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<p>Chronic wounds colonized by methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) prolong hospitalization, heighten amputation risk and accelerate antimicrobial resistance (AMR). To counter this, we exploited the acidic pH (4.5-6.0) of infected tissue and employed ICH Q8/Q9 Quality-by-Design (QbD) to fuse mucoadhesive, cationic chitosan (Cs) with high-surface-area, pH-sensitive graphene oxide (GO), creating a nanocomposite that sustainably releases levofloxacin (LVX) at the wound site, thereby reducing dosing frequency and selection pressure for resistance. This QbD-driven study developed Cs-GO nanocomposite hydrogel for pH-responsive LVX release, optimized via Box-Behnken design (BBD) and response surface methodology (RSM) in Design-Expert<sup>®</sup> v13.0. Risk assessment (ICH Q9) identified four critical process parameters (CPPs); Cs: GO ratio (X₁), glutaraldehyde concentration (X₂), stirring speed (X₃), and sonication time (X₄) to refine critical quality attributes (CQAs) like entrapment efficiency and particle uniformity, yielding nanoparticles with 82.31% entrapment, 180&#xa0;nm size, -29.86 mV zeta potential, and polydispersity index of 0.293 (R² &gt;0.85). These LVX-loaded Cs-GO nanoparticles were subsequently dispersed in an HPMC/Eudragit hydrogel matrix (TGLN4) to produce the final nanocomposite hydrogel dressing. The formulation exhibited pH-dependent release kinetics (85% LVX over 20&#xa0;h at pH 5.5, mimicking infected wounds), driven by ionic gelation, hydrogen bonding, and glutaraldehyde crosslinking, with anomalous diffusion (Peppas <i>n</i> = 0.65). In vitro assessments demonstrated enhanced mechanical properties (viscosity ≈ 3.4 × 10³ cP) and an effective MRSA inhibition (MIC 0.5&#xa0;µg/mL). The LVX/GO combination produced rapid bacterial killing consistent with oxidative damage reported for GO-based materials. In vivo studies in a rat MRSA wound model confirmed 90% bacterial reduction and complete re-epithelialization by day 21, with fivefold lower pro-inflammatory cytokines versus controls. ICH stability studies affirmed shelf-life viability (minimal degradation over 6 months). This scalable QbD platform advances manufacturable bionanocomposites for topical antimicrobial therapeutics, reducing dosing frequency and AMR risks while enabling a scalable platform with potential for further manufacturing development.</p>

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Box-Behnken Design Optimization of pH-Responsive Chitosan-Graphene Oxide Nanocomposite Hydrogel for Sustained Levofloxacin Delivery in Antimicrobial Wound Therapeutics

  • 期刊论文

  • 发表日期：

    2026年1月9日

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  • Priyanka Rathore,
  • Prem Prakash Singh,
  • Peeyush Bhardwaj,
  • Anshu Awasthi,
  • Brajesh Lodhi,
  • Prakash Chandra Yadav,
  • Ankita Kishore,
  • Prashant Pandey,
  • Alok Kumar Mahor

摘要

Chronic wounds colonized by methicillin-resistant Staphylococcus aureus (MRSA) prolong hospitalization, heighten amputation risk and accelerate antimicrobial resistance (AMR). To counter this, we exploited the acidic pH (4.5-6.0) of infected tissue and employed ICH Q8/Q9 Quality-by-Design (QbD) to fuse mucoadhesive, cationic chitosan (Cs) with high-surface-area, pH-sensitive graphene oxide (GO), creating a nanocomposite that sustainably releases levofloxacin (LVX) at the wound site, thereby reducing dosing frequency and selection pressure for resistance. This QbD-driven study developed Cs-GO nanocomposite hydrogel for pH-responsive LVX release, optimized via Box-Behnken design (BBD) and response surface methodology (RSM) in Design-Expert® v13.0. Risk assessment (ICH Q9) identified four critical process parameters (CPPs); Cs: GO ratio (X₁), glutaraldehyde concentration (X₂), stirring speed (X₃), and sonication time (X₄) to refine critical quality attributes (CQAs) like entrapment efficiency and particle uniformity, yielding nanoparticles with 82.31% entrapment, 180 nm size, -29.86 mV zeta potential, and polydispersity index of 0.293 (R² >0.85). These LVX-loaded Cs-GO nanoparticles were subsequently dispersed in an HPMC/Eudragit hydrogel matrix (TGLN4) to produce the final nanocomposite hydrogel dressing. The formulation exhibited pH-dependent release kinetics (85% LVX over 20 h at pH 5.5, mimicking infected wounds), driven by ionic gelation, hydrogen bonding, and glutaraldehyde crosslinking, with anomalous diffusion (Peppas n = 0.65). In vitro assessments demonstrated enhanced mechanical properties (viscosity ≈ 3.4 × 10³ cP) and an effective MRSA inhibition (MIC 0.5 µg/mL). The LVX/GO combination produced rapid bacterial killing consistent with oxidative damage reported for GO-based materials. In vivo studies in a rat MRSA wound model confirmed 90% bacterial reduction and complete re-epithelialization by day 21, with fivefold lower pro-inflammatory cytokines versus controls. ICH stability studies affirmed shelf-life viability (minimal degradation over 6 months). This scalable QbD platform advances manufacturable bionanocomposites for topical antimicrobial therapeutics, reducing dosing frequency and AMR risks while enabling a scalable platform with potential for further manufacturing development.