5.3 Treatment of chronic wounds
10 min read•august 21, 2024
Chronic wounds pose a significant challenge in medicine, resisting conventional treatments. Plasma-based interventions offer new hope, targeting infection control, tissue regeneration, and wound microenvironment modulation. Understanding chronic wound characteristics is crucial for developing effective plasma therapies.
devices, , and plasma-functionalized materials are key tools in this emerging field. These treatments work through multiple mechanisms, including reactive species generation, UV radiation, and electric field interactions, to combat infection and promote healing in various chronic wound types.
Chronic wound characteristics
- Chronic wounds represent a significant challenge in plasma medicine due to their persistent nature and resistance to conventional treatments
- Understanding the unique features of chronic wounds is crucial for developing effective plasma-based interventions and optimizing patient outcomes
Types of chronic wounds
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Frontiers | Microbiota of Chronic Diabetic Wounds: Ecology, Impact, and Potential for Innovative ... View original
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Functional evaluation of diabetic patients with foot ulcers | Scientific Journal of the Foot & Ankle View original
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- result from neuropathy and vascular insufficiency in diabetic patients
- develop due to impaired blood flow and venous hypertension
- form from prolonged pressure on bony prominences (heels, sacrum)
- occur in patients with peripheral artery disease and inadequate blood supply
Factors impeding healing
- Persistent inflammation prolongs the wound healing process and damages surrounding tissues
- Impaired blood supply reduces oxygen and nutrient delivery to the wound bed
- Bacterial colonization and infection interfere with normal healing cascades
- Comorbidities (diabetes, vascular disease) negatively impact overall wound healing capacity
- Advanced age decreases cellular regenerative potential and slows healing responses
Biofilm formation
- Biofilms consist of complex microbial communities encased in a self-produced extracellular matrix
- Biofilm development occurs in stages: attachment, microcolony formation, maturation, and dispersion
- Mature biofilms exhibit increased antibiotic resistance and tolerance to host immune responses
- Extracellular polymeric substances (EPS) in biofilms protect bacteria from environmental stressors
- Quorum sensing allows bacteria in biofilms to coordinate gene expression and virulence factors
Plasma-based wound treatments
- Plasma-based treatments offer a novel approach to chronic wound management by leveraging the unique properties of ionized gases
- These innovative therapies aim to address multiple aspects of wound healing simultaneously, including infection control, tissue regeneration, and modulation of the wound microenvironment
Cold atmospheric plasma devices
- (DBD) systems generate plasma between two electrodes separated by a dielectric barrier
- Plasma jets produce a stream of reactive species directed at the wound surface
- use the wound itself as the second electrode for plasma generation
- create plasma using high-frequency electromagnetic waves
- Surface microdischarge (SMD) technology generates plasma on a large area electrode for wound treatment
Plasma-activated liquids
- Plasma treatment of water creates a solution rich in reactive oxygen and nitrogen species
- Plasma-activated saline solutions can be used for wound irrigation and dressing applications
- Plasma-treated cell culture media may enhance cellular responses in wound healing
- Plasma-activated buffers can serve as carriers for antimicrobial and pro-healing compounds
- Long-lived reactive species in plasma-activated liquids allow for extended therapeutic effects
Plasma-functionalized materials
- Plasma treatment of wound dressings enhances their antimicrobial and cell-adhesive properties
- Plasma-deposited coatings on medical devices improve biocompatibility and reduce infection risks
- Plasma-modified hydrogels can serve as advanced drug delivery systems for wound care
- Plasma-treated nanofibers provide a scaffold for cell growth and tissue regeneration
- Plasma-functionalized sutures exhibit improved wound closure and reduced risk of surgical site infections
Mechanisms of plasma action
- Plasma treatments exert their therapeutic effects through multiple interconnected mechanisms
- Understanding these mechanisms is crucial for optimizing plasma-based therapies and predicting their efficacy in different wound types
Reactive oxygen and nitrogen species
