD approaches to define CQAs (e.g., precise equilibrium swelling ratios matched to exudate volume, and controlled matrix erosion kinetics aligned with clinical dressing change intervals). For drug-containing hydrogel wound dressings, stability testing may be guided by ICH Q1A(R2) using product-appropriate long-term and accelerated storage conditions, while degradation-product profiling and in vitro release testing should be performed using validated, product-specific analytical methods and IVRT/IVPT configurations suitable for semi-solid or hydrogel-based topical matrices. Photostability (Q1B) addresses UV induced crosslinking rupture.¹⁷² Phase I/II trials focus on PK/PD correlation with imaging (e.g., MRI for swelling), while post approval REMS monitor hypersensitivity. Lot-release specifications may include pH-response behavior, swelling ratio, rheological properties, mechanical integrity, sterility, endotoxin limits where relevant, and drug-release performance, but acceptable ranges must be justified using validated assays and product-specific clinical requirements. Development timelines and regulatory pathways vary substantially depending on product classification, novelty, risk profile, therapeutic claims, manufacturing complexity, and the extent of required nonclinical and clinical evidence. Factors in regulatory pathways for pH sensitive bioinspired hydrogel given in Table 6.

Table 6 Regulatory pathways for pH sensitive bioinspired hydrogel

S. no.	Challenge category	Key issues	Mitigation strategies	Regulatory implication	Ref.
1	Formulation Stability	Variability, hydrolysis, fragility	Hybrid crosslinking, lyophilization	ICH Q1A compliance	173
2	Scalability	Low yields, sterilization effects	Continuous flow synthesis	GMP scale up validation	174
3	Biocompatibility	Inflammation, fibrosis	Surface PEGylation	ICH S6 testing	175
4	Drug interactions	Aggregation, burst release	Ion exchange tuning	USP dissolution specs	176

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5.1.1. Sterilization considerations. Sterilization is a critical yet challenging aspect of pharmaceutical development for bioinspired pH sensitive hydrogels, as these materials must be rendered free of viable microorganisms while preserving their intricate pH-responsive properties, mechanical integrity, and drug loading capacity. Unlike conventional small molecule drugs, the porous, hydrated structure of hydrogels—often composed of natural polymers like chitosan or alginate renders them highly susceptible to structural alterations during sterilization, potentially shifting pH transition thresholds, inducing chain scission, or triggering premature crosslinking. This section delves into key sterilization considerations, evaluating common methods, their impacts, and mitigation strategies within the broader context of formulation stability and regulatory compliance.

Sterilization of terminally sterile wound dressings grapples with preserving thermosensitive APIs, as moist heat (121 °C, 15 psi) denatures proteins in collagen scaffolds, while dry heat exacerbates Maillard reactions in carbohydrate based systems.¹⁷⁷ Radiation methods gamma (25–40 kGy) or e-beam induce free radical mediated peroxidation in poly(vinyl alcohol) hydrogels, compromising mechanical integrity, whereas ethylene oxide (EtO) residuals pose cytotoxicity risks per ISO 11135 limits (<1 ppm) (Parenteral Drug Association, 2008). Aseptic processing can avoid direct terminal-sterilization stress on sensitive hydrogel matrices and bioactive payloads, but it does not eliminate contamination risk; therefore, it requires validated sterile processing, environmental and particulate monitoring, and cleanroom controls consistent with applicable GMP requirements, such as EU GMP Annex 1 where relevant.

QbD optimizes via Critical Process Parameters (CPPs) such as irradiation dose, dwell time, and shielding, modelled through DoE to achieve overkill factors (e.g., bioburden <10 CFU per unit) without CQAs deviation.¹⁷⁸ Emerging alternatives like supercritical CO₂ or vaporized H₂O₂ show promise for heat labile antimicrobials like silver nanoparticles, with cycle development leveraging FMEA to balance microbial lethality and product stability. Validation hurdles include dose mapping nonuniformity in heterogeneous dressings and post sterilization leachable, necessitating extractables/leachable studies per USP 〈1663〉.¹⁷⁹ Bioinspired pH sensitive hydrogels demand sterilization techniques that achieve a sterility assurance level (SAL) of 10⁻⁶ while minimizing physicochemical changes, as mandated by ISO 11135, ISO 17665, and USP 〈71〉 guidelines.¹⁸⁰ Autoclaving at 121 °C/15 psi for 15–20 minutes is cost effective and penetrates well but induces hydrolytic degradation in pH labile bonds (e.g., Schiff bases or esters), potentially reducing molecular weight by 20–40% and broadening pH sensitivity windows by 0.5–1.0 pH units due to partial ionization of pendant groups. Swelling ratios can increase by 150–300% post autoclaving from chain relaxation, leading to burst release of encapsulated drugs (up to 30% payload loss).¹⁸¹ Natural polymer hydrogels like alginate chitosan hybrids fare worst, with gel sol transitions observed after multiple cycles. Moist heat exacerbates microbial residue inactivation but accelerates Maillard reactions in proteinaceous bioinspired components.¹⁸²

Gamma irradiation (25–40 kGy Co-60 source) offers deep penetration ideal for bulk hydrogel formulations but generates ROS that cleave C–C and C–O bonds, thereby decreasing overall polymer molecular weight and crosslinking density. Comparatively, electron beam (E-beam, 10–25 kGy) provides faster processing with less penetration (suitable for thin slabs <10 cm), yet induces radiolysis of water, forming peroxides that oxidize ionizable groups and reduce responsiveness e.g., carboxylic acid protonation efficiency drops from 90% to 70%. Bioinspired motifs (e.g., peptide crosslinkers) suffer dose dependent racemization, compromising biocompatibility. Furthermore, matrix-drug interactions can degrade, leading to the premature oxidation or inactivation of sensitive incorporated antimicrobial or antioxidant payloads.¹⁸³ EtO gas penetrates hydrogels effectively at 30–50 °C but leaves cytotoxic residuals (ethylene chlorohydrin, ethylene glycol) detectable up to 14 days post-aeration, potentially violating biocompatibility thresholds established by ISO 10993-7 guidelines and risking localized tissue irritation when applied to exposed wound beds. Hydrogen peroxide plasma (e.g., STERRAD) is milder for heat sensitive gels, achieving SAL via low temperature vapor (45–55 °C), but penetrates poorly into dense matrices (>2 mm thick), leaving 10³–10⁴ CFU g⁻¹ residuals and oxidizing sulfhydryl groups in bioinspired thiomer hydrogels.¹⁸⁴

Sterile filtration of precursor solutions followed by aseptic filling or in situ gelation under ISO 5/Grade A critical processing conditions can avoid direct sterilization of the final hydrogel, but this strategy requires sterile-grade raw materials, filter-compatibility validation, validated hold times, environmental monitoring, particulate control, and process validation. Supercritical CO₂ or UV-C irradiation (254 nm) shows promise for surface sterilization but fails for internal sterility in opaque, swollen gels. The bioinspired architecture amplifies sterilization vulnerabilities: hierarchical porosity traps contaminants, while natural polymers foster biofilm formation pre sterilization.¹⁸⁵ Crosslink fracture reduces compressive modulus from 0.2 MPa to <0.05 MPa, risking syringeability loss in injectable formats.¹⁸⁶ pH shifts during sterilization (e.g., +0.3 units from carboxyl loss) can trigger payload precipitation, destabilizing sensitive biotherapeutics or growth factors incorporated within the matrix.¹⁸⁷ Sterilization exacerbates polydispersity, with coefficient of variation in release kinetics jumping from 10% to 35%.¹⁸⁸ Sterilization of pH sensitive bioinspired hydrogels given in Table 7.

Table 7 Sterilization of pH sensitive bioinspired hydrogels

Sterilization method	SAL achievement	Key impacts on hydrogels	Mitigation	SAL verification	Ref.
Autoclaving	Excellent	Hydrolysis, pH shift (+0.5 units)	Stabilizers, short cycles	Biological indicators (Geobacillus)	189
Gamma Irradiation	Excellent	ROS chain scission (20% Mw loss)	Antioxidants, low dose	Dosimetry (alanine)	190
E-beam	Good (shallow)	Peroxide formation, oxidation	Lyophilization	F0 cycle validation	191
EtO	Excellent	Residuals toxicity	Extended aeration	Residual gas chromatography	192
Aseptic processing	Variable	No direct damage	Cleanroom grade A	Media fills USP 〈797〉	193

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5.1.2 Regulatory considerations. Advanced drug-delivery systems may be regulated as combination products (drug + device). Regulatory bodies such as the U.S. FDA and EMA evaluate both pharmaceutical and device aspects concurrently because the matrix material itself directly influences payload pharmacokinetics. Conversely, if hydrogels are intended solely for structural support or wound fluid management, they may be evaluated strictly under device regulations. Furthermore, when hydrogel components are derived from biological sources (e.g., alginate, chitosan), additional scrutiny regarding biological sourcing, purity, and immunogenicity applies.¹⁷¹ Sterilized hydrogel products are not automatically classified as terminally sterilized combination products; their regulatory pathway depends on intended use, product composition, jurisdiction, and primary mode of action, while sterilization validation and release requirements should be justified according to the selected sterilization method, product classification, and applicable regulatory standards. Parametric release may be considered for appropriately validated terminal sterilization processes, particularly moist-heat sterilization, when critical physical CPPs are shown to assure sterility, but acceptance criteria and validation requirements must be established product-specifically. Post-sterilization stability should include product-specific assessment of physicochemical stability, sterility or microbial quality where relevant, degradation products, extractables/leachables, mechanical properties, pH responsiveness, and release performance; ICH Q1A(R2) may guide drug-containing products, whereas microbial and sterility tests should be selected according to product classification and intended use. Early regulatory interactions may help clarify product classification, sterilization strategy, CMC expectations, nonclinical testing, and clinical-development requirements, but no single sterilization method or CMC timeline should be assumed for all hydrogel platforms. Noncompliance risks full batch rejection, underscoring sterilization as a pivotal CMC bottleneck in advancing these platforms to market. US FDA Guidance for combination products (21 CFR Parts 3, 4, 5). Depending on the primary mode of action (PMOA), hydrogels could fall under CDER (drugs) or CDRH (devices).¹⁹⁴

5.1.3. Quality by design framework. The QbD approach is now mainstream in complex DDS development and is strongly encouraged by ICH guidance (Q8–Q11). For pH sensitive hydrogels, QbD ensures robust, consistent performance by identifying and controlling variability.¹⁹⁵ QbD reorients development from empirical formulation toward knowledge-driven design, beginning with a Quality Target Product Profile (QTPP) that defines product-specific attributes such as intended wound type, dressing residence time, exudate-management capacity, antimicrobial duration, moisture-vapour transmission, mechanical integrity, pH responsiveness, drug-release profile, sterility, and biocompatibility. Risk assessment tools, such as FMEA and fishbone diagrams, identify high-impact Critical Material Attributes (CMAs)—such as the alginate guluronic-to-mannuronic (G/M) acid ratio, polymer molecular weight, or nanofiber diameter—which feed directly into a DoE framework to establish a robust design space where specific CPPs maintain desired product CQAs.¹⁹⁶ ICH Q12 provides tools for lifecycle management and structured post-approval change management, but any regulatory flexibility depends on the approved control strategy, established conditions, product type, and jurisdiction-specific assessment. Future trajectories integrate AI-driven DoE and real time release testing (RTRT) via NIR, enhancing agility amid supply chain volatilities.¹⁹⁷

The QbD framework for bioinspired pH sensitive hydrogels begins with the establishment of a Target Product Profile (TPP), which defines the intended clinical application, route of administration, dosage form, release characteristics, and critical performance requirements, including a predictable swelling response to physiological pH variations, adequate mechanical integrity, and biocompatibility thresholds. For wound-healing applications, the TPP may specify clinically relevant pH responsiveness across acidic, neutral, or alkaline wound conditions depending on the target wound type, together with controlled or stimulus-triggered release kinetics, adequate mechanical integrity, local tolerability, cytocompatibility, and hemocompatibility where blood contact is relevant. CQAs are subsequently identified to ensure product performance and safety, encompassing polymer molecular weight distribution, cross link density and network homogeneity, pH-responsive swelling ratio, drug loading and release efficiency, and acceptable limits for residual solvents, leachables, and extractables. These CQAs are directly influenced by CMAs and Critical CPPs, including monomer purity, crosslinker chemistry, initiator concentration, drug polymer interaction characteristics, polymerization temperature, mixing shear rates, curing duration, and drying protocols. Systematic risk assessment tools such as FMEA and DoE are employed to quantitatively establish relationships between CMAs, CPPs, and CQAs, enabling robust process understanding and optimization. A comprehensive control strategy is then implemented, incorporating in process monitoring methods such as real time rheological measurements and particle size analysis, alongside product release tests including pH triggered responsiveness assays, dissolution or release profiling, and validated stability indicating methods. Lifecycle management is maintained through continuous process verification using Process Analytical Technology (PAT) and structured post approval change management in alignment with prevailing regulatory expectations. Benefits of QbD are enhanced predictability, robustness, streamlined regulatory submissions with stronger justification of specifications, reduced batch failures and faster tech transfers.

