ADVANCES IN WOUND THERAPY - · PDF fileWe presented Advances in Wound Therapy: ... veloping...

ADVANCES IN WOUND THERAPY

Materials in this supplement were reviewed and approved by the SAWC committee for the CME lecture.

This supplement was not subject to WOUNDS® peer-review process.

Supported by Osiris Therapeutics, Inc.

UNDERSTANDING DIFFERENCES BETWEEN CELLULAR AND ACELLULAR THERAPIES IN THE TREATMENT OF CHRONIC WOUNDS

Supplement to WOUNDS®

Osiris_cover.indd 1 7/16/14 3:35 PM

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ADVANCES IN WOUND THERAPY: UNDERSTANDING DIFFERENCES BETWEEN CELLULAR AND ACELLULAR THERAPIES IN THE TREATMENT OF CHRONIC WOUNDSLawrence Lavery, DPM, MPH and Dot Weir, RN, CWON, CWS

The continued development of advanced wound therapies is quickly changing the field of wound care. With im-provements in treatment, clinicians are able to help patients heal quicker and more easily, especially when utilizing cellular and acellular treatment modalities.

We presented Advances in Wound Therapy: Understanding Differences between Cellular and Acellular Therapies in the Treatment of Chronic Wounds in an accredited continuing medical education presentation at the SAWC Spring/WHS 2014 meeting at the Gaylord Palms Hotel and Convention Center in Orlando, Florida. The following non-CME supplement has been adapted from that presentation.

As we continue to emphasize multidisciplinary disease management in the treatment of high-risk patients with chronic wounds, facilitating an optimal wound healing environment and improving the time to healing are critical.

Accordingly, our discussion in this supplement begins with a conceptual framework and the current tools available for treating chronic wounds in our field. We differentiate between cellular and acellular modalities, noting the ben-efits and risks of each based on current research.

We then launch into a discussion about stem cells and how they are significantly altered in patients with diabetes. Advanced therapies can help address these issues by preserving stem cells and maintaining their functionality.

We reviewed the landscape of various advanced wound care treatments, assessing the clinical and scientific data, and levels of evidence for each. We also explored various case-based scenarios involving some of these advanced modalities in the treatment of chronic wounds.

We would like to thank Osiris Therapeutics for their support of this supplement. We hope that the insights gener-ated through this discussion will help those of us who treat chronic wounds to achieve improved outcomes for our patients.

— Lawrence Lavery, DPM, MPH, and Dot Weir, RN, CWON, CWS

The thoughts and opinions expressed in this supplement are those of the authors and not necessarily those of Osiris Therapeutics.

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FACULTY

DISCLOSURESDr. Lavery is a consultant for Innovative Therapies, Inc. (ITI), KCI Medical, and PamLab. He is on the speaker’s bureau for Innovative Therapies, Inc. (ITI), KCI Medical, PamLab, and Shire Regenerative Medicine. Dr. Lavery has received grant/research support from GlaxoSmithKline, Integra Lifesciences, KCI Medical, MacroCure, Osiris Thera-peutics, Smith & Nephew, and ThermoTek. He has received royalties or holds patents with Diabetica Solutions. Dr. Lavery is a stock shareholder with Diabetica Solutions and Prizm Medical Resources.

Ms. Weir is on the advisory board or is a consultant for Mölnlycke Health Care, Spiracur, Smith & Nephew, Hollis-ter, Organogenesis, and Central Medical Systems. She is on the speaker’s bureau for Osiris Therapeutics, Spiracur, Smith & Nephew, Hollister, Organogenesis, Mölnlycke Health Care, and BSN Medical.

Lawrence Lavery, DPM, MPH, is a Professor in the Department of Plastic Surgery, as well as Director of Clinical Research in the Department of Plastic Surgery, at the University of Texas South-western Medical Center, Dallas, TX. His

research group has published 208 peer-reviewed papers and has received extramural funding from the VA, NIH, AHRQ, American Diabetes Association, and two Ameri-can College of Foot and Ankle Surgeons.

He is the past chair of the American Diabetes As-sociation Foot Care Council and the American Public Health Association Foot Section. He serves on the ed-itorial board for Diabetes Care and has authored more than 100 peer-reviewed papers and several books. His areas of research interest include amputation prevention in high-risk diabetics, epidemiology of diabetic-related amputations, the use of footwear and insoles to prevent re-ulceration in high-risk diabetics, and fracture compli-cations in diabetes.

Dot Weir, CWON, CWS, has been a reg-istered nurse for 38 years, with 34 of those in wound and ostomy care. She has practiced in all areas of healthcare as well as industry. She is board certified by the Wound, Ostomy and Continence Nurses

Certification Board (CWON) and the American Board of Wound Management (CWS). She practices part-time at the Wound Healing Center of Osceola Regional Medical Center in Kissimmee, Florida as well as the Wound Care and Hyperbaric Medicine Center at Health Central Hospi-tal in Ocoee, Florida. Ms. Weir is the Co-Chair of the Sym-posium on Advanced Wound Care (SAWC), was on the founding board of the Association for the Advancement of Wound Care (AAWC), and has held positions as treasur-er and president. She has been a member of the WOCN since 1980, the FAET since 1979, and a member of the WHS since 2008. Ms. Weir has authored and co-authored many journal articles and 6 book chapters. She is on the faculty of the Wound Certification Prep Course, Founding Editor of Today’s Wound Clinic, and Co-Chair of Present Wounds for Nurses and Therapists, an e-learning site.