- Plasma generates short-lived (ROS) (hydroxyl radicals, superoxide)
- Longer-lived ROS (hydrogen peroxide, ozone) contribute to sustained antimicrobial effects
- (RNS) (nitric oxide, peroxynitrite) modulate cellular signaling pathways
- Synergistic interactions between ROS and RNS enhance overall therapeutic efficacy
- Plasma-induced oxidative stress triggers adaptive responses in cells and tissues
UV radiation effects
- Plasma-generated UV-A radiation (315-400 nm) stimulates cellular repair mechanisms
- UV-B radiation (280-315 nm) induces DNA damage in microbial cells, leading to inactivation
- UV-C radiation (100-280 nm) provides potent germicidal effects but limited penetration depth
- Plasma-induced UV emissions can activate photosensitive compounds for enhanced therapeutic effects
- Controlled UV exposure from plasma devices may promote vitamin D synthesis in wound tissues
Electric field interactions
- Plasma-generated electric fields influence cell membrane permeability and ion transport
- Electroporation effects facilitate the uptake of antimicrobial agents and growth factors
- Electric fields can guide cell migration and orientation during wound healing (galvanotaxis)
- Plasma-induced changes in cellular electrical properties may modulate intracellular signaling
- Interactions between electric fields and the extracellular matrix influence tissue remodeling
Antimicrobial effects
- Plasma treatments offer a multifaceted approach to combating wound infections and biofilms
- The combination of physical and chemical antimicrobial mechanisms makes plasma therapy a promising alternative to conventional antibiotic treatments
Bacterial inactivation
- Direct oxidative damage to bacterial cell membranes by plasma-generated ROS and RNS
- Intracellular oxidative stress leads to protein denaturation and DNA damage in bacteria
- Plasma-induced electroporation enhances the uptake of antimicrobial agents by bacterial cells
- Synergistic effects between plasma components (UV, electric fields, reactive species) increase bacterial killing
- Gram-negative bacteria (E. coli) generally show higher susceptibility to plasma treatment than gram-positive bacteria (S. aureus)
Biofilm disruption
- Plasma-generated reactive species penetrate and degrade the extracellular polymeric substances (EPS) of biofilms
- Mechanical forces from plasma jets can physically disrupt biofilm structures
- Plasma treatment alters biofilm surface properties, reducing bacterial adhesion and promoting detachment
- Inactivation of quorum sensing molecules by plasma components interferes with and maintenance
- Plasma-induced changes in pH and ion concentrations create an unfavorable environment for biofilm persistence
Antibiotic resistance reduction
- Plasma treatment can resensitize antibiotic-resistant bacteria to conventional antibiotics
- Multiple simultaneous plasma-induced stressors make the development of resistance less likely
- Plasma-generated reactive species may damage bacterial efflux pumps, increasing antibiotic retention
- Synergistic effects between plasma and antibiotics allow for lower antibiotic doses, reducing selection pressure
- Plasma treatment can inactivate antibiotic-resistant genes and plasmids, preventing their spread
Wound healing promotion
- Plasma-based therapies not only combat infection but also actively stimulate the wound healing process
- The ability to modulate various aspects of tissue regeneration makes plasma treatments a versatile tool in chronic wound management
Cell proliferation stimulation
- Plasma-generated nitric oxide (NO) activates cellular signaling pathways promoting proliferation
- Low levels of ROS induced by plasma treatment trigger mitogenic responses in fibroblasts and keratinocytes
- Plasma-activated growth factors in wound fluids enhance cellular division and migration
- Electric field effects from plasma devices influence cell cycle progression and mitotic activity
- Plasma treatment can activate latent TGF-β, a key regulator of cell proliferation in wound healing
Angiogenesis enhancement
- Plasma-induced oxidative stress upregulates VEGF expression, promoting new blood vessel formation
- Nitric oxide generated by plasma treatments acts as a potent vasodilator and angiogenic factor
- Plasma modification of the extracellular matrix creates a more favorable environment for endothelial cell migration
- Plasma-activated platelets release pro-angiogenic factors (PDGF, FGF) into the wound bed
- Electrical stimulation from plasma devices can guide the orientation and growth of new blood vessels
Collagen synthesis modulation
- Plasma treatment stimulates fibroblasts to increase collagen production and deposition
