Collaborators

Roy Carr
(Quick-Med Technologies)
Bernd Liesenfeld
(Quick-Med Technologies)
Gregory Schultz
(Quick-Med Technologies, UF)
David Moore
(Quick-Med Technologies)
Jillian Vella
(Quick-Med Technologies)
William Toreki
(Quick-Med Technologies)
Gerald Olderman
(Quick-Med Technologies)

Summary

We have developed a process (NIMBUS^TM) that permanently attaches a quaternary ammonium-based polymeric microbicidal agent onto a range of physical substrates, and this is being commercialized through Quick-Med Technologies (QMT) – with a science team composed of UF alumni. The process has been shown to provide effective protection against pathogenic bacteria (including Staphylococcus aureus and epidermidis, Pseudomonas aeruginosa, MRSA, VRE), viruses and fungi, on a wide array of substrate materials.

NIMBUS technology offers an effective alternative to silver based dressings (currently the state of the art for care in clinical settings), with both lower costs, and excellent activity on antibiotic resistant species widely publicize as being increasingly problematic for health care facilities.

Current commercially available antimicrobial dressings have clearly demonstrated improved healing on chronic wounds, translating into improved patient outcomes. High cost, and the possibility of patients developing resistance to leached agents such as silver or antibiotics, has made prophylactic use of these materials potentially problematic. NIMBUS technology addresses these problems and was recently featured in TIME magazine (Vol 167, issue #12, 2006, p57), in an article that profiled this work as part of a series on technology innovators pioneering societaly relevant scientific advances.

Infection and Inflammation in Wounds

• • Wound Bed preparation. The modern paradigm for the optimal treatment for wounds is summarized neatly by the concepts of wound bed preparation – which leverages knowledge gained by practitioners in the treatment of chronic wounds. The fundamentals of wound bed preparation include the elimination of necrotic tissue and fibrinous exudate, controlling infection, establishing moisture balance, and optimizing the epidermal margin.¹ Control of infection is a critical parameter in this process, and can be achieved with the help of antimicrobial/antibacterial wound dressings.
  • Antimicrobial Wound Dressings as a barrier. A primary function of antimicrobial dressings is to provide a barrier between the wound (entry point for opportunistic pathogens), and the environment. This barrier functions two ways: i) protecting the wound from environmentally present pathogens and ii) preventing the spread of bacteria migrating from colonized dressings (containing imbibed wound exudates) by suppressing growth in the dressing. A contaminated discharge might also spread through patient contact with caregivers, other patients, linens, etc. The emergence of resistant bacteria (i.e. MRSA, VRE…) and increasing awareness of the dangers associated with nosocomial infections show the usefulness of antimicrobial dressings for patients, caregivers, and health facilities as a whole.
  • The suppression of infection and inflammation helps wounds heal faster. The bacterial colonization of a wound initiates a cascade of events that lead to a reduced healing. As bacterial load grows, the inflammatory response is stimulated, which increases protease levels, and in turn drives down the rate at which extracellular matrix (ECM) is formed, and suppresses growth factors, all of which impair healing.² NIMBUS^TM materials have been shown in laboratory tests not only to have bacteriocidal efficacy, but also to bind proteases, thus providing two methods by which the wound healing rate can be improved. Clinical evidence shows that silver based antimicrobial dressings demonstrate significantly improved rates of healing in chronic wounds by suppressing the bacterial challenge to the wound.

Figure 1. Reshedding of bacteria into a wound from a conventional dressing.

• The role for antimicrobial wound dressings as prophylaxis. Wounds in at-risk patients can progress from initial acute wounds with low levels of bacteria to critically colonized or infected wounds, with help from incubation of bacteria within dressings: bacteria shed from the wound can grow in the rich medium provided by wound fluid absorbed into common dressings (gauze, foams, alginates etc.) The bacteria growing in the “reservoir” within dressings can shed back into the wound and promote progression (Figure 1) to critically colonized levels of bacteria. Wound healing is delayed not only through the indirect retardation of healing from inflammation induced protease elevations at the wound, but also through direct production of proteases, as has been characterized from the presence of Pseudomonas aeruginosa (one of the most prevalent wound pathogens.) This sequence of events illustrates the difficulties faced within the chronic wound environment, and supports clinically observed successes associated with the treatment of chronic wounds with antimicrobial dressings. Critically, this sequence illustrates clearly where the use of antimicrobial dressings can be used to interrupt the sequence leading to critical colonization of wounds.

