PDR Technology Overview
In the following pages,
Understanding PDR Technology Overview
The natives of Haiti, known as the Taino people, discovered medicine from the bark of trees such as cinchona and willow. The Taino people used these barks to create medicinal teas and poultices that were used to treat a variety of ailments, including fever, pain, and inflammation. Upon further analysis of the bark’s contents, metal ions have been discovered that reduce the inflammatory effects of wound healing.
The studies were clinically evaluated using the impregnated wound dressing Acutarex™ PDR™.
A summary of the clinical cases studies from those evaluations as depicted below:
Case Number
1
Patient
51 YO male, Type 2 diabetes, asthma, hepatitis, hypertension, and smoking
Wound description
Long-standing ulcer
at the level of the first metatarsal phalangeal joint of his right foot, limited mobility, wound was fibrous and dystrophic
Result of using the impregnated dressing
Marked improvement in the wound noted within the first four weeks of using dressing, with progressive improvement through the 16th week visit, and eventual closure of the wound
Case Number
2
Patient
54 YO male, history of diabetes, periph-eral neuropathy , previous
partial right foot amputation
Wound description
Large open surgical wound be-tween the 3rd and 5th Rays, no extension of abscess, no purulence, no foul odor, superficial desquamation
of the skin, and questionable viability of 3rd and 5th digits.
Result of using the impregnated dressing
After debridement and resection, the wound responded to PDR dressing and progressed toward closure over a 27-week period
Chronic wounds
Chronic wounds have been defined as those that fail to progress through normal, orderly and timely sequence of repair.
Chronic wounds:
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Become out of balance and stall at some point along the healing cascade
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Fail to show signs of healing in two to four weeks
When a wound has stalled, the cells function differently from normal because they are out of balance. That is why it is important to look at the normal healing process to understand where and how a wound gets stalled.
Wound healing
Wound healing is a complex regenerative process to repair or replace injured tissue. The injury often involves some form of ischemia and when injured, the natural balance between cells is disrupted, creating an altered environment.
Cells in the injured tissue immediately begin a process to regain their pre-injury state. This process is comprised of the set of intricate biochemical interactions that take place in a well-orchestrated series of events, or phases as shown in Figure 1.
Phases of healing
These phases of wound healing overlap in time. The time for each phase may vary considerably based upon a person’s age, general health, and other key factors. Over the decades, therapies for the treating chronic wounds have focused on one or more of the phases, assuming that the defect lives in one of the phases and can be treated. In fact, chronic wounds are more complicated. Different defects that cause healing to stall can occur in different phases, e.g., diabetic wounds tend to have defects in the inflammation phase of healing while venomous stasis ulcers have problems in the repair phase as shown in Figure 2.
Figure 1: Natural Wound Healing Cascade of Events
Hemostasis – Vessels have ruptured followed by platelets that aggregate and then degranulate (release growth factors) along with fibrin clot formation
Inflammation – Neutrophils locate in the tissue and consume bacteria and debris and macrophages are present to provide stimulatory signals and matrix turn over
Repair – Migration/proliferation of cells
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Angiogenesis – Formation of new blood vessels
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Fibroplasia – Fibroblasts migrate into wound and replicate; collagen synthesis and deposition underway
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Epithelialization – New skin cells migrate from wound margins and hair follicles
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Contraction – Myofibroblasts pull on wound edges
Remodeling – Changes in matrix composition over time (scar)
Figure 2: Chronic Wound Healing Cascade of Events
Hemostasis – May have been established before the skin was breached
Inflammation – Bacteria may be well established with high levels of MMPs and cytokines. Fewer neutrophils may be in the tissue to consume bacteria and debris and macrophages may be providing excessive stimulatory signals and there is excessive matrix turn over
Repair – Migration/proliferation of cells
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Angiogenesis – Formation of new blood vessels is limited or non-existent
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Fibroplasia – Fibroblasts are senescent and not migrating into wound or replicating; collagen synthesis and deposition is limited
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Epithelialization – cells not replicating – granulation tissue may
not be present
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Contraction – Myofibroblasts may not have formed
Remodeling – Little if any remodeling occurs
DNA micro-arrays can be used to show how PDR™ technology changes gene response. The red indicates genes with increased activity and the green color indicates genes with reduced activity.