- ROS generated by plasma activate matrix metalloproteinases (MMPs) involved in collagen remodeling
- Plasma-induced changes in wound pH optimize conditions for collagen synthesis and cross-linking
- Electric fields from plasma devices influence the alignment and organization of newly synthesized collagen fibers
- Plasma treatment can modify the ratio of different collagen types (type I vs type III) for improved wound strength
Clinical applications
- Plasma-based therapies have shown promising results in various types of chronic wounds
- Tailoring plasma treatments to specific wound characteristics is crucial for maximizing therapeutic outcomes
Diabetic foot ulcers
- Plasma treatments effectively reduce bacterial load and biofilm formation in diabetic foot ulcers
- Cold atmospheric plasma therapy promotes granulation tissue formation and epithelialization
- Plasma-activated liquids can be used for wound irrigation and dressing applications in diabetic foot care
- Combination of plasma treatment with offloading techniques improves overall healing outcomes
- Plasma therapy may help address peripheral neuropathy associated with diabetic foot ulcers
Venous leg ulcers
- Plasma treatments improve microcirculation and reduce edema in venous leg ulcers
- Cold plasma therapy effectively manages bacterial colonization and biofilm formation
- Plasma-functionalized compression bandages enhance the standard care for venous ulcers
- Plasma-induced fibroblast activation promotes faster wound closure in venous leg ulcers
- Combination of plasma treatment with compression therapy yields synergistic healing effects
Pressure ulcers
- Plasma treatments provide effective debridement of necrotic tissue in pressure ulcers
- Cold atmospheric plasma therapy reduces bacterial burden and prevents infection in deep pressure ulcers
- Plasma-activated dressings maintain a moist wound environment while providing antimicrobial effects
- Plasma treatment stimulates granulation tissue formation in stage III and IV pressure ulcers
- Combination of plasma therapy with pressure redistribution techniques improves healing outcomes
Treatment protocols
- Developing standardized protocols for plasma-based wound treatments is essential for consistent and effective clinical outcomes
- Optimization of treatment parameters must consider the specific characteristics of each wound and patient
Dosage and frequency
- Plasma treatment dosage measured by energy density (J/cm²) or treatment time per unit area
- Typical treatment frequencies range from daily to weekly depending on wound severity and healing progress
- Higher initial dosages may be used for heavily contaminated wounds, followed by maintenance treatments
- Gradual increase in dosage over time may be necessary to overcome adaptive responses in chronic wounds
- Personalized dosing schedules based on wound assessment and patient response optimize treatment efficacy
Treatment duration
- Single treatment sessions typically last 1-5 minutes per wound area
- Total treatment course may extend over several weeks to months for chronic wounds
- Duration of each session may be adjusted based on wound size, depth, and healing progress
- Longer treatment durations may be necessary for biofilm disruption and deep tissue penetration
- Periodic reassessment of treatment duration ensures optimal balance between efficacy and safety
Combination with standard care
- Plasma treatments integrated into existing wound care protocols (debridement, dressing changes)
- Combination of plasma therapy with appropriate wound dressings enhances overall treatment efficacy
- Plasma treatment may be used as an adjunct to negative pressure wound therapy for complex wounds
- Integration of plasma therapy with systemic antibiotic treatment for infected wounds
- Combination of plasma treatment with nutritional support and glycemic control in diabetic patients
Safety considerations
- Ensuring the safety of plasma-based wound treatments is paramount for their widespread clinical adoption
- Comprehensive safety assessments and long-term follow-up studies are necessary to establish the risk-benefit profile of plasma therapies
Tissue toxicity assessment
- In vitro cytotoxicity testing on relevant cell types (fibroblasts, keratinocytes) to determine safe plasma doses
- Evaluation of plasma-induced DNA damage and mutagenic potential in treated tissues
- Assessment of oxidative stress markers in wound tissue following plasma treatment
- Histological examination of treated wounds to detect any adverse tissue reactions
- Monitoring of inflammatory markers to ensure plasma treatment does not exacerbate chronic inflammation
Long-term effects
