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Biochemical Imbalances in the Nonhealing Wound

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Vickie Driver
Vickie Driver, DPM, FACFAS, MS
Professor of Orthopedic Surgery Brown University School of Medicine
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Lecture Transcription



Hello! My name is Vickie Driver. I am chief of the Limb Preservation Service at Madigan Army Medical Center in Tacoma Washington. My topic of lecture is biochemical imbalances in the nonhealing wound. I will be focused primarily on the diabetic foot.


Production of this present lecture was made possible by an educational grant from Johnson & Johnson Wound Management, supplier of Regranex Gel, Promogran Matrix, and Actisorb Silver 220 Antimicrobial Dressing. For more information about their fine products, stay tuned after the completion of the lecture, where you will see a brief presentation about their company.


In the past 20 years, we have achieved more advances in wound care than we have in the previous 2000 years. Wound care is not just the art of medicine it is a skill. It requires an astute clinician to understand and treat the whole patient and not just the hole in the patient. As a physician who is specialist in the department of surgery, it is imperative that we now had to treat complicated patients with complex wounds we understanding the science behind the therapies.


Our learning objectives are to describe and differentiate the roles of growth factors and cytokines in the wound bed, describe the normal and abnormal processes of wound repair, describe the normal and pathophysiologic roles of proteases in the wound bed, and discuss issues of and strategies for addressing biochemical imbalances in the wound environment.


Our chosen speciality in medicine has a tremendous opportunity to do good for this particular patient population.


It is estimated that over 15% of the diabetics will develop a lower extremity neuropathic ulcer during their lifetime. Up to 20% of these patients, 86,000 people each year will require an amputation with virtually all amputations being preceded by a nonhealing wound. Diabetic ulcers are the most common cause of lower extremity amputation in the US. These patients are at high risk for second amputation in the 2 years following the first, and up to 50% will die within 3 years of surgery. These facts make the prevention and management of diabetic neuropathic ulcers a major priority for the healthcare system.




There is a significant economic burden associated with diabetic lower extremity ulcerations. For simple ulcers treated on an outpatient basis, i.e., not requiring intravenous antibiotics or amputation, the average cost per ulcer episode is considerably estimated at $7000 to $8000. An infected ulcer needing debridement, hospitalization, and antibiotics costs somewhere between $17,000 and $18,000. The cost can increase to $45,000 or more if amputation becomes necessary excluding the cost of long-term rehabilitation.


In order to understand why chronic wounds fail to heal, it is vital to first understand the process of normal wound healing.


Normal wound healing in the skin can be visualized as a highly coordinated and regulated cascade of events that may be grouped into general phases of hemostasis, inflammation, angiogenesis, granulation tissue formation and disposition, epithelialization, and remodeling the scar that ideally leads to functional repair of tissue damage. These events are temporarily regulated, but occur at overlapping timeframes. The process of wound healing is initiated by almost any type of tissue damage and in the best case, culminates in tissue repair by scar formation. The predominant cell types involved in carrying out these events of wound repair include platelets, neutrophils, monocytes, macrophages, fibroblasts, epithelial cells, and vascular endothelial cells. These cells must be able to efficiently and effectively communicate between and among themselves in order to carry out the roles in varied aspects of the healing process. The forward progression of the normal healing process is highly dependent on specific communication and precise interaction of various cell types with each other and with components of the extracellular matrix. The general way that one cell communicates with another, the target cell is via the intercellular production and extracellular release of the chemicals that convey a specific message or a signal. Cell-to-cell communication and cell matrix interaction in wound healing are regulated by key endogenous chemicals such as growth factors, cytokines, proteases, and their inhibitors.


Now, I take a closer look at a particular class of chemicals in the wound healing process – growth factors. Growth factors are small molecular weight proteins, which essentially transmit messages between cells that result in increased cell proliferation and migration, as well as in the production and disposition of the noncellular tissue components such as collagen, glycosaminoglycans, and proteoglycans.


Growth factors are small molecular weight proteins, which are synthesized by selected cells and released into the extracellular environment where they may bind to specialized surface receptors on another cell. The regulatory actions are vital to the successful coordination of the many cellular and biochemical events in the healing cascade.




The surface binding of a growth factor or cytokine to a target cell receptor initiates intercellular changes, which ultimately result in a biological response. The response to a growth factor binding may be mitogenic, chemotactic, or synthetic. In other words, the target cell divides, migrates, or produces something, usually a protein product such as an enzyme or collagen. Growth factors are sometimes described as having autocrine, paracrine, or exocrine functions based on whether they act on the same cell that produces them or nearby cell or on a distant cell retrospectively.


To achieve the effects, growth factors bind to specific cellular receptors. Growth factor receptors project from the surface of cell and through the cell membrane into the cytoplasm. Different growth factors have unique receptors and specific cell services providing growth factor specificity. Dozens of different growth factors and cytokines are at work throughout the time course of healing. There appears to be a high level of redundancy or overlapping of the roles, which is most likely the result of an evolutionary survival strategy. An expedient healing response to tissue injury is important to avoid sepsis or blood loss. Redundancy in the regulatory pathway ensures that a potential problem in one aspect of the healing process does not have a detrimental effect on wound closure.