Figure 5 illustrates different diabetic and normal fibroblasts are from one another before exposure to PDR™ technology. This is consistent with clinical settings where diabetic patients differ significantly from non-diabetic patients.
Figure 6 illustrates the response of a selected portion of all the genes available for analysis from normal and diabetic fibroblasts when exposed to PDR™ technology. The diabetic fibroblasts become more like normal fibroblasts after exposure to PDR™ technology.
Figure 5: Gene array of normal and diabetic fibroblasts before treatment
Figure 6: Gene array of normal and diabetic fibroblasts after exposure to PDR™ technology
Altering the wound environment
Clinicians understand that they must do something to alter the wound environment in their efforts to jump-start the wound. That is why they change treatments whenever a wound fails to respond after a couple of weeks. There are a few diagnostic tools available to benchmark the condition of a wound before treatment begins and to monitor the changes as healing progresses. Nonetheless, experienced clinicians have sharp observational skills and have developed techniques to assess when a chronic wound is responding favorably to treatment without knowing precisely why.
A wound dressing can alter the environment of an:
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Absorbing excess fluid
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Helping to manage microbes in the wound
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Absorbing and altering the activity of MMPs
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Impacting the signaling of nitric oxide
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Influencing any of the numerous integrated biochemical pathways and environmental factors
The result will be manifested in observable changes in the appearance and size of the wound.
PDR technology is proving to be effective
The case studies studies on following pages demonstrate some of the favorable results observed with use of PDR™ technology.
Patient GJ
Non-healing diabetic foot ulcer
Patient History
Patient GJ is a 51-year-old male with a history of Type 2 diabetes, (insulin requiring), asthma, hepatitis, hypertension, and smoking. He had a long-standing ulcer at the level of the first metatarsal phalangeal joint of his right foot. The patient had previous injuries, surgical intervention, and skin grafting that left him with a partially marsupialized lesion over the medical aspect of his right foot, limited mobility, and a chronic wound which was fibrous and dystrophic.
Initial Wound Description
Prior to the use of PDR™ dressing (figure 6), the ulcer was full thickness, measured 4.4 cm x 3.8 cm, and had been present to varying degrees for about two years. There was moderate to heavy drainage that was serous and non-purulent. There was no malodor or bloody discharge noted. The peri-wound skin was pink, indurated, and somewhat macerated. The wound bed contained 100% fibrous sloug with no granulation tissue present.
Prior Wound Management
Off-loading and in-office sharp and enzymatic debridement were completed with little success.
New Wound Management
The wound was surgically debrided and PDR™ dressing was placed over the clean wound bed and covered with sterile gauze and gauze wrap.
Case Study Results
Marked improvement in the wound was noted within the first four weeks of using PDR™ dressing (Figure 7), with progressive improvement through the 16th week visit (Figure 8), and to eventual closure of the wound (Figure 9). The exact date of wound closure is not known.
Case Summary
This case study highlights a 51-year-old patient with Type 2 (insulin requiring) diabetes and a full thickness, long-standing chronic wound over the medial aspect of his right foot that was stalled in a non-healing state for approximately two years.
Figure 6: The initial wound (full thickness, 4.4 cm X 3.8 cm)
Figure 7: The wound after 4 weeks of Acutarex™ dressing use.
Figure 8: The wound approaching
closure after 16 weeks of Acutarex™ dressing use.
Figure 9: Wound closure occurred sometime prior to this visit.