- Follow-up studies to assess wound healing outcomes and recurrence rates after plasma treatment
- Evaluation of potential systemic effects from repeated plasma exposures
- Monitoring of scar quality and tissue function in healed wounds treated with plasma
- Assessment of potential carcinogenic risks associated with long-term plasma therapy
- Investigation of plasma-induced changes in the wound microbiome over time
Contraindications
- Caution in patients with active bleeding or coagulation disorders due to potential anticoagulant effects
- Avoidance of plasma treatment in patients with pacemakers or other implanted electronic devices
- Contraindication in pregnancy due to limited safety data and potential fetal risks
- Caution in patients with photosensitivity disorders due to UV emissions from plasma devices
- Avoidance of plasma treatment on or near malignant lesions due to potential stimulation of cancer cells
Comparative efficacy
- Evaluating the effectiveness of plasma-based treatments against conventional and other advanced therapies is crucial for establishing their place in wound care protocols
- Comparative studies help guide clinical decision-making and resource allocation in chronic wound management
Plasma vs conventional treatments
- Plasma therapy shows faster bacterial reduction compared to topical antibiotics in infected wounds
- Cold atmospheric plasma treatment demonstrates superior biofilm disruption compared to chemical antiseptics
- Plasma-based debridement offers more precise and less painful tissue removal than mechanical debridement
- Combination of plasma therapy with standard wound care yields higher healing rates than standard care alone
- Plasma treatment may reduce the need for systemic antibiotics in chronic wound management
Plasma vs other advanced therapies
- Plasma therapy shows comparable efficacy to negative pressure wound therapy in promoting granulation tissue formation
- Cold plasma treatment demonstrates faster wound closure rates compared to hyperbaric oxygen therapy in some studies
- Plasma-activated liquids offer similar antimicrobial effects to silver-based dressings with potentially fewer side effects
- Combination of plasma therapy with growth factor treatments shows synergistic effects on wound healing
- Plasma treatment may provide a more cost-effective alternative to some biological dressings in chronic wound care
Future directions
- The field of plasma medicine for chronic wound treatment continues to evolve rapidly
- Ongoing research and technological advancements promise to further enhance the efficacy and applicability of plasma-based therapies
Personalized plasma medicine
- Development of point-of-care diagnostics to guide plasma treatment parameters for individual wounds
- Integration of artificial intelligence algorithms to optimize plasma therapy based on patient-specific factors
- Tailoring of plasma compositions to address specific wound healing deficits in different patient populations
- Personalized combination therapies incorporating plasma treatment with other advanced wound care modalities
- Development of wearable plasma devices for continuous, personalized wound treatment
Novel plasma delivery systems
- Miniaturization of plasma devices for improved portability and ease of use in various clinical settings
- Development of flexible, conformable plasma sources for treatment of complex wound geometries
- Integration of plasma technology into advanced wound dressings for sustained antimicrobial effects
- Creation of plasma-activated hydrogels and scaffolds for controlled release of therapeutic agents
- Design of implantable plasma devices for treatment of deep or chronic internal wounds
Combination therapies
- Exploration of synergistic effects between plasma treatment and stem cell therapies for
- Integration of plasma technology with 3D bioprinting for creation of personalized wound healing constructs
- Combination of plasma treatment with photodynamic therapy for improved antimicrobial efficacy
- Development of plasma-activated nanoparticles for targeted drug delivery in wound care
- Investigation of plasma treatment in conjunction with immunomodulatory therapies for chronic wounds
Key Terms to Review (22)
Argon plasma jet: An argon plasma jet is a device that generates a stream of ionized argon gas at atmospheric pressure, used for various medical and industrial applications. In the context of wound treatment, it provides a non-thermal method to promote healing by delivering reactive species that can aid in cell proliferation, antimicrobial activity, and tissue regeneration. The argon plasma jet creates a unique environment that enhances the healing process without causing thermal damage to surrounding tissues.