Now, let us turn our attention to the components of a nonhealing wound – smaller amounts and fewer types of growth factors, high amounts of inflammatory cytokines, and high amounts of proteases.


When treating a nonhealing wound with smaller amounts and fewer types of growth factors, we now know that we may have an issue with the regulation and coordination of the healing process due to a lack of the communication chemicals in the wounds.




As we reviewed the growth factors on cytokines and healing, we noted that platelets respond to wound by releasing growth factors, which help to stabilize the wound, and new respond cells migrate to the wound including the neutrophils, leucocytes, and macrophages. Cytokines are secreted by macrophages, which in turn stimulate fibroblasts. Growth factors help stimulate the in-growth of new blood vessels. Failure of adequate nutrients including capillary migration to the wound bed results in chronically unhealed wounds.


Cytokines are involved in intercellular communication. They are produced by the immune system cells. They transmit messages related to bacterial defence and debridement during the inflammatory phase. Cytokines levels usually decrease after the inflammatory phase. They are also involved in the elevation of the degrading proteases. In fact, cytokines shift the wound equilibrium toward the destructive process.


A persistent inflammatory state in wound healing can be a considerable problem. This may be cause be increased bacterial burden, tissue degradation products, or repetitive trauma, and often will result in elevation of inflammatory cytokines and elevation of the matrix metalloproteinase production, and degradation of growth factors, receptor, or other structural components.




As we continue to discuss the causes of impaired wound healing, we must not forget the systemic manifestations it relates to wound healing, disease management, medications, nutrition, and all the factors that relate to the wound bed and the limb itself.


Critical or heavy bacterial colonization can upset the delicate balance in the wound by an increased inflammatory response. Then, you will see a delayed healing due to the release of bacterial endotoxins that damage growth factors and increase the levels of MMPs. An important point here is to understand that most wounds will heal, and if you have a stalled wound, you must consider if you have a heavily colonized wound, or consider if it is frankly infected.


When a wound is considered clinically infected, a podiatric physician and surgeon must employ exquisite culturing technical skills. These skills should include curettage of the wound, not a superficial swab. It is important to cleanse and debride the ulcer bed, scrape the ulcer bed with a sterile dermal curette or scalpel to obtain the tissue, send the specimen in a sterile container to your laboratory.


Infection creates a barrier between healthy tissue and any kind of wound care product that you may be applying. Infection and bacteria create and produce a biofilm. Biofilm acts as a barrier to parental antibiotics.




Biofilms are composed of communities of microorganisms including fungi, bacteria, yeast, and protozoa. They are usually encased in extracellular polysaccharide that they themselves synthesize, and this is called a glycocalix. The glycocalix protects the bacteria from antibiotics and accounts for the persistence of the infection. Fragments of the biofilm that slough off at intervals can spread the infection to distant locations within the body.


Let us now turn our attention to what a wound might look like with a high level of inflammation. Consider the fact that this wound has no obvious clinical signs of infection, no erythema, no purulence; however, it does have a very moist yellow slime layer attached to the wound bed. This is consistent with a highly colonized wound. One might consider thorough debridement, post lavage, and perhaps a topical antimicrobial at this point to treat the microenvironment of the wound bed.


As we move from a bacterial colonization to a frank infection, this is a mechanism where advancing infection causes obliteration of the small arteries. ‘A’ shows that this is an early web space infection with just patchy segmental occlusion of the digital and metatarsal vessels. Notice in ‘B’ that we have now seen thrombosis of the arteries adjacent to the web space infection, and finally in ‘C’, there is gangrene of the second and third toe. You may see this when you are treating an infected foot that has a palpable pulse and adequate blood flow, yet you end up with digital gangrene.


We have talked a bit about growth factors in the cytokines and the importance of keeping them in balance. Now, let us turn our attention to a role of another class of endogenous chemicals in the wound healing process – that of proteases. Specifically, a family of proteases known as the matrix metalloproteinase or MMPs.


MMPs are a family of structurally related protein-degrading enzymes that require calcium for structural confirmation, zinc for activity, and function optimally at neutral pH. There are about 20 different members of the family that have been identified and share similar structure. MMPs are usually expressed by cells in response to some type of tissue injury, and are not normally found in detectable levels in healthy, noninjured tissue. MMPs play a role not only in normal physiological processes such as wound healing, but also embryonic development and menstruation; but they are also a part of certain pathological processes such as tumor growth.




An individual MMP may have 1 or multiple protein substrates that they can degrade. Certain MMPs are very specific; as in collagenases only degrade collagen. Collectively, the MMP family of enzymes is capable of digesting almost all of the components of the extracellular matrix.


MMPs are not immediately active upon secretion by a cell. They are produced in an inactive or latent form and require extracellular activation. The proteolytic activity of the MMP is tightly controlled by various mechanisms. If protease activity is excessive or poorly controlled, the consequences may be excessive degradation of tissues in a variety of organ systems including the skin, the joints, and the blood vessels. A number of pathologic conditions are associated with high-level concentrations of proteases including rheumatoid arthritis, osteoarthritis, aneurysm, tumor growth, and metastasis.