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ADVANCES IN WOUND THERAPY:

In the diverse field of wound care, clinicians must be pre-pared with the necessary

education and tools to heal patients. Even then, new chal-lenges will be presented and innovative solutions found. Over the last few decades, wound care has become more advanced. With continually de-veloping technology, the suc-cess rate of healing the most difficult wounds will greatly improve. In order to be suc-cessful in this role, clinicians must begin with the knowl-edge of how far wound care has come and how to create a conceptual framework.

CREATING A CONCEPTUAL FRAMEWORK

We have gone from simple disease awareness to a true fo-cus on disease management as it relates to helping patients heal. We focus more on the wound environment and wound heal-ing. Now we are really think-ing about how we can prepare the wound and how it can ac-tually impact cellular activity and wound healing. We are also

focusing on time to healing, which is not only important from a morbidity and mortality standpoint, but also from a cost perspective. Wound healing is ultimately a multidisciplinary effort involving physicians, po-diatrists, nurses, physical thera-pists, PAs, and other vital staff members.

TOOLS FOR TREATMENTWhen we look at some of

the products that we have to advance wound healing, they can be classified as either be-ing cellular (containing liv-ing cells) or acellular (cells have been devitalized with or without removal from matri-ces). The sources of those can be biologic, coming from an-imals (equine, bovine, porcine, ovine, sharks, etc.), from hu-man sources (cadaveric skin, placental tissues, neonatal fore-skins), or from plants. Cellular products may also be made by combining cells with synthet-ic scaffolds, things that are not naturally present in our tissues but are able to coexist with our tissues, or they may be a com-

posite of cells with both bio-logic and synthetic materials.

The goal of most cellular skin substitutes is to restore some sort of skin barrier and to pro-mote wound closure. We want the cells to be able to secrete things like collagen and other extracellular matrix proteins. Cellular skin substitutes have the ability to interact and re-spond with their environment, and then synthesize the growth factors and extracellular matrix proteins that are needed based on the needs of that wound.

The cellular modalities are able to provide temporary wound coverage. They also help protect against losing moisture and provide some bacterial pro-tection at least early on after ap-plication. These cellular prod-ucts are not skin grafts. There is no vascularization and no in-growth of vessels into the grafts. They do not integrate into the tissues and there is not necessar-ily any permanent persistence.

Interestingly, a recent study by Hu et al looked at bilayer cell therapies that were placed on partial-thickness skin graft

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donor sites.1 At the end of 10 weeks, they did biopsies to look for the DNA persistence of the cellular product that had been placed on the donor sites and only 2 out of the 10 did have some residual persistence.

Another recent case by Sere-na et al was serendipitous.2 He put a bilayered skin substitute on a large wound. Ten months later, the patient returned with a wound in the previously treat-ed area. A biopsy of the wound for human leukocyte antigen revealed the presence of donor DNA from the bilayered liv-ing cell therapy, suggesting that bilayered living cell therapy in some cases may persist for lon-ger periods in patients without underlying skin disease or im-munosuppression.

One of the advantages of cel-lular therapies is that they do have active living cells in the construct. These cells, such as keratinocytes and fibroblasts, do have the ability to produce and synthesize various types of mediators such as cytokines and growth factors. In a prod-uct with a combination of two

different cell types, a certain set of growth factors may come from the keratinocytes, which would then stimulate the fibro-blast and synthesize other kinds of growth factors or cytokines in that particular wound.

Acellular matrices are usual-ly human- and animal-derived products. They have been pro-cessed to devitalize cells, which can then be removed from matrices or left in them, leav-ing behind the collagen ma-trix and destroying any kind of pathogens by sterilization of the product as well as tak-ing out anything that might cause some kind of an immune response. These are primari-ly collagen products that can be cross-linked. Cross-linking will stabilize them, make them more durable, inhibit or reduce the speed at which they bio-degrade, and help prolong the presence in the wound. Many of these matrices can act as a biological modulator that helps to influence biological process-es such as healing.

Acellular matrices interact with the wound bed. They pro-

vide scaffolding and can act as a sacrificial substrate to bind matrix metalloproteinases. The metalloproteinases then break down the matrix rather than the naturally occurring colla-gen in the wound. They pro-vide support, a temporary scaf-fold for cellular migration and attachment, and can promote granulation tissue formation. At some point, they may contain certain growth factors that may or may not be present when the product is put on the wound. The optimal response is going to be achieved using a matrix

Figure 1. Placental membranes were first de-scribed as a treatment for wounds in 1910. They contain growth factors, collagen-rich extracellular matrix, and viable cells such as neonatal fibroblasts, epithelial cells, and mesenchymal stem cells.