5.2. Safety and biocompatibility

Safety profiling for advanced wound dressings should follow a risk-based biological evaluation strategy, including cytotoxicity, sensitization, irritation or intracutaneous reactivity, and other endpoints as appropriate for contact duration, wound condition, degradation products, and material composition; residual reactive crosslinkers such as glutaraldehyde require careful control because they can contribute to cytotoxicity, irritation, or sensitization.¹⁹⁸ Biocompatibility considerations favour materials that promote a moist wound healing environment, such as hydrocolloids and foams. Some synthetic polymers may contribute to foreign-body responses depending on their chemistry, surface properties, degradation behavior, and implantation context; however, fibrotic responses should not be attributed universally to polyurethane or silicone through a single TLR4-mediated mechanism. In contrast, natural polymers such as hyaluronan are generally biocompatible, but their biological effects can depend on molecular weight, purity, modification chemistry, endotoxin burden, degradation fragments, and batch-to-batch consistency.¹⁹⁹ Systemic absorption of active components like silver sulfadiazine or zinc oxide mandates thorough genotoxicity (Ames test) and sensitization assessments, paired with rigorous extractables and leachables qualification thresholds tailored to topical application configurations.

QbD links CMAs (e.g., crosslinking density) to biocompatibility CQAs through multivariate models, iteratively refining via in vitro 3D skin equivalents and ex vivo porcine models.²⁰⁰ Clinical translation challenges include interpatient variability in protease rich chronic wounds degrading scaffolds prematurely, addressed by enzyme responsive linkers.²⁰⁰

A comprehensive safety evaluation of pH-responsive dressings requires careful characterization of their local and, where relevant, systemic safety profiles, degradation pathways, and formulation reproducibility. Although many natural polysaccharides are generally considered biocompatible, their chemical modification, crosslinking chemistry, residual reagents, and degradation products can introduce distinct biological risks. For example, hydrogels crosslinked through dynamic covalent imine chemistry may undergo pH-dependent hydrolysis or bond exchange, generating amine- and aldehyde-containing polymer fragments or residual reactive groups under acidic or alkaline conditions. If reactive dialdehydes such as glutaraldehyde are used, residual crosslinker and degradation-product levels must be tightly controlled because they may cause cytotoxicity, oxidative stress, irritation, sensitization, or delayed inflammatory responses. Therefore, contemporary design should prioritize lower-toxicity crosslinking strategies, such as appropriately purified oxidized polysaccharides or genipin, while still verifying residual reagents, degradation products, and biological safety for each formulation. Genipin is often considered less cytotoxic than glutaraldehyde and has been widely explored as a natural crosslinker, but its degradation products, residual content, dose-dependent effects, and clearance should be evaluated formulation-specifically rather than assumed to be universally benign. Additionally, when non-biodegradable synthetic polymers such as poly(acrylic acid) are incorporated, their persistence, local retention, degradation behavior, extractables/leachables, and tissue compatibility should be evaluated, particularly for dressings intended for prolonged or repeated application. Thus, translational development should evaluate degradation-product profiles, residual crosslinker content, extractables/leachables, pH-cycling stability, and batch-to-batch reproducibility before clinical application.

5.3 Regulatory pathways for safety evaluation

Bioinspired pH sensitive hydrogels must meet stringent safety requirements because they interact intimately with biological systems. Regulatory agencies require a comprehensive safety dossier detailing the toxicological profile of all device components and chemical precursors. Biocompatibility testing must be conducted per ISO 10993 series, including, cytotoxicity (ISO 10993-5), sensitization and irritation (ISO 10993-10), systemic toxicity and implantation studies if applicable. These tests verify that hydrogel materials and degradation byproducts do not elicit harmful local or systemic responses.²⁰¹ Many pH sensitive hydrogels degrade via hydrolysis or enzymatic processes. Regulatory bodies expect identification of degradation pathways, characterization of by-products (chemical identity, concentration) and toxicity profiling (in vitro and in vivo). This aligns with regulatory expectations regarding the safety evaluation of degradation products derived from novel biomaterials and topical combination systems.²⁰²

Pharmacokinetic and pharmacodynamic studies are conducted to evaluate drug release kinetics in physiologically relevant pH environments and to establish a correlation between polymer swelling behaviour and drug bioavailability. These studies provide a mechanism based justification for product performance. Before progressing to human trials, efficacy and safety are typically demonstrated in appropriate animal models.²⁰³ For products intended for clinical use, regulatory submission is required in the form of an Investigational New Drug application (IND) or a Clinical Evaluation Report (CER), depending on the product category and jurisdiction. Clinical development generally involves phase I–III trials for therapeutic agents, performance evaluation in the intended patient population, and the establishment of post marketing surveillance plans to ensure long term safety and effectiveness. In parallel, there is a critical need for standardization of characterization methods. The absence of universally accepted protocols for assessing pH-responsiveness remains a challenge. Regulatory authorities may require harmonized compendial methods, and demonstration of cross laboratory reproducibility is considered essential for regulatory approval.²⁰⁴

Because the translation from bench to industrial scale introduces potential variability in hydrogel network formation, regulatory filings must include detailed manufacturing controls. Furthermore, rigorous validation of sterilization processes is mandatory to account for potential gamma irradiation or thermal effects on hydrogel network integrity, which must be accompanied by an environmental risk assessment (ERA) for manufacturing effluents alongside comprehensive worker safety data for handling raw monomers, crosslinkers, and polymerization initiators.¹⁷¹ Integrating a systematic QbD approach, rigorous safety evaluation per ISO/ICH standards, and early regulatory engagement is essential for advancing bioinspired pH sensitive hydrogels to clinical and commercial success. Collaboration with regulators and adoption of emerging guidance on nanomaterials and smart DDS will streamline approval pathways and ensure patient safety.^205,206

Beyond regulatory compliance, clinical translation requires a more critical consideration of how pH-responsive hydrogels will perform in real wound-care settings. Human chronic wounds are highly heterogeneous, with differences in diabetes status, ischemia, infection severity, biofilm composition, exudate burden, protease activity, immune dysfunction, and local pH distribution. Therefore, hydrogels optimized in simplified buffer systems or small rodent wounds may not reproduce the same swelling, adhesion, degradation, or drug-release behaviour in complex human wounds. Future translational studies should compare pH-responsive hydrogels against guideline-recommended commercial dressings, use clinically relevant endpoints such as time to closure, bacterial burden, pain, exudate control, dressing-change frequency, recurrence, and scarring quality, and include large-animal validation before clinical trials. These considerations are essential for determining whether pH-responsive hydrogels can progress from promising experimental biomaterials to practical wound-care products.

Stable and clinically effective pH-responsive hydrogels require careful control of formulation stability, sterilization, and degradation to preserve drug activity, mechanical integrity, and pH sensitivity. QbD and regulatory frameworks (ICH, FDA, EMA, ISO) guide optimization of critical quality attributes, manufacturing consistency, and safety evaluation. Successful clinical translation depends on validated sterilization methods, proven biocompatibility, and rigorous regulatory approval to ensure safe, scalable, and reliable wound dressing products. Bridging the gap between experimental promise and clinical realization requires the formulation of coherent design rules capable of integrating pharmaceutical performance, safety, quality considerations, and regulatory expectations into a unified developmental framework for pH-responsive hydrogel wound dressings.

6. Design rules and decision framework for pH-responsive hydrogel wound dressings

Despite the prolific expansion of pH-responsive hydrogel literature, a profound “translational stagnation” persists, where high performing laboratory prototypes rarely transition into clinical wound care.²⁰⁷ The gap between the lab and the clinic exists because research often focuses on a simple ‘on/off’ pH response in controlled settings. In reality, the chronic wound environment is far more chaotic, involving fluctuating exudate volumes and enzymatic activity that these simplified models fail to account for.^207,208 To move beyond incremental summarization of “smart” materials, it is imperative to establish a hierarchical decision framework that integrates wound pathophysiology, hydrogel design principles, and therapeutic outcomes (Fig. 3). Such a framework must reconcile the chemical kinetics of pH-responsiveness with the physiological imperatives of wound chronicity, ensuring that material sensitivity is not merely a laboratory curiosity but a targeted response to the specific pathological thresholds of persistent tissue alkalinity or localized micro-environmental deviations.

Fig. 3 Design framework for pH-responsive hydrogel wound dressings. The schematic links wound microenvironmental cues to hydrogel design and therapeutic outcomes. Chronic wounds exhibit pH shifts, biofilms, enzymes, ROS, and exudate. Rational hydrogel design enables pH-dependent drug release and may support controlled therapeutic delivery, antibacterial activity, inflammation reduction, and tissue regeneration.

A key design rule is to ensure ‘trigger fidelity’, which means the hydrogel responds precisely to the specific pH levels of the wound. This requires matching the material's chemical reaction to the narrow pH changes that occur as a wound becomes chronic or infected. While the transition from the “acid mantle” of healthy skin (pH 4.5–6.0) to the alkaline state of chronic or infected wounds (pH 7.0–9.0) provides a clear theoretical switch,²⁰⁹ critical evaluation reveals that many current systems lack the sensitivity to distinguish between subtle physiological fluctuations and true pathological shifts. Effective design requires moving beyond simple binary “on/off” swelling. Instead, the incorporation of alkaline-responsive motifs must be strategically calibrated to a specific pK_a window that suppresses premature drug leakage at the acidic-to-neutral pH values characteristic of healthy healing tissue, while ensuring rapid network ionization and payload mobilization at or above the pH 8.0 threshold typical of chronic bacterial colonization. Conversely, for early stage acidic management, the challenge lies in maintaining structural integrity against the degradative enzymes of the exudate while exploiting mild acidity for controlled therapeutic flux. Ultimately, the decision framework must prioritize “responsiveness to noise” ratios, ensuring that dynamic bonding equilibria are tuned to physiological realities rather than idealized laboratory buffers.

The choice of triggering mechanism is a key design consideration in pH-responsive hydrogels, as chemical responsiveness must be balanced with the structural stability required for effective wound protection. In polymeric networks, pH-dependent behaviour is engineered by exploiting shifts in the hydrophilic–hydrophobic balance via the ionization of pendant functional groups, or by driving controlled alterations in crosslinking density through the reversible cleavage or rearrangement of dynamic covalent crosslinks.^210,211 Polymers containing ionizable groups such as carboxyl or amine moieties may undergo protonation or deprotonation depending on environmental pH, leading to changes in network swelling, permeability, and diffusion of encapsulated therapeutic agents. Although ionization driven swelling offers a predictable mechanism for stimulus responsive drug release, excessive hydration may reduce mechanical integrity and compromise the protective function of the dressing. Alternatively, hydrogels can incorporate dynamic covalent bonds such as Schiff base linkages or boronate ester interactions. These bonds may break or rearrange under specific pH conditions, leading to controlled degradation of the hydrogel network and triggered release of therapeutic agents.²¹² However, the reversible nature of these chemistries can also affect stability in complex wound environments. Consequently, hybrid crosslinking strategies that combine a stable structural backbone with pH-labile linkages are increasingly explored to balance mechanical robustness with responsive drug delivery.

Beyond pH–triggered drug release, hydrogel wound dressings must also meet several practical requirements for effective wound management. While traditional reviews often treat functions such as moisture retention and microbial protection as secondary features, these properties are increasingly recognized as key determinants of clinical performance. Accordingly, effective dressings should maintain a moist environment, absorb exudate, provide a barrier against microbial contamination, and support tissue repair processes.²¹³ These functional demands create a balance between stimulus responsiveness and mechanical reliability at the wound interface. For example, incorporating bioinspired motifs such as catechol groups can improve adhesion to wet tissues, but excessive crosslinking intended to strengthen the hydrogel network may restrict swelling and reduce pH-responsiveness. Natural biopolymers, including polysaccharides and proteins, are often attractive because of their biocompatibility and similarity to extracellular matrix components, although their batch to batch variability can complicate large scale production. As a result, many current strategies favour hybrid hydrogel architectures that combine a synthetic polymer backbone for mechanical stability and reproducibility with bioinspired functional groups that provide biological activity and pH-responsive drug release.