A certain level of protease activity is a requisite part of the normal wound healing process. The extracellular matrix must be degraded in order to allow the various cells involved in wound repair to migrate over or through it. Epithelial cells must detach from the basal lamina in order to migrate across granulation tissue. Endothelial cells must detach and migrate through provisional matrix during angiogenesis, and the newly deposited matrix itself must be degraded and reorganized for optimal tensile strength. All of these healing processes require controlled degradation of extracellular matrix components. Immune cells secrete MMPs as they debride, devitalize tissue, and phagocytize bacteria. Proteases also play a role in activating growth factors, which are stored in or are bound to extracellular matrix components.


As podiatric physicians and surgeons, we must remember to treat the whole patient to include all core healing principles including the patient factors, physical factors, macroscopic and microscopic environment. Epidemiologic studies have suggested that there are several types of patient factors that have an impact on their risk for developing wounds as well as their expected rate of wound healing. Such factors may be characteristics of the patient’s physical constitution such as their age and ethnicity. Patient factors that effect wound healing may also be characterized of their lifestyle or habit, such as the use of alcohol or smoking or a social support system, which may effect compliance. As it relates to physical aspect of the wound, there are key characteristics of the wound itself that have an impact on the healing rates for the patient concerned. These characteristics include the overall shape and dimensions of the wound, the location, whether there is 1 or multiple wounds, the quality of the tissue, the temperature, and the quality and quantity of wound exudate. Additional characteristics of the wound may be indicative of an infective process such as the presence of cellulitis, odor, or pain, condition of wound margins or content status. Also, the duration of time that the wound has been present or if it has recurred seems to correlate with healing rates.


The center 2 rings of the core healing principle seems to be the future of wound care research. The macroscopic and microscopic biochemical environment of the wound is the focus of today’s medicine. There are also key macroscopic aspects of the overall biochemistry of the body, which can impact the biochemistry or cells involved in the healing process. These, of course, include the patient’s metabolic control, nutritional status, immune status, perfusion, presence of infection, and the moisture balance in the exposed tissues of the wound. The microscopic aspects of the wound effect cells or biochemistry might include the level of tissue proteases, the level of key intercellular communication chemicals such as cytokines and growth factors, the presence and duration of tissue hypoxia, the proliferative capacity of the cells, especially the fibroblasts, and the level of bacteria and bacterial biproducts in the wound.


Now that we have discussed key events in normal wound healing, let us focus on where these processes can go right.


Chronic wounds are characterized by senescence. Key cells are incapable of dividing and have only a muted ability to respond to growth factors’ stimulation. It has been shows that cells from biopsy specimens obtained from the margins of chronic wounds are significantly less capable of proliferating in response to exogenous growth factors than corresponding cells from acute wounds. Additionally, growth factor levels in chronic wounds appear to be insufficient to sustain proper levels of cell proliferation. In contrast to normal healing, wounds that have a high level of mitogenic activity, wound fluid collected from chronic wounds does not stimulate DNA synthesis. Epithelial cells from a chronic wound have a reduced capacity for migration. It has been shown that wounds that do not close epithelialize faster than 0.5 mm per week are likely not to heal.


Chronic wounds show a number of other defects that together impair their ability to heal properly. They are deficient in granulation tissue, which is essential for establishing that network needed to support reparative tissue. Chronic wounds also show delayed epithelialization as a result of a decreased cellular proliferative and migratory capacity. They have defective formation of the supportive stroma. Chronic wounds also often exhibit excessive protease production, which can lead to growth factor degradation of the proliferative capacity of the wound. These defects coupled with cellular senescence help to explain why chronic wounds are so difficult to heal.




Excessive level of MMPs in wounds can degrade protein growth factors, not only those produced endogenously in the wound, but also exogenous growth factor molecules that are applied therapeutically such as ________ gel. Therefore, the control of proteases is recognized as an important goal in good wound care.


The future of medicine as it relates to our field of wound healing and limb preservation is really focussed on controlling the levels of MMPs and TIMPs in nonhealing wounds. Additionally, we are, of course, looking closely at growth factor supplementation, vis-à-vis a topical growth factor, platelet-rich plasma, gene therapy, or regenerative tissue matrix.


One of the more advanced active wound care products, ORC collagen, has been brought about to modify the hostile chemistry of the nonhealing wound environment to more closely resemble that of a healing wound. Theoretically, it is thought that it this will improve the efficacy of many other wound care treatments such as topical growth factor and bioengineered tissues. ORC collagen inactivates proteases, and therefore, protects growth factors from enzymatic degradation.


This is a study looking at ORC collagen. This study looks at the overall proteolytic activity in pooled human wound fluid obtained from a group of diabetic patients treated with either ORC collagen, plain gauze, or no dressing. Note the reduction in MMP activity over time for each set of colored lines over the 24-hour time course. There was a significant reduction in MMP activity when the wound fluid was incubated with ORC collagen –the red line – decreasing to 6% of original within 30 minutes, which is the 0.5 time point. Wound fluid incubated with gauze – green line – showed no significant difference in MMP activity compare to wound fluid alone. This suggests that the ORC collagen strikingly reduces the MMP activity. One might think of ORC collagen as a sponge that soaks up and inactivates wound proteases, thereby protecting growth factors that these proteases would normally degrade.