Patient ES
Non-healing diabetic foot ulcer
Patient History
Patient ES is a 54-year-old male with a history of diabetes, peripheralneuropathy and a previous partial right foot amputation. He was initially seen as in in-patient for an abscess and suspected 4th metatarsal osteomyelitis. He was taken to the OR for debridement, resection of non-viable bone and soft tissue, and lavage. The 4th toe was amputated with a partial 4th Ray resection.
Initial Wound Description
Prior to the use of PDR™ dressing (Figure 10), there was a large open surgical wound between the 3rd and 5th Rays. There was no extension of abscess, no purulence, and no foul odor. There was superficial desquamation of the skin, and questionable viability of the 3rd and 5th digits.
New Wound Management
PDR™ dressing was used as a wound packing and primary dressing beginning 6 days after the surgical resection and amputation was complete (Figure 10). The dressing was held in place with sterile gauze and gauze wrap changed daily. After discharge from the hospital, the use of PDR™ dressing continued at home. The dressings were changed daily by the patient with PDR™ (PDR) dressing packed to the depths of the wound. The patient was seen weekly for about a month by the foot and ankle surgeon, and then every two weeks until the wound closed. Sharp debridement was performed as needed.
Case Study Results
Marked improvements in the wound were noted within the first two to three weeks of using PDR™ dressing (Figure 11), with continued and progressive improvements observed throughout the period of use (Figure 12). Wound closure occurred after approximately 27 weeks of use (Figure 13).
Case Summary
This case study highlights a 54-year-old patient with a history of diabetes and a large surgical debridement and resection wound of the 4th metatarsal due to abscess and osteomyelitis. After debridement and resection, the wound responded to PDR™ dressing and progressed toward closure over a 27-week period.
Figure 10: 6 days post-surgery.
Acutarex™ dressing use was initiated.
Figure 11: 16 days post-surgery and 10 days
after initiation of Acutarex™ dressing use. Marked improvements in the wound were
noted.
Figure 12: 11 weeks post after
initiation of Acutarex™ dressing use.
Figure 13: wound closure after
27 weeks of Acutarex™ dressing use.
Clinical Evaluations
Diabetic ulcer
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In existence for 3 months prior to treatment
Week 0
Week 6
Clinical Evaluations
Diabetic ulcer
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In existence for 3 months prior to treatment
Week 0
Week 6
Clinical Evaluations
Acute Wound
Initial wound took 4 weeks to heal.
Week 0
Week 4
Glossary
Angiogenesis – The process of developing new blood vessels.
Biochemical – The substances making up bodily tissues and fluids.
Biofilm – A structured community of microorganisms encapsulated within a self-developed polymeric matrix and adherent to a living or inert surface.
Contraction – Around a week after the wounding takes place, fibroblasts have differentiated into myofibroblasts and the wound begins to contract. In full thickness wounds, contraction peaks at 5 to 15 days post wounding and can last for several weeks and continues even after the wound is completely reepithelialized. Contraction occurs in order to reduce the size of the wound.
Epithelialization – The process where epithelial cells migrate over granulation tissue in the wound bed to form a barrier between the wound and the environment. Cells advance in a sheet across the wound site and proliferate at its edges, ceasing movement when they meet in the middle.
Extracellular matrix – Created and modified by fibroblasts consisting of a network of collagen.
Fibroblasts – A type of cell in wounds that synthesizes and maintains the extracellular matrix (the structural framework for many tissues) and plays a critical role in wound healing. They are the most common cells of connective tissue
in animals.
Fibroplasia – A stage in wound healing normally beginning 2-5 days after the injury and ending 2-4 weeks later.
Granulation tissue – Tissue consisting of new blood vessels, fibroblasts, inflammatory cells, endothelial cells, myofibroblasts, and the components of a new, provisional extracellular matrix. Required for a wound to heal.
Hemostasis – A response occurring shortly after injury. Bleeding creates fi brin clots at the ends of severed blood vessels. The clots become a temporary matrix responsible for promoting coagulation of blood cells and migration of cells that trigger the release of various growth factors.