To transition from empirical “trial and error” synthesis to a predictive design science, the field must adopt a rigorous benchmarking strategy that moves beyond heterogeneous, study specific metrics. Current studies report widely varying polymer compositions, pH trigger windows, therapeutic cargos, and biological outcomes, which complicates direct comparison between systems.²¹² Comparative evaluation nevertheless highlights a recurring balance between responsiveness and structural stability. Highly dynamic architectures, such as networks incorporating reversible boronate ester linkages, may enable rapid pH-triggered drug release but can lack the mechanical durability required for multi day wound dressing applications. In contrast, densely crosslinked hydrogels often provide superior mechanical strength but may respond more slowly to environmental changes, leading to delayed therapeutic release. These observations suggest that benchmarking should assess not only whether a hydrogel responds to pH changes, but also how effectively drug release aligns with the physiological demands of the wound environment. Establishing standardized performance criteria may therefore help determine whether responsive hydrogel systems offer meaningful advantages over conventional wound dressings.

The path from benchtop to bedside is hindered by a “translational gap” that many laboratory scale studies fail to critically address: the biological unpredictability of the wound interface. Wound pH can vary substantially among patients and may fluctuate during different stages of healing, which complicates the precise tuning of stimulus-responsive materials. In addition, biofilm formation and protein rich wound exudates can modify the local chemical environment and partially buffer pH changes, potentially reducing the responsiveness of hydrogel systems.²¹⁴ Beyond biological variability, practical considerations such as sterilization methods, long term storage stability, and large scale reproducibility of polymer synthesis must also be addressed. For example, highly dynamic or complex hydrogel architectures may exhibit desirable pH-triggered behaviour in laboratory settings but can lose structural integrity or responsiveness during sterilization processes or prolonged storage. Consequently, the design of next generation pH-responsive hydrogels should incorporate early evaluation of physiological variability, material stability, and manufacturing feasibility to ensure that responsive biomaterials can realistically progress toward clinical wound care applications.

Taken together, the rational design of pH-responsive hydrogel wound dressings requires a decision framework that integrates wound physiology, polymer chemistry, and therapeutic function. Rather than simply incorporating pH-sensitive components, future systems should be designed so that their physicochemical responses are aligned with the evolving biochemical conditions of the wound environment. In particular, matching hydrogel responsiveness to the alkaline or near neutral pH typically associated with chronic and infected wounds may improve the timing and efficiency of therapeutic release. At the same time, successful designs must balance stimulus responsiveness with practical requirements such as mechanical stability, scalability of synthesis, and regulatory feasibility. By integrating these considerations, pH-responsive hydrogel platforms may progress from experimental responsive materials toward clinically useful wound-care systems capable of delivering therapeutics in a controlled and context-dependent manner.

A clear distinction must be established between conventional hydrogel dressings and advanced smart, stimulus responsive hydrogel platforms when assessing the current commercial and translational landscape. Commercially available hydrogel dressings, such as Purilon® Gel and Intrasite® Gel, primarily function as passive moisture retentive or water donating matrices, facilitating wound hydration and autolytic debridement. However, these systems lack engineered responsive macromolecular networks and are therefore incapable of modulating their physicochemical behaviour, including swelling dynamics or therapeutic release profiles, in response to changes within the wound microenvironment.²¹⁵ In contrast, truly pH-responsive hydrogel systems currently undergoing advanced preclinical evaluation and early phase clinical investigation are designed with specialized chemical functionalities, such as ionizable polymeric frameworks or acid labile molecular linkages. These smart architectures remain inert under physiological skin conditions but undergo selective structural or functional activation in response to the alkaline shifts characteristic of chronic and infected wound environments.²⁰¹

A primary driver of translational stagnation in smart wound care is the heavy reliance on small animal models, which fail to accurately replicate human skin physiology. Most preclinical proof of concept evaluations are conducted on rodents. However, mice and rats possess a dense panniculus carnosus muscle layer, meaning their wounds heal primarily through contraction rather than the re-epithelialization and granulation tissue formation characteristic of humans. Furthermore, rodent skin is loose and possesses distinct immunological and vascular architectures, resulting in a tolerance to bacterial colonization that does not accurately reflect human wound pathology. To achieve meaningful clinical translation, advanced hydrogels must be validated in large animal models, preferably porcine.²¹⁶ White Duroc or Landrace pigs feature thick, firmly adherent epidermis, sparse hair, and vascular structures that closely mirror human skin architecture, making their healing kinetics highly predictive of human outcomes. However, moving into large animal validation introduces severe economic barriers to commercialization. The cost of running porcine chronic wound models is exponentially higher than rodent studies. This is further complicated by high industrial scaling costs and strict regulatory classifications, where hydrogels loaded with active pharmaceutical payloads are designated as combination device drug products. This classification requires expensive, multi centre phase I–III clinical trials, creating an economic bottleneck that often deters venture capital investment and stalls promising prototypes at the benchtop stage.²¹⁷ Despite promising laboratory results, pH-responsive hydrogels face major translational barriers due to complex wound environments, limited trigger precision, and challenges in balancing responsiveness with mechanical stability. Successful clinical design requires a predictive framework integrating wound physiology, polymer chemistry, and practical dressing functions such as moisture control, durability, and scalable manufacturing. Advancing these smart hydrogels to bedside use depends on standardized benchmarking, validation in human-like large animal models, and overcoming regulatory and economic hurdles.

7. Conclusion and future perspectives

Bioinspired pH-responsive hydrogels have emerged as a promising class of advanced wound dressings, transforming conventional passive barriers into dynamic, microenvironment-responsive therapeutic platforms capable of simultaneously sensing pathological changes and delivering targeted interventions. By exploiting wound-associated pH variations linked to infection, inflammation, and delayed tissue repair, these materials enable controlled and localized therapeutic release while recapitulating essential structural and biological features of the extracellular matrix. Recent advances in natural polymer engineering, particularly involving chitosan, alginate, collagen, and hyaluronic acid, combined with bioinspired strategies such as catechol-mediated adhesion and dynamic covalent crosslinking, have enabled multifunctional hydrogel systems with enhanced tissue adhesion, mechanical adaptability, intrinsic antimicrobial performance, and regenerative bioactivity. Preclinical evidence consistently demonstrates improved wound closure rates, enhanced angiogenesis, and superior collagen remodelling compared with conventional dressings, highlighting their significant therapeutic potential.

However, several critical translational challenges remain unresolved, including variability in wound pH dynamics across different pathological states, long-term hydrogel stability under physiologically fluctuating and highly exudative conditions, reproducible large-scale manufacturing of naturally derived polymers, and the need for standardized regulatory frameworks. Several key unanswered questions also remain in the field. First, it is still unclear how reliably pH-responsive hydrogels can distinguish transient physiological pH fluctuations during normal repair from sustained pathological pH shifts associated with bacterial infection, chronic inflammation, or microbial biofilm formation. Second, the extent to which these systems can maintain predictable and reversible swelling-deswelling behaviour under dynamic osmotic stress, high exudate burden, protease activity, and repeated dressing deformation remains insufficiently defined. Third, the relationship between pH-triggered material responses and true biological outcomes, including immune resolution, angiogenesis, collagen remodelling, and prevention of wound recurrence, requires more standardized investigation.

Addressing these limitations will require the development of next-generation hybrid hydrogel architectures that combine robust structural integrity with precisely engineered pH-sensitive domains and move beyond conventional binary polymer systems. Future directions are likely to emphasize the integration of cell-free regenerative therapeutics, including stable plant-derived or mesenchymal stem cell-derived exosomes, to further enhance angiogenesis and tissue repair. Moreover, coupling pH-responsive hydrogels with emerging biosensing technologies, flexible wireless monitoring systems, colorimetric diagnostic interfaces, and advanced fabrication approaches such as 3D bioprinting may enable the development of closed-loop theragnostic wound dressings capable of real-time wound assessment and adaptive modulation of therapeutic release. Collectively, the rational design and interdisciplinary advancement of bioinspired pH-responsive hydrogels hold substantial promise for redefining wound care through personalized, feedback-regulated, and microenvironment-guided regenerative therapy.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research data, software, or code were generated or analysed as part of this review article. All information discussed in this work is derived from previously published literature cited within the manuscript.

Acknowledgements

Authors are thankful to Research and Development Committee, Integral University for providing necessary facilities required for completion of this work and assigning manuscript communication number (MCN-IU/R&D/2026-MCN0004520). The authors acknowledge the use of https://www.BioRender.com for creating some graphical components included in the figures and graphical abstract of this article.

Authors state that they have used Grammarly for grammar correction and language clarity of the manuscript. No AI tool was used for generation of text and authors take full responsibility of the same.