This next study examines the ability of ORC collagen to protect PDGF activity when the growth factor is exposed to human wound fluid. The bar on the left shows the baseline biologic activity of PDGF in the study system. When chronic wound fluid is added, PDGF – platelet derived growth factor – is rapidly degraded to undetected levels, second bar from left. The addition of gauze to the system does not have any protective effect for PDGF activity, which is the third bar from the left. However, when ORC collagen Promogram is incubated with platelet derived growth factor and chronic wound fluid, there was a significant rentention of PDGF biological activity. This data indicates that ORC collagen able to protect platelet derived growth factor in a degradative environment.


This study shows that ORC collagen can also bind and sustain release platelet derived growth factor over time. Approximate 81% of the bound PDGF is released from the ORC collagen matrix within 3 days under physiological condition. This indicates that ORC collagen not only inactivates proteases and protects growth factor, but also binds and slowly releases active growth factor over a period of days. Therefore, ORC collagen matrix may be useful in treating chronic wound in protecting the activity of growth factor.


Platelet derived growth factor is a key growth factor involved in wound healing. Some of the specific deficiencies found in chronic wounds include deficiencies in platelet derived growth factor.


An early version of growth factor therapy was an autologous formation called Procuren, a platelet release aid developed in 1980s. Blood was drawn from the patient, and platelets isolated and treated to release the content of the alpha granules. The resulting released aid was applied to the wound. Such autologous formation had certain drawbacks relating to the manufacturing, lack of standardization, the patient’s heterogenicity, and lack of characterized component. They also did not have successful control trials to show a significant difference. In the 1990s, recombinant biotechnology was used to develop pure recombinant human platelet drive growth factor. Each molecule of PDGF consisted of 2 peptide chains. PDGF-BB was produced by genetically engineered yeast cells into which the gene for the platelet derived growth factor B chain is inserted. ________ was approved by the marketing by the FDA for management of chronic diabetic ulcers in 1997. Clinical trials have shown that ________ is safe and effective for increasing the incidence of complete wound closure when used in conjunction with good standard wound care.


One of the most important growth factors in wound healing is platelet derived growth factor-BB. While it was once thought that PDGF exerted only indirect functions on angiogenesis, it is now known that PDGF directly stimulates angiogenesis in a number of ways. It binds to its receptor, it actives endothelial cells to proliferate, it induces endothelial cell migration, is involved in differentiation into capillary vessel formation, and lastly it is involved in recruiting small muscle cells to newly formed blood vessels to stabilize the structures.


This slide shows that PDGF-BB has the ability to directly communicate with multiple cell types, fibroblasts, macrophage, endothelial cells and epithelial cells, as well as smooth muscle cells. PDGF-BB is able to communicate to all of the cells at the same time. These cells also have the ability to communicate between one another.


This is an example of 2 advanced wound care modalities that allows us to add exogenous growth factors using ________ and a bilayer skin substitute.


A study was published in 1996 showing that sharp debridement alone can improve the incidence of complete wound closure in a clinical trial studying diabetic neuropathic ulcers. Importantly, the addition of sharp debridement to Regranex or ________ gel therapy nearly tripled the incidence of completely healed wound over 80% when compared with debridement alone.


One of the newest wound healing devices that is being evaluated today is an autologous blood derived platelet-rich plasma. This is a machine that allows for centrifuging of blood so that the clinician will yield platelet-rich plasma that will then the released back into the patient’s wound.




This is a case that will illustrate the need for growth factor or platelet-rich plasma. This particular patient is a diabetic male in his mid 60s who had, on initial presentation, a chronic wound, neuropathic, of approximately 2-1/2 months’ duration. He is status post kidney transplant, has congestive heart failure, obese, and has a very dense diabetic neuropathy to his knee. His wound was consistent with osteomyelitis on both bone scan and MRI, which you can see on your screen.


We then moved to perform a subtotal calcanectomy as well as treated this patient with 4 weeks of IV antibiotics. We attempted to close this gentleman 3 weeks status post his subtotal calcanectomy with the late primary closure; he dehisced. We attempted this 2 more times and he dehisced again. We then moved forward with deciding to utilize platelet-rich plasma.


In this slide, you will see us actually applying the platelet-rich plasma in the top left hand corner and you will also see that one of the machines used to centrifuge the platelet rich from the platelet pure plasma. Once you have placed the gel in the wound, you leave it there for 5 to 7 days, you cover with a nonstick pad, and you cover with a composite dressing. The platelet gel application is usually done every 2 weeks. In this particular case for this gentleman, within 4 months, his wound was healed. We decided to use the rich plasma. We could have used a growth factor, exogenous growth factor, and the ________ the same way. The idea here is to apply growth factor in a patient who had very poor healing factors in the first place. He had no ability to proliferate cells on his own. He had no ability to granulate tissue. Once we aided his granulation tissue, he went on to epithelialize and closed it for months.