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ADVANCES IN WOUND THERAPY:that is as close as possible to the tissue that it is replacing. How-ever, most collagen products are biologically recognized, which means that the source is not typically a problem.

We also have the human pla-

centa, the use of which was first described in a large series of wounds as far back as 1910 (Figure 1).3 Fresh placenta is a combination of growth fac-tors, collagen rich extracellular matrix, and viable cells such as

neonatal fibroblasts, epithelial cells, and mesenchymal stem cells (Figure 2).

When we look at the tissue composition, we look at the actual structure of the placenta (Figure 2). There is the amni-

Figure 2. This figure shows the actual structure of the placenta’s tissue composition, including the active cells in the epithelial layer, the base-ment membrane, the compact layer, and stromal type cells.

TISSUE COMPOSITION

Amnion

Chorion

Trophoblast Layer

Basement Membrane

Stromal Layer in Chorion

Sponge Layer

Epithelial Cell

Fibroblast

MSC

Collagen

Other ECM

Trophoblast Cell

Stromal Layer in Amnion

Epithelial Layer Basement Membrane Compact Layer

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on with active cells in the ep-ithelial layer, the active base-ment membrane, the compact layer, and other cells, including stromal type cells.

In amniotic products alone, there are a variety of native extracellular matrix proteins, structural ones that help to provide tissue integrity such as the various collagens as well as elastin. In human tissue, we know this allows for elasticity, provides an organization to the matrix, a reservoir for growth factors, and other types of mol-ecules. Proteoglycans help to retain moisture, and glycopro-teins promote cell migration, adhesion, and mediate the in-teractions between the cells and extracellular matrix.

STEM CELLS Stem cells provide matrix

proteins, cytokines, and growth factors. The promise of stem cells is that they will be able to regulate things that we don’t even know need to be regu-lated. Stem cells should iden-tify areas where there is high inflammation and down-regu-

late that; stimulate blood ves-sel formation; and recruit and support fibroblast and epitheli-al cell functions.

In patients with diabetes, there are a reduced number of stem cells and they are less effec-tive (Figure 3).4 These patients have lower levels of growth factors and decreased numbers of functional stem cells. Their morphology is altered, growth is decreased, differentiation is decreased, and there are more dysfunctional cells that are se-nescent with increased apopto-sis (Table 1).5 As the population ages and obesity increases, we are going to have older people with less functional stem cells in their native state. Applying a product that will provide stem cells could be an advantage for these patients.

The plethora of new products and some of the new changes in reimbursement have made us look to and learn more about the pathways for regulatory ap-proval for some of these prod-ucts. A lot of these products, collectively called human cel-lular- and tissue-based products

or HCT/Ps, can be obtained from human tissue donors, pro-cessed and used in the exact same role in the recipient. It is tissue for tissue, skin for skin, tendon for tendon, bone for bone. The uses are regulated so they are intended for homolo-gous use. They are expected to undergo minimal manipulation but they are strictly registered. Registration establishes proven good tissue practices and other procedures to prevent introduc-tion, transmission, and spread of any kind of communicable dis-ease by the modality.6

When we look at the placen-tal-derived acellular products, they are conceptually similar to the other acellular products. Most of them are comprised of dehydrated amnion and/or chorion membrane, and they re-portedly retain the biologically active growth factors, cytokines, and tissue inhibitors of metal-loproteinases 1, 2, and 4.7 They also contain other soluble medi-ators, but not the mesenchymal stem cells (MSCs) themselves. The soluble mediators may be able to recruit host MSCs and

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provide biological extracellular matrix for cell ingrowth.

When we look at the cellu-lar placental products, they are manufactured so they do retain the cells. They retain the extra-cellular matrix and the growth

factors that are naturally found. They also contain those younger healthier neonatal MSCs. They contain epithelial cells, fibroblasts, and extracel-lular matrices that provide the three-dimensional support that

allows for and promotes cellu-lar adhesion and migration.7

One method of preserving these and having them avail-able for our use is through cryopreservation. The majority of the studies on cryopreserva-

Figure 3. Diabetes patients have a reduced number of stem cells and they are less effective.

DIABETES DIMINISHES THE NUMBER AND EFFECT OF STEM CELLS AVAILABLE FOR REPAIR

Cianfarani F, Toietta G, Di Rocco G, et al. Diabetes impairs adipose issue-derived stem cell function and efficiency in promoting wound healing. Wound Repair Regen. 2013;21(4):545-553.

Normal

Stem Cell Number (x105) Growth Factor Secretion

NormalDiabetic

1.2

1

0.8

0.6

0.4

0.2

0DiabeticVEGF-A HGF IGF-1

Rela

tive

Amou

nt

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tion pertain to ocular science but there is significant impact on the structure and function of placental tissues. Comparing fresh tissue vs. dried vs. cryo-preserved, there are differences when looking at the architec-ture (Table 2 and Figure 4).8-11

CELLULAR THERAPIES VS ACELLULAR THERAPIES

There has been an explosion of products in this market, in-cluding bioengineered tissue, skin substitutes, and acellular dermal matrix products. How-ever, one question remains: are cellular therapies better than acellular therapies?