References

1. L. Martinengo, M. Olsson, R. Bajpai, M. Soljak, Z. Upton, A. Schmidtchen, J. Car and K. Järbrink, Prevalence of chronic wounds in the general population: systematic review and meta-analysis of observational studies, Ann. Epidemiol., 2019, 29, 8–15,  DOI:10.1016/j.annepidem.2018.10.005.
2. C. K. Sen, Human Wound and Its Burden: Updated 2022 Compendium of Estimates, Adv. Wound Care, 2023, 12, 657–670,  DOI:10.1089/wound.2023.0150.
3. J. F. Guest, N. Ayoub, T. McIlwraith, I. Uchegbu, A. Gerrish, D. Weidlich, K. Vowden and P. Vowden, Health economic burden that different wound types impose on the UK ‘s National Health Service, Int. Wound J., 2017, 14, 322–330,  DOI:10.1111/iwj.12603.
4. P. Schilrreff and U. Alexiev, Chronic Inflammation in Non-Healing Skin Wounds and Promising Natural Bioactive Compounds Treatment, Int. J. Mol. Sci., 2022, 23, 4928,  DOI:10.3390/ijms23094928.
5. G. Patroklou, E. Triantafyllopoulou, P.-E. Goula, V. Karali, M. Chountoulesi, G. Valsami, S. Pispas and N. Pippa, pH-Responsive Hydrogels: Recent Advances in Pharmaceutical Applications, Polymers, 2025, 17, 1451,  DOI:10.3390/polym17111451.
6. Z. Li, R. Chen, Z. Hao, Y. E, Q. Guo, J. Li and S. Zhu, Hydrogel inspired by “adobe” with antibacterial and antioxidant properties for diabetic wound healing, Mater. Today Bio, 2025, 31, 101477,  DOI:10.1016/j.mtbio.2025.101477.
7. K. Ding, M. Liao, Y. Wang and J. R. Lu, Advances in Composite Stimuli-Responsive Hydrogels for Wound Healing, Mechanisms and Applications, Gels, 2025, 11, 420,  DOI:10.3390/gels11060420.
8. Q. T. H. Shubhra, Iron oxide nanoparticles in magnetic drug targeting and ferroptosis-based cancer therapy, Med. Rev., 2023, 3, 444–447,  DOI:10.1515/mr-2023-0029.
9. A. Oyane, H. Araki, M. Nakamura, Y. Shimizu, Q. T. H. Shubhra, A. Ito and H. Tsurushima, Controlled superficial assembly of DNA-amorphous calcium phosphate nanocomposite spheres for surface-mediated gene delivery, Colloids Surf., B, 2016, 141, 519–527,  DOI:10.1016/j.colsurfb.2016.02.010.
10. A. K. M. M. Alam, M. D. H. Beg, R. M. Yunus, M. R. Islam and Q. T. H. Shubhra, Tailoring the dispersibility of non-covalent functionalized multi-walled carbon nanotube (MWCNT) nanosuspension using shellac (SL) bio-resin: Structure-property relationship and cytotoxicity of shellac coated carbon nanotubes (SLCNTs), Colloids Interface Sci. Commun., 2021, 42, 100395,  DOI:10.1016/j.colcom.2021.100395.
11. X. Jia, Z. Dou, Y. Zhang, F. Li, B. Xing, Z. Hu, X. Li, Z. Liu, W. Yang and Z. Liu, Smart Responsive and Controlled-Release Hydrogels for Chronic Wound Treatment, Pharmaceutics, 2023, 15, 2735,  DOI:10.3390/pharmaceutics15122735.
12. Y. Gou, L. Hu, X. Liao, J. He and F. Liu, Advances of antimicrobial dressings loaded with antimicrobial agents in infected wounds, Front. Bioeng. Biotechnol., 2024, 12, 1431949,  DOI:10.3389/fbioe.2024.1431949.
13. J. Jia, X. Wang, T. Zhang, Q. Sun, S. Yang and W. Wu, Stimuli-responsive hydrogels based on cascade reactions: a novel strategy to promote the efficient repair of diabetic wounds, Theranostics, 2026, 16, 3105–3135,  DOI:10.7150/thno.126282.
14. Y. E. Moon, J.-O. Jeong and H. Choi, Inflammation-Responsive Hydrogels in Perioperative Pain and Wound Management: Design Strategies and Emerging Potential, Gels, 2025, 11, 691,  DOI:10.3390/gels11090691.
15. H. Xue, C. Zhang, D. Lin, Q. Gu, C. Sun, X. Lin, C. Zhang, L. Lei and L. Liu, Isoliquiritigenin micellar microneedle for pH monitoring and diabetic wound healing, Mater. Today Bio, 2025, 35, 102356,  DOI:10.1016/j.mtbio.2025.102356.
16. M.-H. Fan, J.-K. Pi, C.-Y. Zou, Y.-L. Jiang, Q.-J. Li, X.-Z. Zhang, F. Xing, R. Nie, C. Han and H.-Q. Xie, Hydrogel-exosome system in tissue engineering: A promising therapeutic strategy, Bioact. Mater., 2024, 38, 1–30,  DOI:10.1016/j.bioactmat.2024.04.007.
17. K. Järbrink, G. Ni, H. Sönnergren, A. Schmidtchen, C. Pang, R. Bajpai and J. Car, The humanistic and economic burden of chronic wounds: a protocol for a systematic review, Syst. Rev., 2017, 6, 15,  DOI:10.1186/s13643-016-0400-8.
18. S. R. Nussbaum, M. J. Carter, C. E. Fife, J. DaVanzo, R. Haught, M. Nusgart and D. Cartwright, An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds, Value Health, 2018, 21, 27–32,  DOI:10.1016/j.jval.2017.07.007.
19. M. Olsson, K. Järbrink, U. Divakar, R. Bajpai, Z. Upton, A. Schmidtchen and J. Car, The humanistic and economic burden of chronic wounds: A systematic review, Wound Repair Regen., 2019, 27, 114–125,  DOI:10.1111/wrr.12683.
20. C. K. Sen, Human Wound and Its Burden: Updated 2020 Compendium of Estimates, Adv. Wound Care, 2021, 10, 281–292,  DOI:10.1089/wound.2021.0026.
21. V. Falanga, R. R. Isseroff, A. M. Soulika, M. Romanelli, D. Margolis, S. Kapp, M. Granick and K. Harding, Chronic wounds, Nat. Rev. Dis. Primers, 2022, 8, 50,  DOI:10.1038/s41572-022-00377-3.
22. X. Han, L. S. Ju and J. Irudayaraj, Oxygenated Wound Dressings for Hypoxia Mitigation and Enhanced Wound Healing, Mol. Pharm., 2023, 20, 3338–3355,  DOI:10.1021/acs.molpharmaceut.3c00352.
23. K. S. Hussien, G. T. Abdulmughni, A. M. Othman, H. Z. Al-Shami, N. M. Al-Haidary, R. M. Assayaghi and K. H. Jahzer, Antimicrobial susceptibility patterns of bacteria isolated from wound infections in Al-Bayda Governorate -Yemen, BMC Infect. Dis., 2025, 25, 868,  DOI:10.1186/s12879-025-11250-5.
24. G. Akkus and M. Sert, Diabetic foot ulcers: A devastating complication of diabetes mellitus continues non-stop in spite of new medical treatment modalities, World J. Diabetes, 2022, 13, 1106–1121,  DOI:10.4239/wjd.v13.i12.1106.
25. S. Holloway and S. Bradbury, Wound dressings, Surgery, 2024, 42, 805–813,  DOI:10.1016/j.mpsur.2024.08.009.
26. R. Laurano, M. Boffito, G. Ciardelli and V. Chiono, Wound dressing products: A translational investigation from the bench to the market, Eng. Regener., 2022, 3, 182–200,  DOI:10.1016/j.engreg.2022.04.002.
27. M. P. Ferraz, Wound Dressing Materials: Bridging Material Science and Clinical Practice, Appl. Sci., 2025, 15, 1725,  DOI:10.3390/app15041725.
28. L. Zhao, J. Chen, B. Bai, G. Song, J. Zhang, H. Yu, S. Huang, Z. Wang and G. Lu, Topical drug delivery strategies for enhancing drug effectiveness by skin barriers, drug delivery systems and individualized dosing, Front. Pharmacol., 2024, 14, 1333986,  DOI:10.3389/fphar.2023.1333986.
29. C. Choi, S. Vafaei-Nodeh, J. Phillips and G. de Gannes, Approach to allergic contact dermatitis caused by topical medicaments, Can. Fam. Physician, 2021, 67, 414–419,  DOI:10.46747/cfp.6706414.
30. B. D. Gimza and J. E. Cassat, Mechanisms of Antibiotic Failure During Staphylococcus aureus Osteomyelitis, Front. Immunol., 2021, 12, 638085,  DOI:10.3389/fimmu.2021.638085.
31. L. Soraci, A. Cherubini, L. Paoletti, G. Filippelli, F. Luciani, P. Laganà, M. E. Gambuzza, E. Filicetti, A. Corsonello and F. Lattanzio, Safety and Tolerability of Antimicrobial Agents in the Older Patient, Drugs Aging, 2023, 40, 499–526,  DOI:10.1007/s40266-023-01019-3.
32. J. Aisa and M. Parlier, Local wound management: A review of modern techniques and products, Vet. Dermatol., 2022, 33, 463–478,  DOI:10.1111/vde.13104.
33. O. T. Olubodun, Beyond the bandage: Smart dressings and the future of wound care, InnovAiT, 2026, 19, 297–302,  DOI:10.1177/17557380261416858.
34. C. Casadidio and R. Censi, Prospects of Hydrogels in Wound Healing: Toward the Next Generation of Smart Biomaterials, Pharmaceutics, 2025, 17, 1486,  DOI:10.3390/pharmaceutics17111486.
35. W. Su, J. Chen, Y. Zhang, X. Luo, C. Lin and P. Li, Chitosan/agarose hydrogel dressing: pH response real-time monitoring and chemo-/photodynamic therapy synergistic treatment of infected wounds, Int. J. Biol. Macromol., 2024, 277, 134513,  DOI:10.1016/j.ijbiomac.2024.134513.
36. P. Yang, Y. Hu, Y. Ju, N. Hsiung, J. Ye, A. Jian, L. Lei and B. Fang, DNA–Inspired Multi–Functional Double–Cross–Linking Self–Healing Hydrogel Promotes the Healing of Diabetic Wounds, Adv. Sci., 2026, 13, e13784,  DOI:10.1002/advs.202513784.
37. I. S. Protsak and Y. M. Morozov, Fundamentals and Advances in Stimuli-Responsive Hydrogels and Their Applications: A Review, Gels, 2025, 11, 30,  DOI:10.3390/gels11010030.
38. N. Raina, R. Pahwa, J. Bhattacharya, A. K. Paul, V. Nissapatorn, M. de Lourdes Pereira, S. M. R. Oliveira, K. G. Dolma, M. Rahmatullah, P. Wilairatana and M. Gupta, Drug Delivery Strategies and Biomedical Significance of Hydrogels: Translational Considerations, Pharmaceutics, 2022, 14, 574,  DOI:10.3390/pharmaceutics14030574.
39. J. Cao, P. Yuan, B. Wu, Y. Liu and C. Hu, Advances in the Research and Application of Smart-Responsive Hydrogels in Disease Treatment, Gels, 2023, 9, 662,  DOI:10.3390/gels9080662.
40. S. Khattak, I. Ullah, M. T. Yousaf, S. Ullah, H. Yousaf, Y. Li, H. Jin, J. Shen and H.-T. Xu, Advancements in hydrogels: A comprehensive review of natural, synthetic, and hybrid innovations for wound healing, Int. J. Biol. Macromol., 2025, 327, 147270,  DOI:10.1016/j.ijbiomac.2025.147270.
41. P. Sim, X. L. Strudwick, Y. Song, A. J. Cowin and S. Garg, Influence of Acidic pH on Wound Healing In Vivo: A Novel Perspective for Wound Treatment, Int. J. Mol. Sci., 2022, 23, 13655,  DOI:10.3390/ijms232113655.
42. A. R. M. Ribeiro, B. A. S. Oliveira, A. I. Barbosa, C. L. Seabra, S. Reis and H. P. Felgueiras, Nanomaterial-based scaffolds endowed with halochromic properties for skin healing purposes, J. Drug Delivery Sci. Technol., 2025, 108, 106950,  DOI:10.1016/j.jddst.2025.106950.
43. J. Guo, Y. Cao, Q.-Y. Wu, Y.-M. Zhou, Y.-H. Cao and L.-S. Cen, Implications of pH and Ionic Environment in Chronic Diabetic Wounds: An Overlooked Perspective, Clin., Cosmet. Invest. Dermatol., 2024, 17, 2669–2686,  DOI:10.2147/CCID.S485138.
44. E. Padan, E. Bibi, M. Ito and T. A. Krulwich, Alkaline pH homeostasis in bacteria: New insights, Biochim. Biophys. Acta, Biomembr., 2005, 1717, 67–88,  DOI:10.1016/j.bbamem.2005.09.010.
45. L.-P. Tricou, M.-L. Al-Hawat, K. Cherifi, G. Manrique, B. R. Freedman and S. Matoori, Wound pH-Modulating Strategies for Diabetic Wound Healing, Adv. Wound Care, 2024, 13, 446–462,  DOI:10.1089/wound.2023.0129.
46. A. Jin, H. Xue, Z. Jia, Y. Wang, C. Sun, L. Lei and X. Lin, NIR/pH–Responsive Multifunctional Hydrogel for Monitoring and Treating Diabetic Wounds, Adv. Healthcare Mater., 2026, 15, e05403,  DOI:10.1002/adhm.202505403.