Inflammation – The complex biological response of tissues to harmful stimuli, such as bacteria, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a synonym for infection.
Inflammatory cytokines – Signaling biomolecules responsible for communication between cells.
Ischemia – A restriction in blood supply resulting in damage of tissue.
Macrophages – Cells essential to wound healing. They replace neutrophils as the predominant cells in the wound by two days after injury. Attracted to the wound site by growth factors released by platelets and other cells. The main role of the macrophages is to engulf and remove bacteria and damaged tissue, and it also debrides damaged tissue by releasing proteases.
Mitogenic activity – Leading to cell division.
Mitotically competent cells – Cells capable of dividing.
MMP – Matrix metalloproteinases – Enzymes that break down proteins. They are also thought to play a major role in many different cell functions.
Myofi broblasts – A cell that is in between a fi broblast and smooth muscle cells that are then capable of speeding wound repair by contracting the edges of the wound.
Neutrophils – White blood cells normally found in the bloodstream that react within an hour of tissue injury and are the hallmark of acute infl ammation.
Protease – An enzyme that breaks down proteins.
Remodeling – Part of the wound healing process
where repaired tissue is modifi ed to become more like uninjured tissue.
Repair – Regenerative process to replace tissue lost to injury.
RNS – Reactive nitrogen species – Produced through
the reaction of nitric oxide with superoxide (O2−) to form peroxynitrite (ONOO−). They act together with ROS to carry out detrimental effects on cells.
ROS – Reactive oxygen species – Natural byproducts of the normal cell metabolism of oxygen and have important roles in cell signaling. These can increase dramatically leading to signifi cant damage to cell structures.
Stalled wound – Wound that is not healing and is not reducing in size or improving in appearance.
TIMP – Tissue inhibitors of metalloproteinases (TIMPs).
References for this 510K Product
1. Diegelmann RF, Evans MC. Wound healing: an overview of acute,
fibrotic and delayed healing. Front Biosci. 2004 Jan 1;9:283-9.
2. Mustoe TA, O’Shaughnessy K, Kloeters O. Chronic Wound Pathogenesis and Current Treatment Strategies: A Unifying Hypothesis. Plastic and Reconstructive Surgery Volume 117(7S) SUPPLEMENT, June 2006, pp 35S-41S.
3. Stadelmann WK, Digenis AG, Tobin GR. Physiology and healing dynamics of chronic cutaneous wounds. Am J Surg.
1998 Aug;176(2A Suppl):26S-38S.
4. Broughton G, Janis JE, Attinger CE. The basic science of wound healing. Plast Reconstr Surg. 2006 Jun;117(7 Suppl):12S-34S.
5. Campos AC, Groth AK, Branco AB. Assessment and nutritional aspects of wound healing. Curr Opin Clin Nutr Metab Care. 2008 May;11(3):281-8.
6. Mathus-Vliegen EM. Old age, malnutrition, and pressure sores: an ill-fated alliance. J Gerontol A Biol Sci Med Sci. 2004 Apr;59(4):355-60.
7. Yager DR, Kulina RA, Gilman LA. Wound fluids: a window into the wound environment? Int J Low Extrem Wounds.
2007 Dec;6(4):262-72.
8. Komesu MC, Tanga MB, Buttros KR, Nakao C. Effects of acute diabetes on rat cutaneous wound healing. Pathophysiology.
2004 Oct;11(2):63-67.
9. Rushton I. Understanding the role of proteases and pH in wound healing. Nurs Stand. 2007 Apr 18-24.
10. Shilo S, Roy S, Khanna S, Sen CK. MicroRNA in cutaneous wound healing: a new paradigm. DNA Cell Biol. 2007 Apr;26(4):227-37.
11. Schäfer M, Werner S. Transcriptional control of wound repair.
Annu Rev Cell Dev Biol. 2007;23:69-92.
12. Cooper L, Johnson C, Burslem F, Martin P. Wound healing and
inflammation genes revealed by array analysis of ‘macrophageless’ PU.1 null mice. Genome Biol. 2005;6(1):R5. Epub 2004 Dec 23.