This is the final slide of a very successful case. In 4 months, we were able to close this wound for this very sick patient with a very chronic wound of osteomyelitis, utilizing a combination of advanced foot surgery with advanced wound care modality.


There is a plethora of regenerative tissue matrix available for the clinician today. They deliver matrix proteins in growth factors. They mimic human scan. They are contraindicated, however, for infected or heavily exudating wounds. They contain dermal fibroblasts, neonatal foreskin, collagens, etc. Important when considering a tissue matrix is what characteristics are right for you, your patient, the wound, and your institution. Consider cost, handling, storability; for example, some can be stored 2 years while others have a shelf life for 2 days; size, shape, and thickness. Do you need a bilayer skin graft or would a dermal layer do? These are important characteristics that must be considered when utilizing regenerative tissue matrix.


There is yet another a new product in the market that can stimulate healing of chronic wounds at the molecular level. It is the ultrasound debrider. It is a non-contact, non-thermal device that increases collagen synthesis. It activates inflammatory cells, which releases growth factor. It is reported to aid rapid migration of macrophages, fibroblasts, and endotheliocytes.


As we look to increase our knowledge in good wound healing practices, we must remember that it all begins with an accurate diagnosis of the wound that you are attempting to heal. We need to be involved other colleagues and consult as it relates to disease management, infection control, systemic conditions, we need to be very aware of our dressing selections, and of course we need to look to the future research for new technology.


Now, we will turn to a few cases that will illustrate the micro and macro imbalances in chronic wounds.


This is a gentleman who is a 59-year-old male with paraplegia due to lumbar spine injury who sustained a decubitus medial heel ulceration. He was diagnosed with stenosis of his femoral artery, which was stented in August 2003. His wound continued to be a nonhealing wound despite serial debridement and p.o. antibiotics. Once the infection was cleared, it was decided to place the patient on topical growth factor to be followed with an application of skin equivalent. This gentleman healed within 2 months of beginning advanced therapy.


This is a patient is a 53-year-old female with IDDM, PVD, ESRD, calciphylaxis, and a history of 4 months with distal dry necrotic digits treated conservatively by vascular surgeons. She was not a candidate for surgical removal of the digits unless infected.


This woman was clinically obviously infected. We took this patient to the operating room and proceeded to perform an incision and drainage. We resected all infected soft tissue and bone, took deep soft tissue and bone cultures, pulse lavaged the wound, placed antibiotic beats utilizing vancomycin and tobramycin, and packed the wound open.


While this patient did not have adequate blood flow to heal the more distal partial foot amputation, she was able to heal the transmetatarsal amputation. The concern was the heavy amount of exudate. This was the imbalance issue that we were fighting in the wound. We were able to manage the exudate level very nicely with the employment of the VAC therapy suction device for approximately 2 months.


The final touches for this patient, of course, was to add a TAL to the transmetatarsal amputation to restore the function and decrease the forefoot pressure, as well as to add a silicone mold and a sock to decrease the sheer force.


This is a 72-year-old diabetic male who is immediate post revascularization. Please notice the extensive necrosis both with his posterior calcaneus, his Achillis, as well as his hallux. This was a last ditch effort to save this limb as his contralateral limb had been taken just 2 months prior.


This case depicts not an advanced wound care modality that was required to help this patient, but instead a very good vascular surgeon who was able to provide revascularization. Our input was to help with a limb preserving amputation surgery that would allow this patient to push off and be at home with his wife for the remainder of his life.


This is a case where it was not quite obvious the imbalance that you are fighting. The gentleman presented with a very painful great toe. He was in the institution for a myriad of other comorbid issues. When his great toe worked up, it was noted on range of motion that he had severe pain in his first metatarsal. Upon x-ray, it was noted that his first metatarsal had obvious signs of osteomyelitis while the wound looked very benign. Intraoperatively, you can see the cortex had been penetrated and purulence was abundant. The wound was débrided of all soft tissue and bone, and the patient was given 4 weeks of IV antibiotics. The wound was closed uneventfully and healed at 6 weeks.


This is a 37-year-old patient with spina bifida with thermal injury to the plantar aspect of her foot. The treatment that was rendered was a windowed total contact cast and topical growth factor daily. The patient’s wound closed in 4 weeks.


This is a diabetic male, 65 years old, who sustained a Chopart amputation on one side and a transmetatarsal amputation on the other approximately 8 years ago. He went on to develop an anterior ulceration about 6 months ago on his right leg, and the vascular surgeons proceeded to apply a split thickness skin graft, which failed both distally and proximally. You will notice in the second slide from the top left hand corner of your screen that we placed a cadaver skin substitute, which began to take. As you follow you screen to the right, you will notice some necrosis and some yellow tissue with exudate. The graft started to fail. It was decided at that time that we were seeing a critically colonized wound bed; therefore, in your right lower corner, we moved to fenestrate the cadaver skin and combined it with a silver dressing, which was successful and healing this cadaver skin graft.