Cellular therapies probably require slightly more work because they have to be stored in a freezer or delivered in a specific time period rather than being stored on a shelf for a longer period of time. Right now, there is no direct com-parison as it is cost-prohibi-tive. Medicare is dividing these products into three catego-ries for hospital-based clinics: high cost, low cost, and pass-throughs. Depending on your

CMS carrier, some of the products from each category will be approved for reimburse-ment (Table 3). When deciding which products to use, the ev-idence pyramid, ranging from double-blind randomized con-trolled trials to in vitro research, should be part of the decision.

CURRENTLY AVAILABLE PRODUCTS

There are currently a large number of products available. Dermagraft (Organogenesis,

Inc.) is a cryopreserved human fibroblast derived from neona-tal foreskin. It has three ran-domized clinical studies with two of the studies demonstrat-ing effectiveness for diabetic foot ulcers (DFUs) and one study not demonstrating effec-tiveness for venous leg ulcers (VLUs).12-14 The pivotal trial on the platelet derived growth factor data for diabetic foot ul-cers took place nearly 20 years ago.15 Our standard of care and what we expect from clinical

TABLE 1. DIABETES ALTERS THE REGENERATIVE POTENTIAL OF MSCs

Cramer C, Freisinger E, Jones RK, et al. Persistent high glucose concentrations alter the regenerative potential of mesenchymal stem cells. Stem Cells Dev. 2010;19(12):1875-1884.

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trials has changed. Regarding the clinical results from the study by Marston et al, only 30% of people healed in the 12-week study with Derma-graft and 18% healed in the control group.12 These are not impressive results. The time to healing was not reported, but there was significant reduc-tion in infection in the people who got Dermagraft and they healed faster.

Apligraf (Organogenesis, Inc.) is a bilayered, epidermal and

dermal layer product derived from neonatal foreskin. It is not cryopreserved. There are several high-level randomized clinical studies, including DFU stud-ies and VLU studies, for this product.16-18 In a randomized DFU study involving 208 pa-tients, 56% of people healed in the treatment group and 38% healed in the control group.16 There was faster healing time, but not a significant difference in infections. Only in the sub-group with osteomyelitis was

there a difference in adverse events. The VLU data was also significant.18

EpiFix (MiMedx Group, Inc.) is an acellular product made from placental tissue. It has collagen types IV, V, and VII. It is a prod-uct you can put on the shelf and it is not cryopreserved. There is a small, single-center, randomized clinical study on this product with 25 people in the treatment groups (13 EpiFix, 12 control).19 It has the best results that have ever been reported in any DFU study

TABLE 2. Cryopreservation Maintains Structure and Functionality of Placental TissuesStructural and Functional Characteristics Fresh Dried Cryopreserved

Tissue Architecture and ECM

Tissue thickness 85-90 mM 45 mM 90mM

Tissue degeneration Not observed Vacuolar degeneration Not observed

Basement membrane ECMs Intact Degraded Intact

Growth Factor and Cytokine Release After 120 Hours

TIMPs, TGFs, CTGF, IL-1ra, etc Not reported Not detectable Sustain

Epithelial Cell Outgrowth

Number of supported cultures Not reported 30% 100%

Outgrowth area after day 18 Not reported 10-20 mm2 >100 mm2

Niknejad H, Deihim T, Solati-Hashjin M, Peirovi H. The effects of preservation procedures on amniotic membrane’s ability to serve as a substrate for cultivation of endothelial cells. Cryobiology. 2011;63(3):145-151. von Versen-Höynck F, Syring C, Bachmann S, Möller DE. The influence of different preservation and sterilisation steps on the histological properties of amnion allografts--light and scanning electron microscopic studies. Cell Tissue Bank. 2004;5(1):45-56. Rodríguez-Ares MT, López-Valladares MJ, Touriño R, et al. Effects of lyophilization on human amniotic membrane. Acta Ophthalmol. 2009;87(4):396-403. Thomasen H, Pauklin M, Steuhl KP, Meller D. Comparison of cryopreserved and air-dried human amniotic membrane for ophthalmologic applications. Graefes Arch Clin Exp Ophthalmol. 2009;247(12):1691-1700.

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for the treatment group and probably the worst for the control group but the study is under-powered. There was a significant reduction in the time to healing. No infections were reported in the treatment group whereas 17% of the con-trol group had infections.

Grafix (Osiris Thera-peutics, Inc.) is a cryopre-served product derived from placental tissues in planned C-sections. This product has a sin-gle-blind clinical study that is currently still in review and a case series that was published last December.20 In the phase 4 clini-cal study, 62% of people healed in the treatment group, 21% in the control group, with significantly faster healing and fewer adverse events in the treatment group.