47. J.-D. Rembe, M. Witte, N. Ertas, J. Dissemond, W. Garabet, M. Hovhannisyan, K. Beckamp, H. Schelzig, M. U. Wagenhäuser and E. K. Stuermer, pH profiling reveals progressive wound acidification during healing and higher pH in chronic non-healing wounds: a prospective, multicenter cohort study, Sci. Rep., 2026, 16, 10522,  DOI:10.1038/s41598-026-45000-7.
48. I. Yamberla, C. Pupiales, A. J. Chiliquinga, T. Sulca-Villamarín, A. Plasencia, F. Cabrera Aulestia, R. F. Díaz, A. Caicedo and P. M. Barba, Pseudomonas aeruginosa Pathogenicity and Its Interaction with Other Microorganisms During the Skin Wound Healing Process, Int. J. Mol. Sci., 2025, 26, 9677,  DOI:10.3390/ijms26199677.
49. Y. Shi, S. Guo, J. Tian, X. Xie, J. Shi, X. Zhang and C. Wang, Biomaterials-mediated sequential drug delivery: Emerging trends for wound healing, Asian J. Pharm. Sci., 2025, 20, 101088,  DOI:10.1016/j.ajps.2025.101088.
50. B. Cullen and A. Gefen, The biological and physiological impact of the performance of wound dressings, Int. Wound J., 2023, 20, 1292–1303,  DOI:10.1111/iwj.13960.
51. E. M. Jones, C. A. Cochrane and S. L. Percival, The Effect of pH on the Extracellular Matrix and Biofilms, Adv. Wound Care, 2015, 4, 431–439,  DOI:10.1089/wound.2014.0538.
52. H. L. Haller, F. Sander, D. Popp, M. Rapp, B. Hartmann, M. Demircan, S. P. Nischwitz and L. P. Kamolz, Oxygen, pH, Lactate, and Metabolism—How Old Knowledge and New Insights Might Be Combined for New Wound Treatment, Medicina, 2021, 57, 1190,  DOI:10.3390/medicina57111190.
53. K. Gao and K. Xu, Advancements and Prospects of pH-Responsive Hydrogels in Biomedicine, Gels, 2025, 11, 293,  DOI:10.3390/gels11040293.
54. V. Vardan, Influence of pH on the Stability of Pharmaceutical Compounds in Japan, J. Chem., 2024, 3, 21–30,  DOI:10.47672/jchem.2404.
55. M. Rahban, F. Ahmad, M. A. Piatyszek, T. Haertlé, L. Saso and A. A. Saboury, Stabilization challenges and aggregation in protein-based therapeutics in the pharmaceutical industry, RSC Adv., 2023, 13, 35947–35963,  10.1039/D3RA06476J.
56. A. Zhao, J. Sun and Y. Liu, Understanding bacterial biofilms: From definition to treatment strategies, Front. Cell. Infect. Microbiol., 2023, 13, 1137947,  DOI:10.3389/fcimb.2023.1137947.
57. D. Anokwah, E. Asante-Kwatia, J. Asante, D. Obeng-Mensah, C. A. Danquah, I. K. Amponsah, E. O. Ameyaw, R. P. Biney, E. Obese, L. Oberer, D. G. Amoako, A. L. K. Abia and A. Y. Mensah, Antibacterial, Resistance Modulation, Anti-Biofilm Formation, and Efflux Pump Inhibition Properties of Loeseneriella africana (Willd.) N. Halle (Celastraceae) Stem Extract and Its Constituents, Microorganisms, 2023, 12, 7,  DOI:10.3390/microorganisms12010007.
58. W. X. Hong, M. S. Hu, M. Esquivel, G. Y. Liang, R. C. Rennert, A. McArdle, K. J. Paik, D. Duscher, G. C. Gurtner, H. P. Lorenz and M. T. Longaker, The Role of Hypoxia-Inducible Factor in Wound Healing, Adv. Wound Care, 2014, 3, 390–399,  DOI:10.1089/wound.2013.0520.
59. J. Guo, Y. Cao, Q.-Y. Wu, Y.-M. Zhou, Y.-H. Cao and L.-S. Cen, Implications of pH and Ionic Environment in Chronic Diabetic Wounds: An Overlooked Perspective, Clin., Cosmet. Invest. Dermatol., 2024, 17, 2669–2686,  DOI:10.2147/CCID.S485138.
60. A. Krejner and T. Grzela, Modulation of matrix metalloproteinases MMP-2 and MMP-9 activity by hydrofiber-foam hybrid dressing – relevant support in the treatment of chronic wounds, Cent. Eur. J. Immunol., 2015, 40, 391–394,  DOI:10.5114/ceji.2015.54605.
61. T. A. Wilgus, S. Roy and J. C. McDaniel, Neutrophils and Wound Repair: Positive Actions and Negative Reactions, Adv. Wound Care, 2013, 2, 379–388,  DOI:10.1089/wound.2012.0383.
62. I. Cavallo, F. Sivori, A. Mastrofrancesco, E. Abril, M. Pontone, E. G. Di Domenico and F. Pimpinelli, Bacterial Biofilm in Chronic Wounds and Possible Therapeutic Approaches, Biology, 2024, 13, 109,  DOI:10.3390/biology13020109.
63. W. Ma, Z. Huang, Y. Zhang, K. Liu, D. Li and Q. Liu, Interaction between inflammation and biofilm infection and advances in targeted biofilm therapy strategies, Microbiol. Res., 2025, 298, 128199,  DOI:10.1016/j.micres.2025.128199.
64. J. Dawi, K. Tumanyan, K. Tomas, Y. Misakyan, A. Gargaloyan, E. Gonzalez, M. Hammi, S. Tomas and V. Venketaraman, Diabetic Foot Ulcers: Pathophysiology, Immune Dysregulation, and Emerging Therapeutic Strategies, Biomedicines, 2025, 13, 1076,  DOI:10.3390/biomedicines13051076.
65. X. Ding, P. Kakanj, M. Leptin and S. A. Eming, Regulation of the Wound Healing Response during Aging, J. Invest. Dermatol., 2021, 141, 1063–1070,  DOI:10.1016/j.jid.2020.11.014.
66. M. Ju, Y. Kim and K. W. Seo, Role of nutrition in wound healing and nutritional recommendations for promotion of wound healing: a narrative review, Ann. Clin. Nutr. Metab., 2023, 15, 67–71,  DOI:10.15747/ACNM.2023.15.3.67.
67. A. T. Hofmann, P. Slezak, S. Neumann, J. Ferguson, H. Redl and R. Mittermayr, Ischemia Impaired Wound Healing Model in the Rat—Demonstrating Its Ability to Test Proangiogenic Factors, Biomedicines, 2023, 11, 1043,  DOI:10.3390/biomedicines11041043.
68. B. Wernick, P. Nahirniak and S. P. Stawicki, Impaired Wound Healing, 2026.
69. A. Mansilha and J. Sousa, Pathophysiological Mechanisms of Chronic Venous Disease and Implications for Venoactive Drug Therapy, Int. J. Mol. Sci., 2018, 19, 1669,  DOI:10.3390/ijms19061669.
70. A. M. Howes, N. C. Dea, D. Ghosh, K. Krishna, Y. Wang, Y. Li, B. Morrison, K. C. Toussaint and M. R. Dawson, Fibroblast senescence-associated extracellular matrix promotes heterogeneous lung niche, APL Bioeng., 2024, 8, 026119,  DOI:10.1063/5.0204393.
71. N. Hosseini Mansoub, The role of keratinocyte function on the defected diabetic wound healing, Clin. Diabetol., 2022, 430,  DOI:10.5603/DK.a2022.0004.
72. P. Schilrreff and U. Alexiev, Chronic Inflammation in Non-Healing Skin Wounds and Promising Natural Bioactive Compounds Treatment, Int. J. Mol. Sci., 2022, 23, 4928,  DOI:10.3390/ijms23094928.
73. J. A. Witkowski, L. C. Parish, A. S. Karadag and J. L. Parish, Decubitus ulcers, in Treatment of Skin Disease, Elsevier, 2018, pp. 181–186.  DOI:10.1016/B978-0-7020-6912-3.00054-9.
74. B. Manna, P. Nahirniak and C. A. Morrison, Wound Debridement, 2026.
75. S. Abolhasani, Y. Ahmadi, Y. Rostami, E. Baravar and D. Fattahi, Biomaterials in tissue repair and regeneration: key insights from extracellular matrix biology, Front. Med. Technol., 2025, 7, 1565810,  DOI:10.3389/fmedt.2025.1565810.
76. W.-Y. Quan, Z. Hu, H.-Z. Liu, Q.-Q. Ouyang, D.-Y. Zhang, S.-D. Li, P.-W. Li and Z.-M. Yang, Mussel-Inspired Catechol-Functionalized Hydrogels and Their Medical Applications, Molecules, 2019, 24, 2586,  DOI:10.3390/molecules24142586.
77. W. Zhang, R. Wang, Z. Sun, X. Zhu, Q. Zhao, T. Zhang, A. Cholewinski, F. (Kuo) Yang, B. Zhao, R. Pinnaratip, P. K. Forooshani and B. P. Lee, Catechol-functionalized hydrogels: biomimetic design, adhesion mechanism, and biomedical applications, Chem. Soc. Rev., 2020, 49, 433–464,  10.1039/C9CS00285E.
78. S. Vidovic, J. Stojkovska, M. Stevanovic, B. Balanc, M. Vukasinovic-Sekulic, A. Marinkovic and B. Obradovic, Effects of poly(vinyl alcohol) blending with Ag/alginate solutions to form nanocomposite fibres for potential use as antibacterial wound dressings, R. Soc. Open Sci., 2022, 9, 211517,  DOI:10.1098/rsos.211517.
79. M. Bahadoran, A. Shamloo and Y. D. Nokoorani, Development of a polyvinyl alcohol/sodium alginate hydrogel-based scaffold incorporating bFGF-encapsulated microspheres for accelerated wound healing, Sci. Rep., 2020, 10, 7342,  DOI:10.1038/s41598-020-64480-9.
80. H. Li, C. Teng, J. Zhao and J. Wang, A scalable hydrogel processing route to high-strength, foldable clay-based artificial nacre, Compos. Sci. Technol., 2021, 201, 108543,  DOI:10.1016/j.compscitech.2020.108543.
81. E.-Y. Chuang, C.-W. Chiang, P.-C. Wong and C.-H. Chen, Hydrogels for the Application of Articular Cartilage Tissue Engineering: A Review of Hydrogels, Adv. Mater. Sci. Eng., 2018, 2018, 4368910,  DOI:10.1155/2018/4368910.
82. A. Kaczmarek-Pawelska, Alginate-Based Hydrogels in Regenerative Medicine, in Alginates - Recent Uses of This Natural Polymer, IntechOpen, 2020.  DOI:10.5772/intechopen.88258.
83. I. S. Bayer, Advances in Fibrin-Based Materials in Wound Repair, A Review, Molecules, 2022, 27, 4504,  DOI:10.3390/molecules27144504.
84. Y. Liu, J. Liu, A. Zhang, G. Zhao, B. Jiang and X. Zhao, Application prospect of Marine polysaccharide hydrogels in promoting wound healing: A review, Carbohydr. Res., 2025, 558, 109673,  DOI:10.1016/j.carres.2025.109673.
85. S. B. Behbahani, S. D. Kiridena, U. N. Wijayaratna, C. Taylor, J. N. Anker and T.-R. J. Tzeng, pH variation in medical implant biofilms: Causes, measurements, and its implications for antibiotic resistance, Front. Microbiol., 2022, 13, 1028560,  DOI:10.3389/fmicb.2022.1028560.
86. T. Won, M. Goh, C. Lim, J. Moon, K. Lee, J. Park, K. Chung, Y. Kim, S. Lee, H. J. Hong and K. Gwon, Recent Progress in Cellulose Nanofibril Hydrogels for Biomedical Applications, Polymers, 2025, 17, 2272,  DOI:10.3390/polym17172272.
87. Y. Tang, Z. Fang and H.-J. Lee, Exploring Applications and Preparation Techniques for Cellulose Hydrogels: A Comprehensive Review, Gels, 2024, 10, 365,  DOI:10.3390/gels10060365.
88. P. Zou, J. Yao, Y.-N. Cui, T. Zhao, J. Che, M. Yang, Z. Li and C. Gao, Advances in Cellulose-Based Hydrogels for Biomedical Engineering: A Review Summary, Gels, 2022, 8, 364,  DOI:10.3390/gels8060364.
89. S. Atefyekta, E. Blomstrand, A. K. Rajasekharan, S. Svensson, M. Trobos, J. Hong, T. J. Webster, P. Thomsen and M. Andersson, Antimicrobial Peptide-Functionalized Mesoporous Hydrogels, ACS Biomater. Sci. Eng., 2021, 7, 1693–1702,  DOI:10.1021/acsbiomaterials.1c00029.
90. L. Zhang and R. L. Gallo, Antimicrobial peptides, Curr. Biol., 2016, 26, R14–R19,  DOI:10.1016/j.cub.2015.11.017.
91. H. Zuo, Y. Jiao, J. Chen, S. Tong, Y. Li and W. Zhao, Recent Advances in Smart Stimulus-Responsive Hydrogels for Precision Drug Delivery in Tumours, Gels, 2026, 12, 98,  DOI:10.3390/gels12020098.
92. Q. T. H. Shubhra, A. F. Kardos, T. Feczkó, H. Mackova, D. Horák, J. Tóth, G. Dósa and J. Gyenis, Co-encapsulation of human serum albumin and superparamagnetic iron oxide in PLGA nanoparticles: Part I. Effect of process variables on the mean size, J. Microencapsulation, 2014, 31, 147–155,  DOI:10.3109/02652048.2013.814729.