This is a very interesting case of a 51-year-old morbidly obese female with bilateral Charcot feet. At this point at the clinic, she had appeared with a very severe limb threatening infection of white cell count of 26.1. We have performed an I&D to relieve the purulence and decompress the infection, yielding the wound both dorsally and laterally. We consulted Infectious Disease. She had been placed on 2 IV antibiotics. We also then added the wound VAC to pull the exudate from the tissues. This was very successful in helping to decompress the infection along with the antibiotics and the procedure. Please note in the bottom left hand corner that we had some maceration issues, peri-wound, utilizing the suction device; therefore, we added the silver dressing to decrease the bacterial contamination and inhibit the breakdown of the peri-wound tissue.


You will notice in the top left hand corner that her dorsal wound had healed, her lateral foot wound was healing very nicely; however, she went on to yet another cellulitis and infection with purulence being decompressed on your top right hand corner of the screen. Her wound, I am happy to say, went on to heal very nicely with again the additional help of a silver dressing with alginate and VAC suction device along, of course, with antibiotics, good basic wound debridement at the clinic, and nonweightbearing.


This is a case just to show you the ORC collagen that I mentioned earlier in the presentation. The wound to the left shows a wound that had been stalled, had healed very nicely, then got locally infected. We utilized p.o. antibiotics and topical silver dressing. Continued to heal and then stalled, and then at that time, we utilized the ORC collagen with platelet derived growth factor and the wound healed shortly thereafter.


This is a 74-year-old diabetic African-American female. In the bottom slide, you see a wound with antibiotic beads being placed. The wound had then been débrided. Infection was being controlled. In the top left hand corner, you will see the patient as she came in for debridement and in the top right you, will see her prior to debridement as she came in, in her windowed total contact cast.


The wound began to heal uneventfully in the total contact cast, and daily dressings and weekly debridement; however, she had yet another Charcot event and bone began to probe through the plantar aspect of her wound. It was decided to plain the plantar prominence and close the wound primarily in that there were no clinical signs of infection. You will notice at the top right of your screen, we performed an intraoperative bilobe flap, which was very successful initially and then became a problem.


This is the last slide with this particular case and you will notice an extensive dehiscence of the wound. The patient came in at day 9 with severe foot pain with obvious clinical signs of infection and dehiscence of the wound. It became clear to us at this time perhaps an infection was ensuing pre-bilobe flap that were not aware of; so, she was treated with 4 weeks of IV antibiotics and the wound is healing very well at this time.


This is our last case of the presentation. This is a gentleman who is diabetic that sustained a trauma with a suitcase from dropping it while at the airport on his foot. He sustained a massive infection immediately following and was treated in the operating room with wide resection of his fifth metatarsal due to osteomyelitis. He was admitted to the hospital for IV antibiotics, bedrest, and nonweightbearing; however, he went on to sustain a myocardial infarction. He was then placed in the Intensive Care Unit and no further surgery was available at that time due to his unstable condition. We, therefore, chose to pack his wound daily with sliver dressings to help keep the wound infection at bay or the bacterial load down while waiting for his condition to change. He was also, of course, at that time on IV antibiotics. It was felt that with the initial step of adding the sliver dressing to decrease the bacterial load, it significantly aided in our success in saving this limb. So, the message here really is as physicians and surgeons, we are gifted really with many-many advanced modalities to augment our procedures and our medical care afforded to us via our training.


In summary, you should now be able to differentiate the roles of growth factors and cytokines in the wound bed, you can discuss normal wound healing repair process, describe the normal and pathophysiologic roles in proteases in the wound bed, and learn the issues of and strategies for addressing biochemical imbalance in the wound environment. I hope this has been both interesting and enjoyable for you.


Thank you very much.


Every podiatrist will sometime in their career have a patient with an ulcer that just won't heal. The reason that the chronic wound exists is discussed in this lecture by Dr. Driver. The lecture discusses the balance between cytokines and growth factors in wound healing. She also talks of the role that matrix metalloproteases play in chronic ulcers, and the wound care products such as Promogram and Regranex that can jump start a chronic wound into a healing wound.
Goals and Objectives
After participating in this activity, the viewer should be better able to:
1. Describe and differentiate the roles of growth factors and cytokines in the wound bed.
2. Discuss the normal wound repair process.
3. Describe normal and pathophysiologic roles of proteases in the wound bed.
4. Discuss issues of and strategies for addressing biochemical imbalances in the wound environment.