13. Kapoor M, Kojima F, Appleton I, Kawai S, Crofford LJ. Major enzymatic pathways in dermal wound healing: current understanding and future therapeutic targets. Curr Opin Investig Drugs. 2006 May;7(5):418-22.
14. Xue M, Le NT, Jackson CJ. Targeting matrix metalloproteases to improve cutaneous wound healing. Expert Opin Ther Targets.
2006 Feb;10(1):143-55.
15. Ravanti L, Kähäri VM. Matrix metalloproteinases in wound repair
(review). Int J Mol Med. 2000 Oct;6(4):391-407.
16. Wysocki AB, Staiano-Coico L, Grinnell F. Wound fl uid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol. 1993 Jul;101(1):64-8.
17. Madlener M, Parks WC, and Werner S. Matrix Metalloproteinases
(MMPs) and Their Physiological Inhibitors (TIMPs) Are Differentially Expressed during Excisional Skin Wound Repair. Experimental Cell Research 242, 201–210 (1998).
18. Soo C, Shaw WW, Zhang X, Longaker MT, Howard EW, Ting K. Differential expression of matrix metalloproteinases and their tissue-derived inhibitors in cutaneous wound repair. Plast Reconstr Surg. 2000 Feb;105(2):638-47.
19. Menke NB, Ward KR, Witten TM. Impaired wound healing. Clinics in Dermatology (2007) 25, 19–25.
20. Schultz G. MMP-9 Protease levels as an indicator of wound bed preparation and healing. The World Union of Wound Healing Societies, Third Congress, Toronto, Canada 2008
PDR™
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FDA compliance with 510(k)
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The PDR™ formulation includes a composition consisting of potassium, zinc, calcium, and rubidium to aid in the healing of chronic and advanced wounds. Chronic wounds are generally defined as wounds that have not healed after thirty days of consistent clinical treatment, and include diabetic ulcers, burns, pressure ulcers (bedsores), and venous stasis ulcers. PDR™ acts at the level of gene expression to down-regulate the production of Matrix Metalloproteinases (MMPs), enzymes that when they remain in elevated concentrations in the wound, impede wound healing, leading to chronic wounds.
(Approximately 80% of chronic wounds display elevated levels of proteases, including MMPs, which impede or stop the wound-healing process.) In addition to down-regulating MMPs, this product also down-regulates the expression of pro-inflammatory cytokines, and upregulates growth factors, resulting in cell proliferation. PDR™ technology helps rebalance the wound environment, allowing stalled wounds to progress towards healing.
DISCLAIMER:
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All the following representations of product names, packaging, and designations on the following pages are undergoing review and upgrading for 2020. Current technical and
visual information as presented may vary. Acutarex™ is an internationally registered trademark of Advanced Healing Technologies, LLC.
Other product names are currently in various stages of trademark registration.
ACT PDR™-Impregnated
Wound Dressing
Available in non-sterile
and sterile box of 4 or 10
Available in 2 x 2, 4 x 4, 6 x 6, 8 x 8, 12 x 12, and 4 x 8 in
Packaging in tubes of 1, 2, and 4oz (Non-sterile)
Pricing available upon request.
Acutarex™ Advanced Chronic
Which has also been marketed under the trade name Acutarex™. It is a wound care dressing solution that aids in the management of hard-to-heal wounds. It is designed to help jump-start wounds, enabling the wound to progress through the normal healing cascade.
Approval Status
This product received 510(k) clearance from the FDA in May 2005. It is being marketed in the U.S. under the brand name Acutarex™. It is now being produced in the U.S. under the current FDA 510(k) clearance. Based on the current 510(k), it will be marketed as Acutarex™ Advanced Wound Care Dressings in many other countries.
*All packaging illustrations are concept proposals and may or may not represent final packaging. Product names may also change as part of the trademark registration process.
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