93. W. Dong, E. Mazzara, A. Sánchez-Baca, K. Mondal, M. Villamiel, R. Babu, D.-W. Sun and B. K. Tiwari, A comparative study on heterogeneous deacetylation of chitin to chitosan under various ultrasound irradiation and characterization, Ultrason. Sonochem., 2026, 128, 107794,  DOI:10.1016/j.ultsonch.2026.107794.
94. G. Wang, X. Fan and C. Zhao, Synergistic Strategies in the Design of Dynamic Hydrogels: Lessons From the Hydrogen Bonding in the Nature, Macromol. Rapid Commun., 2026, e70277,  DOI:10.1002/marc.70277.
95. L. Liu, J. Zheng, S. Li, Y. Deng, S. Zhao, N. Tao, W. Chen, J. Li and Y.-N. Liu, Nitric oxide-releasing multifunctional catechol-modified chitosan/oxidized dextran hydrogel with antibacterial, antioxidant, and pro-angiogenic properties for MRSA-infected diabetic wound healing, Int. J. Biol. Macromol., 2024, 263, 130225,  DOI:10.1016/j.ijbiomac.2024.130225.
96. F. Hong, P. Qiu, Y. Wang, P. Ren, J. Liu, J. Zhao and D. Gou, Chitosan-based hydrogels: From preparation to applications, a review, Food Chem.: X, 2024, 21, 101095,  DOI:10.1016/j.fochx.2023.101095.
97. S. Naveedunissa, R. Meenalotchani, M. Manisha, S. Ankul Singh, S. Nirenjen, K. Anitha, N. Harikrishnan and B. G. Prajapati, Advances in chitosan based nanocarriers for targetted wound healing therapies: a review, Carbohydr. Polym. Technol. Appl., 2025, 11, 100891,  DOI:10.1016/j.carpta.2025.100891.
98. J. Zhang, C. Hurren, Z. Lu and D. Wang, pH-sensitive alginate hydrogel for synergistic anti-infection, Int. J. Biol. Macromol., 2022, 222, 1723–1733,  DOI:10.1016/j.ijbiomac.2022.09.234.
99. A. Pal, J. Bajpai and A. K. Bajpai, Poly (acrylic acid) grafted gelatin nanocarriers as swelling controlled drug delivery system for optimized release of paclitaxel from modified gelatin, J. Drug Delivery Sci. Technol., 2018, 45, 323–333,  DOI:10.1016/j.jddst.2018.03.025.
100. G. Scopelliti, C. Ferraro, O. I. Parisi and M. Dattilo, Recent Developments in Protein-Based Hydrogels for Advanced Drug Delivery Applications, Pharmaceutics, 2026, 18, 74,  DOI:10.3390/pharmaceutics18010074.
101. N. Petit, Y. J. Chang, F. A. Lobianco, T. Hodgkinson and S. Browne, Hyaluronic acid as a versatile building block for the development of biofunctional hydrogels: In vitro models and preclinical innovations, Mater. Today Bio, 2025, 31, 101596,  DOI:10.1016/j.mtbio.2025.101596.
102. X. Peng, Q. Peng, M. Wu, W. Wang, Y. Gao, X. Liu, Y. Sun, D. Yang, Q. Peng, T. Wang, X.-Z. Chen, J. Liu, H. Zhang and H. Zeng, A pH and Temperature Dual-Responsive Microgel-Embedded, Adhesive, and Tough Hydrogel for Drug Delivery and Wound Healing, ACS Appl. Mater. Interfaces, 2023, 15, 19560–19573,  DOI:10.1021/acsami.2c21255.
103. J. Zhang, X. Cai, R. Dou, C. Guo, J. Tang, Y. Hu, H. Chen and J. Chen, Poly(β-amino ester)s-based nanovehicles: Structural regulation and gene delivery, Mol. Ther. – Nucleic Acids, 2023, 32, 568–581,  DOI:10.1016/j.omtn.2023.04.019.
104. L. M. El-Samad, M. A. Hassan, A. A. Basha, S. El-Ashram, E. H. Radwan, K. K. Abdul Aziz, T. M. Tamer, M. Augustyniak and A. E. Wakil, Carboxymethyl cellulose/sericin-based hydrogels with intrinsic antibacterial, antioxidant, and anti-inflammatory properties promote re-epithelization of diabetic wounds in rats, Int. J. Pharm., 2022, 629, 122328,  DOI:10.1016/j.ijpharm.2022.122328.
105. E. M. Bachelder, T. T. Beaudette, K. E. Broaders, J. Dashe and J. M. J. Fréchet, Acetal-Derivatized Dextran: An Acid-Responsive Biodegradable Material for Therapeutic Applications, J. Am. Chem. Soc., 2008, 130, 10494–10495,  DOI:10.1021/ja803947s.
106. R. Gannimani, P. Walvekar, V. R. Naidu, T. M. Aminabhavi and T. Govender, Acetal containing polymers as pH-responsive nano-drug delivery systems, J. Controlled Release, 2020, 328, 736–761,  DOI:10.1016/j.jconrel.2020.09.044.
107. J. Zhang, L.-Y. Chu, Y.-K. Li and Y. M. Lee, Dual thermo- and pH-sensitive poly(N-isopropylacrylamide-co-acrylic acid) hydrogels with rapid response behaviors, Polymer, 2007, 48, 1718–1728,  DOI:10.1016/j.polymer.2007.01.055.
108. Y. Zhou, Y. Yang, R. Liu, Q. Zhou, H. Lu and W. Zhang, Research Progress of Polydopamine Hydrogel in the Prevention and Treatment of Oral Diseases, Int. J. Nanomed., 2023, 18, 2623–2645,  DOI:10.2147/IJN.S407044.
109. C. Hu, L. Long, J. Cao, S. Zhang and Y. Wang, Dual-crosslinked mussel-inspired smart hydrogels with enhanced antibacterial and angiogenic properties for chronic infected diabetic wound treatment via pH-responsive quick cargo release, Chem. Eng. J., 2021, 411, 128564,  DOI:10.1016/j.cej.2021.128564.
110. S. Moayedi, W. Xia, L. Lundergan, H. Yuan and J. Xu, Zwitterionic Polymers for Biomedical Applications: Antimicrobial and Antifouling Strategies toward Implantable Medical Devices and Drug Delivery, Langmuir, 2024, 40, 23125–23145,  DOI:10.1021/acs.langmuir.4c02664.
111. A. J. Rosario and B. Ma, Stimuli-Responsive Polymer Networks: Application, Design, and Computational Exploration, ACS Appl. Polym. Mater., 2024, 6, 14204–14228,  DOI:10.1021/acsapm.4c00002.
112. E. T. Pashuck, Engineering dynamic hydrogels to overcome translational bottlenecks in therapeutic delivery, J. Controlled Release, 2026, 395, 114920,  DOI:10.1016/j.jconrel.2026.114920.
113. O. F. Dingus and M. A. Grunlan, Leveraging Dynamic Electrostatic and Hydrophobic Interactions for Biomedical Hydrogels, ACS Macro Lett., 2026, 15, 487–499,  DOI:10.1021/acsmacrolett.6c00090.
114. T. Kopač, A. Ručigaj and M. Krajnc, The mutual effect of the crosslinker and biopolymer concentration on the desired hydrogel properties, Int. J. Biol. Macromol., 2020, 159, 557–569,  DOI:10.1016/j.ijbiomac.2020.05.088.
115. D. Sinha Roy and B. D. Rohera, Comparative evaluation of rate of hydration and matrix erosion of HEC and HPC and study of drug release from their matrices, Eur. J. Pharm. Sci., 2002, 16, 193–199,  DOI:10.1016/S0928-0987(02)00103-3.
116. J. Shan and W. Jiao, Unveiling the rheological secrets of hydrogels: from lab to clinical translation, RSC Adv., 2026, 16, 16194–16210,  10.1039/D5RA09160H.
117. A. P. Dhand, J. H. Galarraga and J. A. Burdick, Enhancing Biopolymer Hydrogel Functionality through Interpenetrating Networks, Trends Biotechnol., 2021, 39, 519–538,  DOI:10.1016/j.tibtech.2020.08.007.
118. S. Khattak, I. Ullah, H. Xie, X.-D. Tao, H.-T. Xu and J. Shen, Self-healing hydrogels as injectable implants: Advances in translational wound healing, Coord. Chem. Rev., 2024, 509, 215790,  DOI:10.1016/j.ccr.2024.215790.
119. B. E. Nagay, L. Mamizadeh Janghour, L. K. El-Khordagui, B. Akhavan, V. A. R. Barão, V. Dananjaya, C. Abeykoon, S. E. El-Habashy and J. M. Dodda, Multifunctional implantable hydrogels: Smart platforms at the forefront of biomedical innovation, Mater. Today Bio, 2026, 37, 102940,  DOI:10.1016/j.mtbio.2026.102940.
120. P. Nezhad-Mokhtari, M. Hasany, M. Kohestanian, A. Dolatshahi-Pirouz, M. Milani and M. Mehrali, Recent advancements in bioadhesive self-healing hydrogels for effective chronic wound care, Adv. Colloid Interface Sci., 2024, 334, 103306,  DOI:10.1016/j.cis.2024.103306.
121. Y. Li, R. Liang, Y. Ju, R. Pan, L. He, C. Su, Y. Yuan, Q. Lv, L. Yang and B. Li, Magnesium-EGCG composite deer antler decellularized ECM hydrogel for diabetic wound healing, Nano Res., 2026, 19, 94908255,  DOI:10.26599/NR.2025.94908255.
122. B. Yin, Y. Fan, J. Li, C. Li, S. Jiang, X. Li, C. Yan, J. Jiang, P. Wang and C. Jia, ROS-triggered hydrophilicity switching synergizes with pH-responsive nanocarriers for therapy of diabetic wound, Regener. Biomater., 2025, 12, rbaf098,  DOI:10.1093/rb/rbaf098.
123. N. Mohammad, A. Zainab, M. Zahra and A. Mohsen, Stimuli-responsive Systems for Wound Healing, in Carrier-Mediated Gene and Drug Delivery for Dermal Wound Healing, Royal Society of Chemistry, 2023, pp. 215–244.  10.1039/9781837671540-00215.
124. L. Terriac, J.-J. Helesbeux, Y. Maugars, J. Guicheux, M. W. Tibbitt and V. Delplace, Boronate Ester Hydrogels for Biomedical Applications: Challenges and Opportunities, Chem. Mater., 2024, 36, 6674–6695,  DOI:10.1021/acs.chemmater.4c00507.
125. N. Bisht, R. J. Yeo, S. Ramakrishna, S. K. R. S. Sankaranarayanan, C. Dhand and N. Dwivedi, Shape Memorable and Self–Healable Smart Hydrogels and Emerging Directions, Adv. Healthcare Mater., 2026, 15, e03361,  DOI:10.1002/adhm.202503361.
126. M. Yussuf, I. Ugwuanyi, O. Oghenetejiri, C. Awegbe, B. Akinyanju, C. Ifebuzor and E. Olaoye, Peptide Hydrogels as Biocompatible Carriers for Sustained Antibiotic Release Against Multidrug-Resistant Infections, Eur. J. Sci. Res. Rev., 2025, 1, 154–174,  DOI:10.5455/EJSRR.20250307024309.
127. S. Nasra, S. Pramanik, V. Oza, K. Kansara and A. Kumar, Advancements in wound management: integrating nanotechnology and smart materials for enhanced therapeutic interventions, Discover Nano, 2024, 19, 159,  DOI:10.1186/s11671-024-04116-3.
128. J. Wang, Y. Lin, H. Fan, J. Cui, Y. Wang and Z. Wang, ROS/pH Dual-Responsive Hydrogel Dressings Loaded with Amphiphilic Structured Nano Micelles for the Repair of Infected Wounds, Int. J. Nanomed., 2025, 20, 8119–8142,  DOI:10.2147/IJN.S522589.
129. D. Mete, E. Yemeztaşlıca and G. Şanlı-Mohamed, Sorafenib loaded ZIF-8 metal-organic frameworks as a multifunctional nano-carrier offers effective hepatocellular carcinoma therapy, J. Drug Delivery Sci. Technol., 2023, 82, 104362,  DOI:10.1016/j.jddst.2023.104362.
130. F. Zhao, M. Liu, H. Guo, Y. Wang, Y. Zhang, M. He and Z. Cai, Stimuli-responsive hydrogels based on protein/peptide and their sensing applications, Prog. Mater. Sci., 2025, 148, 101355,  DOI:10.1016/j.pmatsci.2024.101355.
131. A. A. Almuraee, Nano-formulated herbal bioactives in animal-based functional foods: A nutritional approach to enhancing bioavailability and health benefits, Appl. Food Res., 2026, 6, 101587,  DOI:10.1016/j.afres.2025.101587.
132. A. Kumari, N. Raina, A. Wahi, K. W. Goh, P. Sharma, R. Nagpal, A. Jain, L. C. Ming and M. Gupta, Wound-Healing Effects of Curcumin and Its Nanoformulations: A Comprehensive Review, Pharmaceutics, 2022, 14, 2288,  DOI:10.3390/pharmaceutics14112288.
133. M. Wang, Y. Wang, G. Chen, H. Gao and Q. Peng, Chitosan-Based Multifunctional Biomaterials as Active Agents or Delivery Systems for Antibacterial Therapy, Bioengineering, 2024, 11, 1278,  DOI:10.3390/bioengineering11121278.