Estimated time to complete this activity is 62 minutes.
Target Audience
Physicians, diabetes educators, and other health care professionals who treat patients with diabetes.
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Biochemical Imbalances in the Nonhealing Wound
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Biochemical Imbalances in the Nonhealing Wound
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Biochemical Imbalances in the Nonhealing Wound
It is the policy of PRESENT e-Learning Systems and it's accreditors to insure balance, independence, objectivity and scientific rigor in all individually sponsored or jointly sponsored educational programs. All faculty participating in any PRESENT e-Learning Systems programs are expected to disclose to the program audience any real or apparent conflict(s) of interest that may have a direct bearing on the subject matter of the continuing education program. This pertains to relationships with pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic. The intent of this policy is not to prevent a speaker with a potential conflict of interest from making a presentation. It is merely intended that any potential conflict should be identified openly so that the listeners may form their own judgments about the presentation with the full disclosure of the facts.
Vickie Driver, DPM, FACFAS, MS Vickie R. Driver, DPM, MS has disclosed that she serves on the Speaker�s Bureau for Eli Lilly, 3M and Ethicon.
Privacy Policy
Biochemical Imbalances in the Nonhealing Wound
This web site will respect the confidentiality of the information that is transmitted on it in accordance with the provisions of this Agreement. The Web Site uses a random identifier, which is a session number attributed to the Registered User as he enters the site. This session number is expunged of the Web Site system as Registered User leaves. Please be advised that the Registered User's visit to the Web Site leaves a retrievable trace that allows the Web Site to gather raw data on the Registered User. Such technical retrieving system is necessary in order to secure the Web Site system.

This web site uses statistic and measurement systems which compile and process information such as IP numbers and number of visited pages. This information is processed in order to establish members' profiles and trends that may lead to, for example, market studies.

By registering to Web Site services, the Registered User agrees that his/her personal information may be archived in the members database of the Web Site and be used to transmit newsletters published by the Web Site and communications such as press releases or commercial information by the Host.

Information We Collect

In this section of our Privacy Policy, we discuss the different types of information we may collect about you, and the ways in which we collect them.

Information We Collect from Unregistered Visitors

Visitors to each of our Web sites can access the Web site's home page and browse some areas of the site without disclosing any personally identifiable information. We do track information provided to us by your browser, including the Web site you came from (known as the "referring URL"), the type of browser you use, the time and date of access, and other information that does not personally identify you. On most of our Web sites, you must register with us to use the entire site.

Information We Collect When You Register

Customers registering for services on our Web sites are asked to provide us with identifying information, such as name, gender, contact information, and other personal information. On our registration screens, we clearly label which information is required for registration, and which information is optional and may be given at your discretion. You will also be given a choice about whether or not you want to receive newsletters and other information that we distribute from time to time. This PRESENT e-Learning Systems Web site will explain how personally identifiable information will be used and ask for your consent before collecting it.

Other Information

Discussion Boards: When you use a discussion board on one of our Web sites, you may post a message and your user name, which is available for all registered users to see. When you are posting publicly, any user of our Web site can see your message. You should not post any information you want or are required by law to keep private to a discussion board or other public forum on our Web sites.

My CV (Curriculum Vitae): On our web site, we offer an online data based profiling tool in which you supply information that is part of your curriculum vitae or professional resume. This tool stores the information that you provide on our servers. The information is accessible by other members and the public, and is designed to advertise you to the online community and allow other's to find you based on the information that you provide. We will always make it clear to you when information you provide to us through a tool will be saved.

Member Lookup: On our website, other members will be able to look you up and send you messages. If you opt not to be listed (blocked), no other members will be able to look you up.

In addition, we gather information about you that is automatically collected by our Web server, such as your IP address and domain name. We will use this information to personalize its offerings and presentations to you, facilitate your movements throughout our Web sites, provide personalized services, and to communicate with you individually.

Continuing Medical Education

When you register for a Continuing Medical Education ("CME") or a Continuing Education ("CE") activity through our web site, we collect certain personally identifiable information from you such as your name, email address and mailing address. We require that you provide the state in which you are licensed and your license number. In addition to personally identifiable information, we collect aggregated non-personally identifiable information about the activities undertaken by our users. We use the information that we collect through CME/CE activities in several ways:

(i) We are accredited by the Accreditation Council for Continuing Medical Education ("ACCME") to provide continuing medical education for physicians, through a sponsorship agreement with the Mount Sinai School of Medicine. As an ACCME accredited entity, we are required periodically to submit aggregated data about CME participants and the CME activities we certify. We also provide personally identifiable information to other accredited CME/CE providers who certify CME/CE activities posted on our Web sites, as required by the ACCME and other accrediting bodies. These reports may include personally identifiable information about you and credits issued to you, for the purpose of maintaining records that you can request from the accredited provider for up to six (6) years;

(ii) Commercial supporters of CME/CE activities on our Web site will receive only a data about CME/CE activities that are relevant to their interests and/or the courses they support;

(iii) Our Editorial and Customer Support Staff will have internal access to files containing personally identifiable information, including evaluation forms and aggregated CME /CE participant information. These files can be accessed in order to respond to your questions or comments. Our staff may also use personally identifiable information, including registration information and evaluation data, in assessing educational needs and planning marketing activities; and we may use the information we collect as otherwise permitted in this Privacy Policy.

Use of Cookies

Cookies are a technology we use to keep track of users as they move through our Web sites. Your browser allows us to place some information on your computer's hard drive that is associated with the computer you are using. We use cookies to personalize our Web sites and to track your usage across all of our Web sites. Your Web browser can be set to allow you to control whether you will accept cookies, reject cookies, or to notify you each time a cookie is sent to you. If your browser is set to reject cookies, Web sites that are cookie-enabled will not recognize you when you return to the Web site, and some Web site functionality may be lost. The Help section of your browser will tell you how to prevent your browser from accepting cookies.