Arterial Ulcers: Arterial ulcers are a type of chronic wound that occurs due to inadequate blood flow to the skin and tissues, often as a result of peripheral artery disease. These ulcers typically appear on the lower legs and feet, presenting as well-defined, punched-out lesions that are painful and have a necrotic base. Understanding arterial ulcers is crucial when considering effective treatment options for chronic wounds and the underlying vascular issues that contribute to their formation.
Biofilm formation: Biofilm formation is the process by which microorganisms, such as bacteria and fungi, adhere to surfaces and develop a structured community encased in a protective extracellular matrix. This phenomenon plays a critical role in various biological contexts, including chronic infections and the challenges faced in wound healing, where biofilms can act as barriers to treatment and recovery.
Cancer treatment: Cancer treatment refers to the various medical approaches used to combat cancer, including surgery, radiation therapy, chemotherapy, and emerging therapies like plasma medicine. The goal is to eradicate cancer cells, shrink tumors, and improve the overall health and quality of life for patients. In recent years, plasma medicine has been recognized as a promising avenue for cancer treatment due to its ability to selectively target and destroy cancer cells while sparing healthy tissues.
Cold atmospheric plasma: Cold atmospheric plasma refers to a partially ionized gas at room temperature that contains a mix of charged particles, neutral atoms, and molecules. Unlike thermal plasmas, which can reach very high temperatures, cold atmospheric plasma operates at ambient conditions, making it suitable for various medical applications, particularly in disinfection, sterilization, and tissue regeneration.
Diabetic foot ulcers: Diabetic foot ulcers are open sores or wounds that commonly occur on the feet of individuals with diabetes, particularly those with neuropathy and peripheral artery disease. These ulcers can result from a combination of factors, including nerve damage, poor circulation, and foot deformities, making them a significant concern in diabetes management. If left untreated, diabetic foot ulcers can lead to serious complications such as infections, gangrene, and even amputations.
Dielectric Barrier Discharge: Dielectric Barrier Discharge (DBD) is a type of electrical discharge that occurs between two electrodes separated by a dielectric material, allowing the generation of non-thermal plasma at atmospheric pressure. This technique is significant because it enables stable plasma generation without the need for high voltages while producing reactive species useful for various applications such as medical treatments, surface modifications, and sterilization.
Enhanced tissue regeneration: Enhanced tissue regeneration refers to the process of accelerating the healing and repair of tissues, particularly in cases where normal healing is compromised or delayed. This involves stimulating various biological mechanisms that promote cell proliferation, migration, and differentiation, leading to improved recovery of damaged tissues. In chronic wounds, this enhancement is critical as it helps restore function and integrity to affected areas, ultimately improving patient outcomes.
FDA Approval: FDA approval refers to the authorization granted by the U.S. Food and Drug Administration (FDA) for a medical product or treatment to be marketed and sold in the United States. This process ensures that products are safe and effective for public use, especially in medical applications such as plasma therapies, which involve innovative technologies and methods.
Floating Electrode DBD Devices: Floating electrode dielectric barrier discharge (DBD) devices are systems that utilize non-thermal plasma generated between two electrodes, where one of the electrodes is not grounded or is isolated from the electric circuit. This setup allows for the generation of plasma at atmospheric pressure, which has unique properties beneficial for various applications, including the treatment of chronic wounds. The floating electrode creates an electric field that enhances the uniformity and efficiency of the plasma discharge, making it suitable for therapeutic use.
ISO Standards: ISO standards are internationally recognized guidelines and specifications developed by the International Organization for Standardization to ensure quality, safety, and efficiency across various industries. These standards play a crucial role in establishing consistency in plasma medicine applications, including plasma parameters, sterilization methods, purification processes, risk assessment, and treatment protocols.