134. P. C. Balaure, A.-G. Niculescu, D. Anghel, A. M. Grumezescu and A. Alberts, Role of Silver Nanoparticles in Wound Healing: Mechanisms, Efficacy, and Clinical Applications, Inorganics, 2025, 13, 401,  DOI:10.3390/inorganics13120401.
135. S. Khattak, I. Ullah, M. Sohail, M. U. Akbar, M. A. Rauf, S. Ullah, J. Shen and H. Xu, Endogenous/exogenous stimuli–responsive smart hydrogels for diabetic wound healing, Aggregate, 2025, 6, e688,  DOI:10.1002/agt2.688.
136. J. Irma, A. S. Kartasasmita, A. Kartiwa, I. Irfani, S. A. Rizki and S. Onasis, From Growth Factors to Structure: PDGF and TGF–β in Granulation Tissue Formation. A Literature Review, J. Cell. Mol. Med., 2025, 29, e70374,  DOI:10.1111/jcmm.70374.
137. G. Guo, X. Li, X. Ye, J. Qi, R. Fan, X. Gao, Y. Wu, L. Zhou and A. Tong, EGF and curcumin co-encapsulated nanoparticle/hydrogel system as potent skin regeneration agent, Int. J. Nanomed., 2016, 11, 3993–4009,  DOI:10.2147/IJN.S104350.
138. Y. He, W. Yang, C. Zhang, M. Yang, Y. Yu, H. Zhao, F. Guan and M. Yao, ROS/pH dual responsive PRP-loaded multifunctional chitosan hydrogels with controlled release of growth factors for skin wound healing, Int. J. Biol. Macromol., 2024, 258, 128962,  DOI:10.1016/j.ijbiomac.2023.128962.
139. X. Deng, J. Ratnayake and A. Ali, Curcumin-Loaded Drug Delivery Systems for Acute and Chronic Wound Management: A Review, Bioengineering, 2025, 12, 860,  DOI:10.3390/bioengineering12080860.
140. Z. Li, D. Xu, X. Li, Y. Deng and C. Li, Redox Imbalance in Chronic Inflammatory Diseases, BioMed Res. Int., 2022, 2022, 9813486,  DOI:10.1155/2022/9813486.
141. P. Feng, Y. Luo, C. Ke, H. Qiu, W. Wang, Y. Zhu, R. Hou, L. Xu and S. Wu, Chitosan-Based Functional Materials for Skin Wound Repair: Mechanisms and Applications, Front. Bioeng. Biotechnol., 2021, 9, 650598,  DOI:10.3389/fbioe.2021.650598.
142. S. L. Percival, W. Slone, S. Linton, T. Okel, L. Corum and J. G. Thomas, The antimicrobial efficacy of a silver alginate dressing against a broad spectrum of clinically relevant wound isolates, Int. Wound J., 2011, 8, 237–243,  DOI:10.1111/j.1742-481X.2011.00774.x.
143. A. C. Bîrcă, O. Gherasim, A.-G. Niculescu, A. M. Grumezescu, B. Ştefan Vasile, D. E. Mihaiescu, I. A. Neacşu, E. Andronescu, R. Truşcă, A. M. Holban, A. Hudiţă and G.-A. Croitoru, Infection-Free and Enhanced Wound Healing Potential of Alginate Gels Incorporating Silver and Tannylated Calcium Peroxide Nanoparticles, Int. J. Mol. Sci., 2024, 25, 5196,  DOI:10.3390/ijms25105196.
144. H. Wang, X. Gao, Y. Zhao, S. Sun, Y. Liu and K. Wang, Exosome-Loaded GelMA Hydrogel as a Cell-Free Therapeutic Strategy for Hypertrophic Scar Inhibition, Clin., Cosmet. Invest. Dermatol., 2025, 18, 1137–1149,  DOI:10.2147/CCID.S520913.
145. P. Zhou, C. Zhang, Z. Rao, X. Ma, Y. Hu, Y. Chen, H. Wang, J. Chen, Y. He, G. Tao and R. Cai, Bioinspired Adhesive Hydrogel Platform with Photothermal Antimicrobial, Antioxidant, and Angiogenic Properties for Whole-Process Management of Diabetic Wounds, ACS Appl. Mater. Interfaces, 2025, 17, 5841–5865,  DOI:10.1021/acsami.4c17310.
146. K. Joshi Navare, L. J. Eggermont, Z. J. Rogers, H. S. Mohammed, T. Colombani and S. A. Bencherif, Antimicrobial Hydrogels: Key Considerations and Engineering Strategies for Biomedical Applications, in Racing for the Surface, Springer International Publishing, Cham, 2020, pp. 511–542.  DOI:10.1007/978-3-030-34475-7_22.
147. J. Jia, X. Wang, T. Zhang, Q. Sun, S. Yang and W. Wu, Stimuli-responsive hydrogels based on cascade reactions: a novel strategy to promote the efficient repair of diabetic wounds, Theranostics, 2026, 16, 3105–3135,  DOI:10.7150/thno.126282.
148. S. Ulusan, V. Bütün, S. Banerjee and I. Erel-Goktepe, Biologically Functional Ultrathin Films Made of Zwitterionic Block Copolymer Micelles, Langmuir, 2019, 35, 1156–1171,  DOI:10.1021/acs.langmuir.8b01735.
149. D. Zheng, M. Zhu, C. Zhang, D. Wu, T. Xie, C. Li, P. Zhao, X. Liu, X. Fu and X. Li, Stimuli-responsive Hydrogels: An Intelligent Tool for Wound Management, Interdiscip. Med., 2025, 4, e70104,  DOI:10.22541/au.176003520.04060772/v1.
150. I. Singh, G. Dhawan, S. Gupta and P. Kumar, Recent Advances in a Polydopamine-Mediated Antimicrobial Adhesion System, Front. Microbiol., 2021, 11, 607099,  DOI:10.3389/fmicb.2020.607099.
151. D. Zheng, C. Huang, X. Zhu, H. Huang and C. Xu, Performance of Polydopamine Complex and Mechanisms in Wound Healing, Int. J. Mol. Sci., 2021, 22, 10563,  DOI:10.3390/ijms221910563.
152. M. E. Astaneh, L. Baldaniya, A. Singh, A. Hussen, A. Hashemzadeh and N. Fereydouni, Exosome–Enhanced Injectable Hydrogels: A Comprehensive Review on Their Emerging Role in Wound Healing, Health Sci. Rep., 2026, 9, e71694,  DOI:10.1002/hsr2.71694.
153. B. Safari, M. Aghazadeh, S. Davaran and L. Roshangar, Exosome-loaded hydrogels: A new cell-free therapeutic approach for skin regeneration, Eur. J. Pharm. Biopharm., 2022, 171, 50–59,  DOI:10.1016/j.ejpb.2021.11.002.
154. P. Bertsch, M. Diba, D. J. Mooney and S. C. G. Leeuwenburgh, Self-Healing Injectable Hydrogels for Tissue Regeneration, Chem. Rev., 2023, 123, 834–873,  DOI:10.1021/acs.chemrev.2c00179.
155. P. Yang, Y. Ju, X. Liu, Z. Li, H. Liu, M. Yang, X. Chen, L. Lei and B. Fang, Natural self-healing injectable hydrogels loaded with exosomes and berberine for infected wound healing, Mater. Today Bio, 2023, 23, 100875,  DOI:10.1016/j.mtbio.2023.100875.
156. S. Bao, T. Ma, Y. Yang, J. Zhang, Y. Wang, L. Yao, P. Zhou, Y. Zhou and Y. Li, Nanocomposite Hydrogels for Wound Management: A Bibliometric Review of Research Trends and Developments, Tissue Eng., Part C, 2025, 31, 309–333,  DOI:10.1177/19373341251372883.
157. S. Zhu, B. Zhao, M. Li, H. Wang, J. Zhu, Q. Li, H. Gao, Q. Feng and X. Cao, Microenvironment responsive nanocomposite hydrogel with NIR photothermal therapy, vascularization and anti-inflammation for diabetic infected wound healing, Bioact. Mater., 2023, 26, 306–320,  DOI:10.1016/j.bioactmat.2023.03.005.
158. Z. Liu, Y. Zhu, Z. Ma, X. Ning, Z. Zhou, J. Liu, Y. Xie, G. Li and P. Hu, Oxidized Dextran/Carboxymethyl Chitosan Dynamic Schiff-Base Hydrogel for Sustained Hydrogen Sulfide Delivery and Burn Wound Microenvironment Remodeling, Pharmaceutics, 2026, 18, 370,  DOI:10.3390/pharmaceutics18030370.
159. J. A. Romero-Antolín, N. Gómez-Cerezo, M. Manzano, J. L. Pablos and M. Vallet-Regí, Anti-inflammatory and antibacterial hydrogel based on a polymerizable ionic liquid, Acta Biomater., 2025, 196, 78–92,  DOI:10.1016/j.actbio.2025.03.015.
160. N. Jangra, A. Singla, V. Puri, D. Dheer, H. Chopra, T. Malik and A. Sharma, Herbal bioactive-loaded biopolymeric formulations for wound healing applications, RSC Adv., 2025, 15, 12402–12442,  10.1039/D4RA08604J.
161. A. P. Veith, K. Henderson, A. Spencer, A. D. Sligar and A. B. Baker, Therapeutic strategies for enhancing angiogenesis in wound healing, Adv. Drug Delivery Rev., 2019, 146, 97–125,  DOI:10.1016/j.addr.2018.09.010.
162. L. Wang, S. He, R. Liu, Y. Xue, Y. Quan, R. Shi, X. Yang, Q. Lin, X. Sun, Z. Zhang and L. Zhang, A pH/ROS dual-responsive system for effective chemoimmunotherapy against melanoma via remodeling tumor immune microenvironment, Acta Pharm. Sin. B, 2024, 14, 2263–2280,  DOI:10.1016/j.apsb.2023.12.001.
163. Y. Cong, L. Zhang, Y. Li, N. Ren, M. Zhang, Z. Shi, L. Lin, G. Yang, C. Shen and Q. Wei, Recent advances in the development of bioactive hydrogel-based dressings for enhanced wound healing, Mater. Today Adv., 2025, 28, 100672,  DOI:10.1016/j.mtadv.2025.100672.
164. N. Carballo-Pedrares, V. M. M. Giménez and M. J. Alonso, Clinical translation of injectable hydrogels: from bioactive polymers to long-acting drug delivery systems, Drug Delivery Transl. Res., 2026, 16, 1685–1708,  DOI:10.1007/s13346-025-02033-1.
165. I. Ferreira, A. C. Marques, P. C. Costa and M. H. Amaral, Effects of Steam Sterilization on the Properties of Stimuli-Responsive Polymer-Based Hydrogels, Gels, 2023, 9, 385,  DOI:10.3390/gels9050385.
166. D. Bhangare, N. Rajput, T. Jadav, A. K. Sahu, R. K. Tekade and P. Sengupta, Systematic strategies for degradation kinetic study of pharmaceuticals: an issue of utmost importance concerning current stability analysis practices, J. Anal. Sci. Technol., 2022, 13, 7,  DOI:10.1186/s40543-022-00317-6.
167. S. Alven, S. Peter, Z. Mbese and B. A. Aderibigbe, Polymer-Based Wound Dressing Materials Loaded with Bioactive Agents: Potential Materials for the Treatment of Diabetic Wounds, Polymers, 2022, 14, 724,  DOI:10.3390/polym14040724.
168. G. Polverino, F. Russo and F. D'Andrea, Bioactive Dressing: A New Algorithm in Wound Healing, J. Clin. Med., 2024, 13, 2488,  DOI:10.3390/jcm13092488.
169. H. S. Jani, K. Ranch, R. Pandya, Y. Patel, S. H. S. Boddu, A. K. Tiwari, S. Jacob and H. K. A. Yasin, An Update on Novel Drug Delivery Systems for the Management of Glaucoma, Pharmaceutics, 2025, 17, 1087,  DOI:10.3390/pharmaceutics17081087.
170. K.-S. Kim, H. J. Cho, F. U. Din, J. H. Cho and H.-G. Choi, Surfactant–Particle Engineering Hybrids: Emerging Strategies for Enhancing Solubility and Oral Bioavailability of Poorly Water-Soluble Drugs, Pharmaceutics, 2025, 18, 37,  DOI:10.3390/pharmaceutics18010037.
171. E. K. Shalini and S. Kumari, Regulation of hydrogel-based products for biomedical applications, in: Hydrogel Tissue Analogues, Elsevier, 2025, pp. 503–513.  DOI:10.1016/B978-0-443-29260-6.00003-2.
172. M. Blessy, R. D. Patel, P. N. Prajapati and Y. K. Agrawal, Development of forced degradation and stability indicating studies of drugs—A review, J. Pharm. Anal., 2014, 4, 159–165,  DOI:10.1016/j.jpha.2013.09.003.
173. A. Rignall, ICHQ1A(R2) Stability Testing of New Drug Substance and Product and ICHQ1C Stability Testing of New Dosage Forms, in ICH Quality Guidelines, Wiley, 2017, pp. 3–44.  DOI:10.1002/9781118971147.ch1.
174. D. Paul and N. Sarkar, Scaling up microbial drug production: strategies to overcome key challenges, in Bioinformatics, AI, and Machine Learning in Microbial Drug Development, ed. V. Dwibedi, N. George, S. K. Rath and S. Kajale, Academic Press, 2026, ch. 13, pp. 283–322.  DOI:10.1016/B978-0-443-33032-2.00006-X.
175. J. Liu, Z. Pan, A. Khan and H. Li, Targeted Drug Delivery System for Pulmonary Fibrosis: Design and Development of Biomaterials, BIO Integr., 2025, 6, 993,  DOI:10.15212/bioi-2025-0016.