Graftjacket (KCI Medical) is an acelluar regenerative tissue matrix. Reyzelman et al did a randomized, multicenter study comparing Graftjacket to moist wound healing for diabetic foot

ulcers.21 It is a little bit unusual because there is a big difference in randomization in the two treatment arms. A noncompliant patient was removed from the study. According to the results, 70% healed, but if you put the noncompliant patient back in the study, 68% healed in the treat-ment group. In the control arm, 46% healed, which is still signif-icant. The P value is .048. There

was a significant difference in the time to healing if you take out the noncompliant patients.

Oasis (Smith & Nephew, Inc.) is an acellular product and there are several small, ran-domized clinical studies.22-25 One of the most vital studies is a VLU study that shows a significant increase in healing with people who are treated with the Oasis product.22 The

Figure 4. When comparing cryopreserved tissue to dried tissue, there are definite differences in the archi-tecture of the tissues.

PRESERVATION OF AMNION TISSUE INTEGRITY

H and E staining

Cryopreserved

Dried (1/2 thickness

of cryo AM)

Vacuolar degeneration

Rodríguez-Ares MT, López-Valladares MJ, Touriño R, et al. Effects of lyophilization on human amniotic membrane. Acta Ophthalmol. 2009;87(4):396-403.

Col IV staining in the basement membrane

Col IV

Col IV

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time to healing is not report-ed. There is not a significant reduction in infections in this group. The DFU studies that involved separate comparisons of Oasis to Regranex (Smith & Nephew, Inc.) and Dermagraft found no significant differenc-es in the proportion of people who healed.23,25

There are a lot of random-ized clinical studies for using Integra (Integra LifeSciences) for burns, but not so much in the diabetic foot. There is one

small descriptive clinical study with 11 patients that suggests 64% wound healing.26 No in-fections were reported but this is a very small retrospective clinical experience.

Theraskin (Soluble Systems, LLC) is a human skin allograft with dermis and epidermis. It has some retrospective case se-ries data in a large number of VLUs and DFUs with a high proportion of wounds that healed. They don’t report heal-ing time or adverse events.27

Looking at the products that have randomized clinical studies and those that have high quality DFU studies that are powered in a reasonable way and report the evidence, there are just a few of products that are commercial-ly available. In the DFU space, Dermagraft, Apligraf, Grafix and Graftjacket have higher-level, randomized clinical studies. In the VLU space, Apligraf and Oa-sis have supportive randomized controlled trials.

We have now changed the way we do clinical studies after looking at these cellular prod-ucts in this space and their heal-ing. Offloading is much better and more studies are requiring debridement on a regular ba-sis as opposed to improvised debridement by the clinician. Perhaps the quality of what we do in the control arm is better but if you look at the data, these studies report 21% healing, 18%, 38%, and 46% in the con-trol arms of these studies (Table 4).12,16,20,21 The time to closure is faster in the three studies that report it (Grafix, Apligraf and Graftjacket) and there are fewer

TABLE 3. Medicare Payment Changes: CTPs*

“High Cost CTPs” “Low Cost CTPs” CTPs with Pass-Through Status in 2014

• Apligraf

• Dermagraft

• Alloderm

• Graftjacket

• Primatrix

• Hmatrix

• Integuply

• Arthroflex

• Dermaspan

• TranZgraft

• Oasis

• Integra

• EZ Derm

• MatriStem

• Unite Biomatrix

• AlloSkin

• Hyalomatrix

• TenSIX

• Surgiment

• Repriza

• Grafix

• EpiFix

• DermACELL

• Talymed

• Theraskin

*As of April 2014



adverse events but not in the Graftjacket group. The odds ratio in the likelihood that the wounds would heal is the high-est in the Grafix group. There is about a sixfold increased likeli-hood that people would heal in the Grafix study and the other studies range from a 2 to 2.4 odds ratio (Table 4).12,16,20,21

CHRONIC WOUNDS: TIME DRIVEN OR PATIENT DRIVEN?

What makes a wound really chronic? The literature states that 90 days is supposedly what defines a wound as chronic. It is unlikely that clinicians will

wait 90 days to determine that a wound is chronic after de-bridement, wound preparation, compression, and offloading. When we look at what makes a wound chronic, is it time driv-en? Has the wound been there because it has been open for a long time? There are a lot of bacteria and proteases because of an extremely hostile envi-ronment. Due to the proteases and the hostility of the envi-ronment, we have growth fac-tors and matrix proteins that are breaking down. We know that the cell surface recep-tors are going to be altered in

one such wound environment. These types of wounds also get stuck in a chronically in-flamed state. There is cellular senescence and there are those wounds that simply have not had adequate treatment. In this case, could the chronicity also be patient driven?