Microwave-excited plasma torches: Microwave-excited plasma torches are devices that utilize microwave energy to create and maintain a high-temperature plasma state, which can be applied for various purposes, including medical treatments. These torches produce a controlled plasma flow that can effectively sterilize surfaces, promote wound healing, and assist in tissue regeneration by delivering thermal and non-thermal effects on biological tissues.
Plasma-activated liquids: Plasma-activated liquids are liquids that have been treated with cold plasma to enhance their chemical and biological properties. This activation process can create reactive species like free radicals and other compounds that can aid in various applications, including disinfection and wound healing. Their unique properties make them particularly valuable in personalized treatments and in addressing chronic wounds, offering targeted therapeutic benefits.
Pressure Ulcers: Pressure ulcers, also known as bedsores or decubitus ulcers, are localized injuries to the skin and underlying tissue resulting from prolonged pressure, typically over bony prominences. These wounds develop when there is sustained pressure that disrupts blood flow, leading to tissue damage and potential complications such as infection. Recognizing their significance in chronic wound management is vital as they can impede recovery and lead to serious health issues.
Prof. S. B. K. Shimizu: Prof. S. B. K. Shimizu is a prominent figure in the field of plasma medicine, known for his research and contributions to the treatment of chronic wounds using cold atmospheric plasma technology. His work has highlighted the potential of non-thermal plasmas in promoting wound healing, demonstrating both antimicrobial effects and the stimulation of cellular processes that aid in tissue repair.
Reactive Nitrogen Species: Reactive nitrogen species (RNS) are highly reactive molecules that contain nitrogen and play essential roles in various biological processes, including signaling pathways and defense mechanisms. These species, such as nitric oxide (NO) and peroxynitrite (ONOO−), can modulate cellular functions, influence inflammation, and contribute to the antimicrobial properties of non-thermal plasma treatments in medical applications.
Reactive Oxygen Species: Reactive oxygen species (ROS) are highly reactive molecules that contain oxygen, such as free radicals and non-radical derivatives. They play a crucial role in cellular signaling, but excessive ROS can lead to cellular damage, influencing processes like apoptosis, inflammation, and various disease states.
Reduced Infection Rates: Reduced infection rates refer to the decrease in the occurrence of infections, particularly in clinical settings, which can significantly improve patient outcomes and recovery times. This concept is critical in various medical applications, as it highlights the effectiveness of innovative treatments and techniques in minimizing the risk of infection during and after procedures. By employing advanced methods, such as certain plasma technologies or comparing new hemostatic techniques with conventional ones, healthcare providers can achieve better results in managing wounds and surgical sites.
Skin Rejuvenation: Skin rejuvenation refers to various cosmetic procedures and treatments aimed at restoring a youthful appearance to the skin by addressing signs of aging, sun damage, and other skin imperfections. This process enhances skin texture, tone, and elasticity, ultimately promoting healthier-looking skin. Techniques for skin rejuvenation can include topical treatments, laser therapy, and advanced technologies like plasma medicine, all designed to stimulate the skin's natural healing processes.
Surface microdischarge technology: Surface microdischarge technology refers to a method of generating low-temperature plasma at the surface of a material through the application of a high-voltage electrical discharge. This technology is significant in medical applications, particularly for its ability to promote wound healing by enhancing the biological response of tissues and controlling bacterial infections.
University of California, Los Angeles: The University of California, Los Angeles (UCLA) is a prestigious public research university located in Los Angeles, California, known for its innovative contributions to various fields, including healthcare and plasma medicine. UCLA has been at the forefront of clinical research and trials that utilize plasma technology for wound healing and oncology treatment, making significant advancements in these medical applications.
Venous leg ulcers: Venous leg ulcers are chronic wounds that occur primarily due to improper functioning of the venous system, typically resulting from venous insufficiency. This condition leads to increased pressure in the veins of the legs, causing fluid leakage into surrounding tissues and ultimately creating an ulceration. These ulcers can be painful and difficult to heal, often requiring comprehensive treatment strategies.