Table 1.

Summary of non-conventional antimicrobial approaches for chronic wound biofilms.

Therapy	Advantages	Limitations	Current Status of the Therapeutic in Wound Infection Management	References
Antimicrobial therapies that directly target microbial processes
Phage therapy	-Highly-specificity for bacterial strains -High-density biofilms could enable -Efficient propagation of phage -Less likelihood of resistance development -Able to infect dormant cells and persister variants	-Maintaining phage viability in the delivery vehicle is a concern -Phage therapy to gain a foothold in infection management	-Several clinical trials conducted for usage and safety in burns and post-surgical infections	[34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54]
Nano-based technologies	-A wide-range of formulations and combinations available -Physical parameters enable penetration into dense biofilm matrix -Can be coated onto dressings, bandages, sutures, drains -Reduced likelihood of resistance development	-Often effective only in combination with conventional antibiotics but not as stand-alone therapy	-Several commercial products based on nanomaterials available and in commercial use	[55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78]
Blue light therapy	-Effective against a wide range of pathogens -Reduced likelihood of resistance development -Ease of administration -Observable adverse effects to host cells minimal -In use for skin ailments such as acne	-Less effective against Gram positive pathogens; important given the polymicrobial nature of wound biofilms	-In vivo preclinical evidence supporting its use -No reports of clinical trials for use in chronic wound biofilms	[79,80,81,82,83,84,85,86,87,88,89,90,91,92,93]
Quorum sensing inhibitors	-Potential to prevent early stage biofilm formation -A wide-range of potential therapeutic molecules available	-Highly strain/species-specific -Toxicity to host cells -Efficacy in complex, in vivo models is reduced -Yet to gain a foothold in infection management	-In vivo preclinical evidence with mixed results -No reports of clinical trials for use in chronic wound biofilms	[94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114]
Antimicrobial therapies that target the chronic wound biofilm microenvironment, indirectly affecting microbial growth and survival
Modulation of pH	-In principle, pH modifying agents are easy to administer onto the wound surface -Less likelihood of resistance development	-Fine-tuning pH in the wound bed is a difficult approach -pH variations have multiple effects on several factors -Effects of pH depend on wound-specific conditions; no universal strategy possible	-Largely in vitro evidence with varied results	[115,116,117,118,119,120,121,122,123]
Negative Pressure Wound Therapy (NPWT)	-Standard of care in wound management -Almost no likelihood of resistance development -Well-suited for use in combination with antiseptic instillation	-Likely to be effective only in combination with conventional antiseptics but not as stand-alone therapy	-Already in use for wound care, can be leveraged to manage wound infections with more clinical studies and evidence-based practice	[124,125,126,127,128,129]
Hyperbaric Oxygen Therapy (HBOT)	-Standard of care in wound management -Almost no likelihood of resistance development -Can have minimal adverse effects if delivered locally	-Cumbersome delivery mechanism; local delivery devices need to be evaluated -Likely to be effective only in combination with other therapies but not as stand-alone therapy	-Already in use for wound care, can be leveraged to manage wound infections with more clinical studies and evidence-based practice	[130,131,132,133,134,135,136,137,138]
Surfactants	-Can be used to coat dressings, sutures, bandages -Less likelihood of resistance development	-Likely to be effective only in conjunction with antibiotics	-FDA approved surfactant polymer dressing available and in use	[139,140,141]
Electrical and Electrochemical approaches	-Almost no likelihood of resistance development -Can be combined with other agents in wound dressings	-Likely to be effective only in combination with other therapeutics but not as stand-alone therapy -Mode of delivery may not convenient	-Few commercial products available	[142,143,144,145,146,147]
Antimicrobial therapies that target bacteria and the chronic wound biofilm microenvironment, both directly and indirectly impacting microbial growth and survival
Probiotics	-An established mode of therapy for other medical conditions -Less toxicity and adverse effects likely -Less likelihood of resistance development	-Could be counterintuitive to administer bacteria to treat an infection, this notion has to be overcome -Mode of delivery needs to be developed	-Reasonable body of in vitro and in vivo evidence; no specific wound infection product available	[148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166]
Mesenchymal stem cells	-Harness the ability of the innate immune system -Less likelihood of resistance development -Can be administered via bioengineered skin grafts or dressings	-Likely to be effective when combined with antibiotics -Ethical considerations (particularly for parenteral administration)	-In vivo preclinical evidence promising -Needs robust clinical evaluation to take it forward, approvals for which are likely to be rigorous	[167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182]