Gallium‐Loaded Dissolvable Microfilm Constructs that Provide Sustained Release of Ga³⁺ for Management of Biofilms

Abstract

The persistence of bacterial biofilms in chronic wounds delays wound healing. Although Ga 3+ can inhibit or kill biofilms, precipitation as Ga(OH) 3 has prevented its use as a topical wound treatment. We report the design of a microfilm construct comprising a polyelectrolyte film that releases non-cytotoxic concentrations of Ga 3+ over 20 days and a dissolvable micrometer-thick film of polyvinylalcohol that enables facile transfer onto biomedically important surfaces. By using infrared spectroscopy, we show that the density of free carboxylate/carboxylic acid and amine groups within the polyelectrolyte film regulates the capacity of the construct to be loaded with Ga 3+ , and that the density of covalent cross-links introduced into the polyelectrolyte film (amide-bonds) controls the release rate of Ga 3+ . Following transfer onto the wound-contact surface of a biologic wound dressing, an optimized construct is demonstrated to release of ~0.7 µg cm −2Correspondence to: Jonathan F. McAnulty, mcanultj@svm.vetmed.wisc.edu; Charles J. Czuprynski, czuprync@svm.vetmed.wisc.edu; Nicholas L. Abbott, abbott@engr.wisc.edu. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript day −1 of Ga 3+ over 3 weeks, thus continuously replacing Ga 3+ lost to precipitation. The optimized construct inhibited formation of P. aeruginosa (two strains; ATCC 27853 and PA01) biofilms for up to 4 days and caused pre-existing biofilms to disperse. Overall, this study provides designs of polymeric constructs that permit facile modification of the wound-contacting surfaces of dressings and biomaterials to manage biofilms.

Acinetobacter baumannii Biofilm Formation in Human Serum and Disruption by Gallium

“…We believe that the potent antibacterial and antibiofilm properties of gallium, combined with its good biocompatibility, make this iron-mimetic metal a suitable candidate for the coating of biomaterials and indwelling medical devices. In support of this possibility, a number of recent reports have highlighted the efficacy of galliumdoped materials in counteracting surface proliferation of some pathogenic bacteria, including A. baumannii (29)(30)(31)(32).…”

Simultaneous Delivery of Multiple Antimicrobial Agents by Biphasic Scaffolds for Effective Treatment of Wound Biofilms

“…[ 22 ] Therefore, Ga 3+ have been repurposed in many studies for treatment against ESKAPE pathogens ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa , and Enterobacter species) in nosocomial infections by interfering with iron‐dependent metabolic pathway. [ 23 ] Vancomycin hydrochloride is a narrow‐spectrum antibiotic, only sensitive and effective to gram‐positive bacteria, such as Streptococcus (especially MRSA), Pneumococcus , and Enterococcus , to name a few. [ 24 ] Based on our results, it appeared that biphasic scaffolds incorporating two or three antimicrobial agents (e.g., AgNO 3 , Ga(NO 3 ) 3 , and vancomycin) resulted in higher efficacy against both MRSA biofilms and MRSA/ P. aeruginosa blend biofilms compared to the scaffolds loaded with a single antimicrobial agent, indicating a synergistic antibactericidal mechanism by combined delivery of antimicrobial agents.…”

Antibiofilm Activity of Gallium(III) Complexed Anionic Polymers in Combination with Antibiotics

“…It is well known that GaCl 3 can hydrolyze in neutral aqueous solutions and form large Ga(OH) 3 precipitates, thus decreasing the available effective Ga(III) to kill the bacteria. [ 16 ] In contrast, the anionic polymer PDMPOH in GaPD can serve as a Ga 3+ carrier to avoid its hydrolysis. The bacterial genus Pseudomonas is a prolific producer of various extracellular enzymes including lipases.…”

“…[10,11] There is intense interest in developing effective therapeutic strategies against infections involving P. aeruginosa biofilms. A variety of methods had been exploited, such as a combination of different antibiotics (e.g., cephalosporins and DOI: 10.1002/marc.202100255 fluoroquinolones, colistin and rifampicin, and colistin plus doripenem), [12] bacteriophage, [13] metal complexes, [14][15][16][17] and polymers. [18][19][20][21][22][23][24][25][26][27][28][29][30] However, the combination of antibiotics showed a high risk of multidrug resistance and side effects on patients.…”