There are studies that have suggested prognostic indicators for time to healing. In regard to VLUs, Gelfand et al and Phil-lips et al found that if there is not a 40% reduction in the ve-nous leg group by week 4, it is unlikely that the wound is go-ing to achieve complete closure

TABLE 4. High Quality DFU RCTsGrafix

N = 97DermagraftN = 245

ApligrafN = 208

GraftjacketN = 86

Healed (%) 62 vs 21* 30 vs 18* 56 vs 38* 68 vs 46*

Time to Closure (days) 42 vs 70* Not stated 65 vs 90* 40 vs 48

Adverse Events (%) 18 vs 36* 19 vs 32* 22 vs 32 Not stated

Odds Ratio 6.04 (2.45-14.88)

1.92 (1.05-3.51)

2.14 (1.23-3.74)

2.40(0.99-5.81)

Marston WA, Hanft J, Norwood P, Pollak R; for the Dermagraft Diabetic Foot Ulcer Study Group. The efficacy and safety of Dermagraft in improv-ing the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003;26(6):1701-1705. Veves A, Falanga V, Armstrong DG, Sabolinski ML; for the Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multicenter clinical trial. Diabetes Care. 2001;24(2):290-295. Lavery LA, Kirsner RS, Serena T. The Wound Care Pipeline: Ongoing Trials. Symposium on Advanced Wound Care Fall. Las Vegas, NV. September 27-29, 2013. Reyzelman A, Crews RT, Moore JC, et al. Clinical effectiveness of an acellular dermal regenerative tissue matrix compared to standard wound management in healing diabetic foot ulcers: a prospective, randomised, multicentre study. Int Wound J. 2009;6(3):196-208.

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by 24 weeks.28,29 For diabetic foot ulcers, Sheehan et al found that if there is not a 50% re-duction in the wound size by 4 weeks, then it is unlikely to achieve complete healing by 12 weeks (Figure 5).30 Keep-ing that in mind, it should give us the impetus to consider ad-vanced wound care modalities as early as possible.

The other things to consid-er about patient selection with more advanced wounds are the type, history, and duration of the wounds. We cannot forget about atypical wounds or traumatic wounds. For example, if a pa-tient has a large avulsive injury on the leg and he or she comes in with hemosiderin staining, there is a bigger picture that we

need to address before expect-ing the wound to heal.

CASE REPORTSCase Report 1

A 34-year-old male patient with a past medical history of diabetes, ischemic cardiomyop-athy, and ventricular tachycar-dia presented with an infected AICD device. His ventricular or cardiac device became in-fected and required remov-al. He was on several different medications for these ailments. The patient was required to wear a life vest to monitor his heart and react in the event that something went wrong until the wound healed. At his initial visit, we applied a cellular am-nion product pre-debridement. The wound closed at day 21 so the patient could have another surgery and have a new device implanted (Figure 6).

Case Report 2In this case, a 42-year-old

male patient with a history of recurrent diabetic foot ulcers, right great toe amputation, hy-pertension, hyperlipidemia, type

Figure 5. Studies on VLUs and DFUs showed prognostic indicators for time to healing.

FOCUS ON TIME TO HEALING: USE OF PROGNOSTIC INDICATORS

VLUs

DFUs

• <50% reduction in wound size by week 4

• Unlikely to achieve complete closure at 12 weeks

• <40% reduction in wound size by week 4

• Unlikely to achieve complete closure at 24 weeks

Gelfand JM, Hoffstad O, Margolis DJ. Surrogate endpoints for the treatment of venous leg ulcers. J Invest Dermatol. 2002;119(6):1420-1425. Phillips TJ, Machado F, Trout R, Porter J, Olin J, Falanga V. Prognostic indicators in venous ulcers. J Am Acad Dermatol. 2000;43(4):627-630. Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care. 2003;26(6):1879-1882.



2 diabetes mellitus for 15 years, and a hemoglobin A1c of 8 pre-sented with a diabetic foot ul-cer that had been present for 6 months. Initially, he was debrid-ed and put into a contact cast. We also used a cellular amnion product on the wound. By day 30, his wound was epithelialized (Figure 7).

CONCLUSIONIn conclusion, our role and

how we interact in these pa-tients’ lives is helping them heal. If we stay patient focused and practice diligence on the pa-tients’ side, but also stay wound focused and use that wound as-sessment to drive the treatment decisions we make, we will ul-timately make good decisions

that lead to proper, efficient wound healing.

Q&A WITH THE PRESENTERSQ: How do you choose cellular vs.

acellular products to treat your patients?Dr. Lavery: I don’t use a lot of

products in this space that don’t have evidence when there are products that do. They are all going to cost a similar amount and you are going to get re-imbursed a similar amount. It depends on the severity of the wound and resources that are available. I tend to use cellular products when possible. I live in a bizarre world where there is a tissue bank that regulates everything that may have ever come in contact with tissue so it is a lot harder for me to get

new products into my facility. In regard to acellular products, Oasis has been on our formu-lary and that is the only one we have been able to get into our facility. My experience has been with Oasis in clinic. In the operating room, I have access because of burns and plastic surgery to Integra, Al-loDerm and Graftjacket. It is not just a clinical decision any-more. There are people filter-ing my choices.

Ms. Weir: I think it is im-portant whenever we can to just get experience and see how things work in our hands. We must learn what is avail-able, where storage is possible, what services or representa-tives from the company are

Figure 6. In case report 1, the patient presented with an infected AICD device (A) and the wound was treated with an amnion product and debrided (B). The wound was closed by day 21 (C).