Although cookies do not normally contain personally identifiable information, if you are a registered user, we may elect to associate your registration information with cookies our Web site places on your computer's hard drive. Associating a cookie with your registration data allows us to offer increased personalization and functionality. For example, you can elect to have our Web sites "remember" your user name and password and bypass the sign-in process on each visit to the site. Without cookies, this functionality would not be possible. Some of our business partners may use cookies on our site (for example, advertisers.) We have told them that we do not want them to use cookie information to track our users' activities once they leave our Web sites. However, because of the way advertisements are served on our Web sites, we do not have total control over how advertisers use cookies on our Web site. If you believe that one of our advertisers is placing an unwanted cookie on your hard drive, please contact privacy officer ( privacy@presentdiabetes.com ) to assist us in resolving the problem.

Uses We Make of Information

In this section of our Privacy Policy, we identify the ways we may use information about you that we have collected.

Aggregate Data

We collect data about visitors to our Web sites for product development and improvement activities. We also use it for market analysis. We may provide information from our Web sites in aggregate form, with identifying information removed, to third parties. For example, we may tell a health care partner what percentage of our registered users are of a particular medical specialty or have certain credentials. Any third party that receives our data must agree not to attempt to re-identify the people it belongs to. For example, we may provide information to a potential advertiser of a product that would appeal to a diabetes patient about what percentage of our users have diabetes. Depending on our agreement with the third parties, we may or may not charge for this information.

Marketing and Advertising

We may target our advertising or marketing depending on information we have about you. For example, a user that is a healthcare professional who treats diabetes may receive advertising for new diabetes therapies (although in neither case will the advertiser have access to any individually identifiable information about you). We may also personalize our Web site based on your interests. For example, you may see different articles in different places on our Web site based on information you have shared with us, or information we have gained by observing your previous behavior, or information we may have gained from your interactions with a third party that shares information with us. We use information for our own internal marketing, research, and related purposes. Third Parties In addition to aggregate information (discussed previously), we may share some kinds of personally identifiable information with third parties as described below.

Other Companies: We have strategic relationships with other companies who offer products and services on our Web sites. When you are interacting with those companies, different rules and privacy policies may apply. We do not control the collection or use of information you provide to these companies, but we do require that those companies clearly state their policies so you can decide whether to give them any information.

Our Employees and Consultants: We contract with other companies and individuals to help us provide services. For example, we may host some of our Web sites on another company's computers, hire technical consultants to maintain our Web-based tools, or work with companies to remove repetitive information from customer lists, analyze data, provide marketing assistance, and provide customer service. In addition, if you are a healthcare professional, we may validate your licensure status and other information against available databases that list licensed health care professionals. In order to perform their jobs, these other companies may have limited access to some of the personal information we maintain about our users. We require all such companies to comply with the terms of our Privacy Policy, to limit their access to any personal information to the minimum necessary to perform their obligations, and not to use the information they may access for purposes other than fulfilling their responsibilities to us. We use our best efforts to limit the use of other companies in areas where personally identifiable information may be involved.

Promotional Offers: Sometimes we send offers to selected groups of customers on behalf of other businesses. When we do this, we do not give that business your name and address. We provide a variety of mechanisms for you to tell us you do not want to receive such promotional offers. For example, we may provide an opt-in box for consumers to receive an email from another business, and we make clear that by opting in you are submitting your data to a third party.

Protection of Information

In this section of our Privacy Policy, we discuss the security measures we take to protect information that we have collected about you.

We have implemented technology and security policies, rules and other measures to protect the personal data that we have under our control from unauthorized access, improper use, alteration, unlawful or accidental destruction, and accidental loss. We also protect your information by requiring that all our employees and others who have access to or are associated with the processing of your data respect your confidentiality. We use security methods to determine the identity of its registered users, so that appropriate rights and restrictions can be enforced for that user. Reliable verification of user identity is called authentication. We use both passwords and usernames, as well as double opt-n verification, to authenticate users. Users are responsible for maintaining their own passwords.

Access to Information and Choices

In this section of our Privacy Policy, we tell you how to obtain and correct information we have about you, and how to choose what types of information you may share with us.

Correction of Information We Have About You

If you believe that registration information collected by our Web site(s) is in error, you may edit your personal profile any time that you like. You can directly edit most of your user profile on the Web site on which you initially registered. Information that you can not edit may only be changed by contacting Web Customer Support (see CONTACTS). Requests for deletion of your record may result in your removal from the registry, but we may keep certain demographic information about you for product improvement purposes. You may contact Web Customer Support and ask for the changes that you would like to make.

Our Employees

Our employees are required to keep customer information private, as a condition of their employment with the company. Only selected, authorized employees are permitted to access personal information. Our employees with access to personally identifiable information are required to attend a confidentiality/privacy training class, and to sign a confidentiality agreement. All employees and contractors must abide by our Privacy Policy, and those who violate that policy are subject to disciplinary action, up to and including termination of their employment and legal action.
Copyright Statement
Biochemical Imbalances in the Nonhealing Wound
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