Antimicrobial Resistance

Resistant organisms are a growing concern in the modern health care environment. Resistant strains of particular concern are the antibiotic resistant strains MRSA, VRSA and VRE. In addition to resistances to antibiotics, bacterial resistance to silver has also been documented, particularly in the UK. Both antibiotics and silver attack metabolic processes in microbes and corrupt replication after they enter through the cell wall.³ Various microbes have found ways to resist these processes (and ways to pass this acquired resistance on to other microbes through plasmid sequences.) Quaternary ammonium compounds (‘quats’ or polyquats in the case of polymeric structures) have a fundamentally different mechanism of antimicrobial activity. Quats chemically destabilize the cell wall structures, inducing cellular collapse, as illustrated in figure 2a and 2b. Since the structural chemistry of the cell wall is relatively immutable, the generation of resistance to this mechanism is extremely unlikely. NIMBUS™ materials are unlikely to stimulate resistance in microbes since they operate based on a cell wall disruption mechanism.

Figure 2 Discussion: Mechanism of microbicidal activity of quaternary polymer. Figure 2a depicts the compromise of a bacterial cell wall by the NIMBUS polymer. The charged polymer chains compromise microbial cell walls, and induce cell lysis, as depicted in the before and after frames of E. coli bacteria (Figure 2b) that have had their cell walls compromised in the manner depicted, as can be seen from their appearance which resembles empty bags, or burst balloons.
Normal bacterial membranes are stabilized by Ca2+ ions binding anionic charged phospholipids. NIMBUS quat-polymer rapidly displaces Ca2+ leading to loss of fluidity and eventual phase separation of different lipids. Domains in the membrane then undergo a transition to more smaller micelles leading to membrane disruption. Ref: Antimicrobial Techniques for Medical Nonwovens – A Case Study by C White & J Olderman,

Safety Testing

*Testing performed on NIMBUS™ treated cotton gauze, by Toxikon Laboratories, Bedford, MA NIMBUS materials have passed all standard toxicology tests for prolonged use materials (1-30 days) in direct contact with breached or compromised skin. The FDA is currently reviewing a 510(k) submission on the material.

Safety tests performed and passed, as per ISO 10993.⁴

• Cytotoxicity
• Kligman Maximization (dermal sensitization)
• Primary Skin Irritation
• Acute Systemic Toxicity

NIMBUS Testing Conclusions

The NIMBUS materials detailed have undergone extensive testing for safety, efficacy, durability and production compatibility. Results are presented based on testing by AATCC method 100-1999 unless otherwise noted. The results demonstrate that NIMBUS materials have broad microbicidal efficacy (Table 2), are long lasting (Table 1), and can stand up to the specific challenge of resistant strains of organisms (Table 3). These tests conclusively show that NIMBUS materials make a safe and effective antimicrobial dressing.

Current NIMBUS projects at UF

The use of NIMBUS antimicrobial technology as the platform for a dressing designed to speed the healing of chemical weapons inducted injuries. This project uses biochemistry that extends readily to injuries common in industrial accidents and to thermal burns.

Advanced wound dressings utilizing NIMBUS technology to integrate protease inhibition features into dressings. The inhibition of proteases has been associated with the improved closure of chronic wounds. The leverage of NIMBUS technology to integrate both antimicrobial and protease inhibitory properties into an economical wound dressing provides the opportunity for UF and QMT to provide wound healing with a new standard of dressing.

Clinical Testing: NIMBUS wound dressing materials are currently pending evaluation in a clinical trial at the University of Florida Burn Unit. This trial is designed to validate the ability of NIMBUS dressings to prevent the colonization of dressing materials by opportunistic, typically either environmental or skin commensurate bacteria. Nosocomial infections represent a significant focus of attention lately, and the species of particular concern for nosocomial infections are the antibiotic resistant species such as MRSA and VRE against which NIMBUS materials have proven highly effective.

Figure 3a: Control

Figure 3b: Nimbus treatment

No zone of inhibition for treated gauze due to immobilization of the polyquats:

Figure 3 discussion: Cotton gauze samples were inoculated with various volumes of 5.8 x 10E3 cfu/mL of E. coli in PBS (counter-clockwise from top right: 0.5 mL, 0.75 mL, 2.0 mL, and 1.25 mL), and then incubated for 15 hours at 37 degrees C tryptic soy agar (Difco) containing 0.01% TTC. Red color indicates areas of bacterial metabolism.

References

1. 1. Schultz GS, Sibbald RG, Falanga V, Ayello EA, Dowsett C, Harding K et al. Wound bed preparation: a systematic approach to wound management. Wound Repair Regen. 2003;11 Suppl 1:S1-S28.
2. 2. Wright, BJ, Lam, K, Olson, ME, Burrell, RE, Is Antimicrobial Efficacy Sufficient? A Question Concerning the Benefits of New Dressings, Wounds, 2003; 15(5):133-142
3. 3. Silver S. Bacterial silver resistance: molecular biology and uses and misuses of silver compounds. FEMS Microbiology Reviews. 2003; 27:341-353.
4. 4. Test reports from Toxikon on file with Quick-Med Technologies
5. US Patent # 7,045,673 (2006) Intrinsically bactericidal absorbent dressing and method of fabrication