A B C

16 August 2014


available, and if there are patient assistance programs. There are a lot of things that can go on, but it still boils down to contracts and other factors within each hospital or hospital system.

Q: Can you comment on how easy

it is to use a cryopreserved product? How is it stored? Do you have to have it delivered on the same day or can you store it in the hospital freez-er? How does it work in practice?

Dr. Lavery: Cryopreserved products are kept in -80° freez-

ers. In the practice environ-ment I was in before I came to Dallas, we had a freezer in clin-ic so we would keep about 20 pieces in our clinic at a time. Our staff was well versed in our wound clinic. They under-

Figure 7. In case report 2, the patient presented with a diabetic foot ulcer that had been present for 6 months (A). After the wound was debrid-ed (B), the patient was placed into a contact cast. The patient subsequently received application of an amnion product on the wound (C). By day 30, the wound was epithelialized (D).

A

C

B

D



stood the preparation process and they would prep the foot and prep the product. It is not a difficult process and it is easy once your team understands how to use it.

Ms. Weir: As the influenc-er or the support person in a clinic, once you learn how to thaw whatever you are using, the products are not particularly difficult to use. It is about how you fit this into your schedule and the tasks that you do in time to get the product ready before the procedure is performed. Any of the cryopreserved prod-ucts for our facility are shipped on dry ice and the individual companies would be able to tell us how long the product can stay in the clinic.

Q: If you were an insurance compa-ny, why would you approve anything?

Dr. Lavery: I think that is an interesting question. With clin-ical outcomes and treatment, what is likely the biggest cost as an insurance provider? It is hospitalization so faster healing and fewer complications mean fewer hospitalizations and few-er amputations. You can proba-

bly treat a lot more people less expensively as an outpatient than you can going over your diagnosis-related group (DRG) with repeat trips to the operat-ing room and imaging and labs for someone who gets admitted to the hospital. As an insurer, you want to keep these peo-ple out of the hospital because once they have a wound, about 60% of people are going to get infected and about a third of those people are going to end up in the hospital. Once that happens, they are coming back. I think it is a lot less expensive to do things in clinic even with expensive products that work. You shouldn’t pay for expensive products that don’t work. The most expensive product is one that doesn’t work.

Ms. Weir: We need to know how these things work in our hands. There is going to come a point in time with outpatient care in which we are going to be given a bundled amount of money and that is all we are giv-en to heal the patient. Spending more money up front or in-curring more cost up front and

healing them in a shorter peri-od of time will probably tip the scales for the better.

REFERENCES1. Hu S, Kirsner RS, Falanga V, Phillips

T, Eaglstein WH. Evaluation of Apligraf persistence and basement membrane restoration in donor site wounds: a pilot study. Wound Repair Regen. 2006;14(4):427-433.

2. Serena TE, Bialas P. Persistence of bilayered living-cell therapy donor DNA 10 months after application: a case report. Ostomy Wound Manage. 2009;55(10):18-22.

3. Davis J. Skin transplantation with a review of 550 cases at the Johns Hop-kins Hospital. Johns Hopkins Med J. 1910;15:307-396.

4. Cianfarani F, Toietta G, Di Rocco G, et al. Diabetes impairs adipose tissue-derived stem cell function and efficiency in promoting wound healing. Wound Repair Regen. 2013;21(4):545-553.

5. Cramer C, Freisinger E, Jones RK, et al. Persistent high glucose concentra-tions alter the regenerative potential of mesenchymal stem cells. Stem Cells Dev. 2010;19(12):1875-1884.

6. Synder DL, Sullivan N, Schoelles KM. Technology assessment: skin sub-stitutes for treating chronic wounds. http://www.ahrq.gov/research/findings/ta/skinsubs/HCPR0610_sk-insubst-final.pdf. Accessed April 8, 2014.

7. Koob TJ, Rennert R, Zabek N, et al. Biological properties of dehy-drated human amnion/chorion composite graft: implications for chronic wound healing. Int Wound J. 2013;10(5):493-500.

8. Niknejad H, Deihim T, Solati-Hashjin M, Peirovi H. The effects of preserva-tion procedures on amniotic mem-

18 August 2014

brane’s ability to serve as a substrate for cultivation of endothelial cells. Cryobiology. 2011;63(3):145-151.

9. von Versen-Höynck F, Syring C, Bach-mann S, Möller DE. The influence of different preservation and sterilisation steps on the histological properties of amnion allografts--light and scanning electron microscopic studies. Cell Tissue Bank. 2004;5(1):45-56.

10. Rodríguez-Ares MT, López-Val-ladares MJ, Touriño R, et al. Effects of lyophilization on human amni-otic membrane. Acta Ophthalmol. 2009;87(4):396-403.

11. Thomasen H, Pauklin M, Steuhl KP, Meller D. Comparison of cryopre-served and air-dried human amni-otic membrane for ophthalmologic applications. Graefes Arch Clin Exp Ophthalmol. 2009;247(12):1691-1700.