176. P. R. Kumbholkar, S. S. M. Mustafa, T. K. Ramchandani, A. Abdulhad, A. k. Yaqub Khan, N. Gaydhane and R. Kalsait, A Review On Ion Exchange Resins As Drug Delivery System, Int. J. Creative Res. Thoughts, 2023, 11, 765–774.
177. Z. Dai, J. Ronholm, Y. Tian, B. Sethi and X. Cao, Sterilization techniques for biodegradable scaffolds in tissue engineering applications, J. Tissue Eng., 2016, 7, 2041731416648810,  DOI:10.1177/2041731416648810.
178. S. F. Mohseni-Motlagh, R. Dolatabadi, M. Baniassadi and M. Baghani, Application of the Quality by Design Concept (QbD) in the Development of Hydrogel-Based Drug Delivery Systems, Polymers, 2023, 15, 4407,  DOI:10.3390/polym15224407.
179. R. Menzel, I. Pahl, S. Dorey, T. Maier and A. Hauk, Equivalence study of extractables from single-use biopharmaceutical manufacturing equipment after X-ray or gamma irradiation, Int. J. Pharm., 2023, 634, 122677,  DOI:10.1016/j.ijpharm.2023.122677.
180. C. S. A. Bento, M. C. Gaspar, P. Coimbra, H. C. de Sousa and M. E. M. Braga, A review of conventional and emerging technologies for hydrogels sterilization, Int. J. Pharm., 2023, 634, 122671,  DOI:10.1016/j.ijpharm.2023.122671.
181. L. Jiang, W. Li, Q. Miao, J. Yang, S. Shan and H. Su, Stimuli-Sensitive Dextran Hydrogel Composited with Clickable Reaction-Based Aggregation-Induced Emission Micelles: A Carrier of Hydrophobic Drugs, ACS Appl. Polym. Mater., 2023, 5, 8495–8505,  DOI:10.1021/acsapm.3c01603.
182. L. Zhao, Y. Zhou, J. Zhang, H. Liang, X. Chen and H. Tan, Natural Polymer-Based Hydrogels: From Polymer to Biomedical Applications, Pharmaceutics, 2023, 15, 2514,  DOI:10.3390/pharmaceutics15102514.
183. A. Iuliano, A. Fabiszewska, K. Kozik, M. Rzepna, J. Ostrowska, M. Dębowski and A. Plichta, Effect of Electron-Beam Radiation and Other Sterilization Techniques on Structural, Mechanical and Microbiological Properties of Thermoplastic Starch Blend, J. Polym. Environ., 2021, 29, 1489–1504,  DOI:10.1007/s10924-020-01972-9.
184. W. Song, J. You, Y. Zhang, Q. Yang, J. Jiao and H. Zhang, Recent Studies on Hydrogels Based on H₂O₂-Responsive Moieties: Mechanism, Preparation and Application, Gels, 2022, 8, 361,  DOI:10.3390/gels8060361.
185. M. Harun-Ur-Rashid, I. Jahan, T. Foyez and A. Bin Imran, Bio-Inspired Nanomaterials for Micro/Nanodevices: A New Era in Biomedical Applications, Micromachines, 2023, 14, 1786,  DOI:10.3390/mi14091786.
186. N. Machado, M. G. Rocha, D. Oliveira, K. G. Reardon, E. Martins and N. C. Lawson, Compressive modulus, translucency, and irradiance transmittance of clear PVS materials used for resin injection molding technique, J. Esthet. Restor. Dent., 2025, 37, 412–422,  DOI:10.1111/jerd.13270.
187. K. Funatsu, H. Kiminami, Y. Abe and J. F. Carpenter, Impact of Ethylene Oxide Sterilization of Polymer-Based Prefilled Syringes on Chemical Degradation of a Model Therapeutic Protein During Storage, J. Pharm. Sci., 2019, 108, 770–774,  DOI:10.1016/j.xphs.2018.09.029.
188. K. Chakravarty and D. C. Dalal, An analytical study of drug release kinetics from a degradable polymeric matrix, Int. J. Biomathematics, 2018, 11, 1850011,  DOI:10.1142/S1793524518500110.
189. A. Zarski, K. Kapusniak, S. Ptak, M. Rudlicka, S. Coseri and J. Kapusniak, Functionalization Methods of Starch and Its Derivatives: From Old Limitations to New Possibilities, Polymers, 2024, 16, 597,  DOI:10.3390/polym16050597.
190. S. Carlotti, R. Carcione, B. D'Orsi, T. Lusetti, A. Finazzi, J. Scifo, I. D. Sarcina, M. Ferrari, A. Cemmi and F. Maggi, Effects of Gamma Irradiation on Solid Propellant Conventional and UV-Cured Binders, Aerospace, 2025, 12, 471,  DOI:10.3390/aerospace12060471.
191. S. Sharifi, M. M. Islam, H. Sharifi, R. Islam, T. N. Huq, P. H. Nilsson, T. E. Mollnes, K. D. Tran, C. Patzer, C. H. Dohlman, H. K. Patra, E. I. Paschalis, M. Gonzalez-Andrades and J. Chodosh, Electron Beam Sterilization of Poly(Methyl Methacrylate)—Physicochemical and Biological Aspects, Macromol. Biosci., 2021, 21, 2000379,  DOI:10.1002/mabi.202000379.
192. I. U. Rehman, K. Wolfs, E. Haghedooren, C. Dukers, A. DeMent and E. Adams, Determination of ethylene oxide residues in sterilized ophthalmic active pharmaceutical ingredients via the full evaporation technique coupled to gas chromatography, Talanta, 2025, 295, 128335,  DOI:10.1016/j.talanta.2025.128335.
193. T. Sandle, Establishing a Contamination Control Strategy for Aseptic Processing, Am. Pharm. Rev., 2017, 22–28.
194. K. Lauritsen and T. Nguyen, Combination Products Regulation at the FDA, Clin. Pharmacol. Ther., 2009, 85, 468–470,  DOI:10.1038/clpt.2009.28.
195. A. S. Sousa, J. Serra, C. Estevens, R. Costa and A. J. Ribeiro, A quality by design approach in oral extended release drug delivery systems: where we are and where we are going?, J. Pharm. Invest., 2023, 53, 269–306,  DOI:10.1007/s40005-022-00603-w.
196. L. X. Yu, G. Amidon, M. A. Khan, S. W. Hoag, J. Polli, G. K. Raju and J. Woodcock, Understanding Pharmaceutical Quality by Design, AAPS J., 2014, 16, 771–783,  DOI:10.1208/s12248-014-9598-3.
197. K. Thakur, S. D. Kaur, D. Kak and D. N. Kapoor, Quality by design in parenteral drug development: addressing formulation challenges and industrial insights, Drug Dev. Ind. Pharm., 2026, 52, 649–666,  DOI:10.1080/03639045.2026.2628937.
198. J. S. Boateng, K. H. Matthews, H. N. E. Stevens and G. M. Eccleston, Wound Healing Dressings and Drug Delivery Systems, A Review, J. Pharm. Sci., 2008, 97, 2892–2923,  DOI:10.1002/jps.21210.
199. A. E. López-Cánovas, M. Victoria-Sanes, G. B. Martínez-Hernández and A. López-Gómez, Methods for Determining the High Molecular Weight of Hyaluronic Acid: A Review, Polymers, 2025, 17, 3289,  DOI:10.3390/polym17243289.
200. J. G. Duarte, M. G. Duarte, A. P. Piedade and F. Mascarenhas-Melo, Rethinking Pharmaceutical Industry with Quality by Design: Application in Research, Development, Manufacturing, and Quality Assurance, AAPS J., 2025, 27, 96,  DOI:10.1208/s12248-025-01079-w.
201. J. M. Calderon Moreno, M. Chelu and M. Popa, Biocompatible Stimuli-Sensitive Natural Hydrogels: Recent Advances in Biomedical Applications, Gels, 2025, 11, 993,  DOI:10.3390/gels11120993.
202. S. A. Stewart, J. Domínguez-Robles, R. F. Donnelly and E. Larrañeta, Implantable Polymeric Drug Delivery Devices: Classification, Manufacture, Materials, and Clinical Applications, Polymers, 2018, 10, 1379,  DOI:10.3390/polym10121379.
203. M. Stielow, A. Witczyńska, N. Kubryń, Ł. Fijałkowski, J. Nowaczyk and A. Nowaczyk, The Bioavailability of Drugs—The Current State of Knowledge, Molecules, 2023, 28, 8038,  DOI:10.3390/molecules28248038.
204. P. K. Limpikirati, S. Mongkoltipparat, T. Denchaipradit, N. Siwasophonpong, W. Pornnopparat, P. Ramanandana, P. Pianpaktr, S. Tongchusak, M. T. Tian and T. Pisitkun, Basic regulatory science behind drug substance and drug product specifications of monoclonal antibodies and other protein therapeutics, J. Pharm. Anal., 2024, 14, 100916,  DOI:10.1016/j.jpha.2023.12.006.
205. S. R. Ranamalla, S. Tavakoli, A. S. Porfire, L. R. Tefas, M. Banciu, I. Tomuţa and O. P. Varghese, A quality by design approach to optimise disulfide-linked hyaluronic acid hydrogels, Carbohydr. Polym., 2024, 339, 122251,  DOI:10.1016/j.carbpol.2024.122251.
206. H. Pan, S. Yang, L. Gao, J. Zhou, W. Cheng, G. Chen, W. Shuhang, N. Li, P. Veranič, R. Musiol, Q. Cai and Q. T. H. Shubhra, At the crossroad of nanotechnology and cancer cell membrane coating: Expanding horizons with engineered nanoplatforms for advanced cancer therapy harnessing homologous tumor targeting, Coord. Chem. Rev., 2024, 506, 215712,  DOI:10.1016/j.ccr.2024.215712.
207. U. Ahmad, W. N. W. Hanaffi, A. Islam, A. Salman, M. M. Khan, F. Shakeel, Q. Cai, X. Cai and Q. T. H. Shubhra, Cutting edge strategies for diabetic wound care: Nanotechnology, bioengineering, and beyond, BMEMat, 2025, 4, e70033,  DOI:10.1002/bmm2.70033.
208. M. R. Islam, M. S. Manir, M. Razzak, M. A. Mamun, M. F. Mortuza, M. J. Islam, S. Yang, H. Pan, A. K. M. M. Alam and Q. T. H. Shubhra, Silk-enriched hydrogels with ROS-scavenging dendrimers for advanced wound care, Int. J. Biol. Macromol., 2024, 280, 135567,  DOI:10.1016/j.ijbiomac.2024.135567.
209. L. A. Schneider, A. Korber, S. Grabbe and J. Dissemond, Influence of pH on wound-healing: a new perspective for wound-therapy?, Arch. Dermatol. Res., 2007, 298, 413–420,  DOI:10.1007/s00403-006-0713-x.
210. M. C. Koetting, J. T. Peters, S. D. Steichen and N. A. Peppas, Stimulus-responsive hydrogels: Theory, modern advances, and applications, Mater. Sci. Eng., R, 2015, 93, 1–49,  DOI:10.1016/j.mser.2015.04.001.
211. S. J. Buwalda, K. W. M. Boere, P. J. Dijkstra, J. Feijen, T. Vermonden and W. E. Hennink, Hydrogels in a historical perspective: From simple networks to smart materials, J. Controlled Release, 2014, 190, 254–273,  DOI:10.1016/j.jconrel.2014.03.052.
212. X. Zhao, H. Wu, B. Guo, R. Dong, Y. Qiu and P. X. Ma, Antibacterial anti-oxidant electroactive injectable hydrogel as self-healing wound dressing with hemostasis and adhesiveness for cutaneous wound healing, Biomaterials, 2017, 122, 34–47,  DOI:10.1016/j.biomaterials.2017.01.011.
213. J. S. Boateng, K. H. Matthews, H. N. E. Stevens and G. M. Eccleston, Wound Healing Dressings and Drug Delivery Systems, A Review, J. Pharm. Sci., 2008, 97, 2892–2923,  DOI:10.1002/jps.21210.
214. G. A. James, E. Swogger, R. Wolcott, E. deLancey Pulcini, P. Secor, J. Sestrich, J. W. Costerton and P. S. Stewart, Biofilms in chronic wounds, Wound Repair Regen., 2008, 16, 37–44,  DOI:10.1111/j.1524-475X.2007.00321.x.
215. H. Chai, Z. Wang, J. Ju and J. Sun, Multifunctional Hydrogel–Based wound Dressings for Scar–Free Healing: Design Principles, Therapeutic Mechanisms, and Clinical Translation Challenges, Adv. NanoBiomed Res., 2026, 6, e202500147,  DOI:10.1002/anbr.202500147.
216. S. Saeed and M. Martins, Green, Animal models for the study of acute cutaneous wound healing, Wound Repair Regen., 2023, 31, 6–16,  DOI:10.1111/wrr.13051.
217. M. Ghanbari, Y. Salkovskiy and M. A. Carlson, The rat as an animal model in chronic wound research: An update, Life Sci., 2024, 351, 122783,  DOI:10.1016/j.lfs.2024.122783.

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