12. Marston WA, Hanft J, Norwood P, Pollak R; for the Dermagraft Diabetic Foot Ulcer Study Group. The efficacy and safety of Dermagraft in improv-ing the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003;26(6):1701-1705.

13. Gentzkow GD1, Iwasaki SD, Her-shon KS, et al. Use of dermagraft, a cultured human dermis, to treat diabetic foot ulcers. Diabetes Care. 1996;19(4):350-354.

14. Harding K, Sumner M, Cardinal M. A prospective, multicentre, randomised controlled study of human fibro-blast-derived dermal substitute (Derma-graft) in patients with venous leg ulcers. Int Wound J. 2013;10(2):132-137.

15. Steed DL, Donohoe D, Webster MW, Lindsley L. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabet-ic Ulcer Study Group. J Am Coll Surg. 1996:183(1):61-64.

16. Veves A, Falanga V, Armstrong DG, Sabolinski ML; for the Apligraf Diabetic Foot Ulcer Study. Graftskin, a human skin equivalent, is effective in the management of noninfected neuropathic diabetic foot ulcers: a prospective randomized multi-center clinical trial. Diabetes Care. 2001;24(2):290-295.

17. Edmonds M. Apligraf in the treatment of neuropathic diabetic foot ulcers. Int J Low Extrem Wounds. 2009:8(1):11-18.

18. Falanga V, Sabolinski M. A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen. 1999;7(4):201-207.

19. Zelen CM, Serena TE, Denoziere G, Fetterolf DE. A prospective ran-domised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. 2013;10(5):502-507.

20. Lavery LA, Kirsner RS, Serena T. The wound care pipeline: ongoing trials. Symposium on Advanced Wound Care Fall. Las Vegas, NV. September 27-29, 2013.

21. Reyzelman A, Crews RT, Moore JC, et al. Clinical effectiveness of an acellular dermal regenerative tissue matrix compared to standard wound management in healing diabetic foot ulcers: a prospective, randomised, multicentre study. Int Wound J. 2009;6(3):196-208.

22. Mostow EN, Haraway GD, Dalsing M, Hodde JP, King D; OASIS Venus Ulcer Study Group. Effectiveness of an ex-tracellular matrix graft (OASIS Wound Matrix) in the treatment of chronic leg ulcers: a randomized clinical trial. J Vasc Surg. 2005;41(5):837-843.

23. Niezgoda JA, Van Gils CC, Frykberg RG, Hodde JP. Randomized clinical

trial comparing OASIS Wound Matrix to Regranex Gel for diabetic ulcers. Adv Skin Wound Care. 2005;18(5 Pt 1):258-266.

24. Romanelli M, Dini V, Bertone MS. Randomized comparison of OASIS wound matrix versus moist wound dressing in the treatment of diffi-cult-to-heal wounds of mixed arterial/venous etiology. Adv Skin Wound Care. 2010;23(1):34-38.

25. Landsman A, Roukis TS, DeFronzo DJ, Agnew P, Petranto RD, Sur-prenant S. Living cells or collagen matrix: which is more beneficial in the treatment of diabetic foot ulcers? Wounds. 2008;20(5):111-116.

26. Yao M, Attalla K, Ren Y, French MA, Driver VR. Ease of use, safety, and ef-ficacy of Integra bilayer wound matrix in the treatment of diabetic foot ulcers in an outpatient clinical setting: a prospective pilot study. J Am Podiatr Med Assoc. 2013;103(4):274-280.

27. Landsman AS, Cook J, Cook E, et al. A retrospective clinical study of 188 consecutive patients to examine the effectiveness of a biologically active cryopreserved human skin allograft (TheraSkin®) on the treatment of dia-betic foot ulcers and venous leg ulcers. Foot Ankle Spec. 2011;4(1):29-41.

28. Gelfand JM, Hoffstad O, Margolis DJ. Surrogate endpoints for the treatment of venous leg ulcers. J Invest Derma-tol. 2002;119(6):1420-1425.

29. Phillips TJ, Machado F, Trout R, Porter J, Olin J, Falanga V. Prognostic indicators in venous ulcers. J Am Acad Dermatol. 2000;43(4):627-630.

30. Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care. 2003;26(6):1879-1882.


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A Natural Approach to Wound Treatment

• Designed for application directly to acute and chronic wounds, including but not limited to, diabetic foot ulcers and venous leg ulcers

• Flexible, conforming and adheres to complex anatomies

• Available in multiple sizes

7015 Albert Einstein DriveColumbia, MD 210461-888-OSIRIS 1www.Osiris.comG14606

a

Randomized Multi-Center Trial Comparing Grafix vs.Conventional Care in 97 Patients With Diabetic Foot Ulcers1a

• Median time to closure was 42 days compared to 70 days for the control group (n =97, p =0.019)

• 50% fewer infections occurred in the Grafix group than control (18% vs. 36%, p = 0.044)

1a. Rate of improvement between healing rates over cont rol.

Reference: 1. Dat a on file.

G14606_GrafixAd.indd 1 7/15/14 2:31 PM

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