new insights into oxygen therapy for wound healing › uploads › [13] new insights into oxygen...

294 WOUNDS www.woundsresearch.com

Throughout history, native healers have recognized that wounds healfaster if a patient is transported from thin mountain air to a richeratmosphere (eg, a low-lying valley). In modernity, oxygen has been

recognized as the element most essential to healing. Clinicians are now ableto diagnose oxygen deficiency and administer oxygen therapy with increas-ingly advanced mechanisms and devices. The following review will examinethe background as well as newer developments in this area.

The Wound Healing ProcessWound healing consists of a series of physiologic events that occur in

response to tissue damage. Many of the vital processes of wound healing areoxygen dependent. Wounds vary greatly, and the healing of a wound mayproceed with different tempo and quality due to local and systemic factorsand due to variation among individuals. Variable healing is present within aspecific wound and within different anatomic locations in the same patient.However, there are common themes to the healing of all wounds. The burnliterature has classically described three zones of injury: necrosis, stasis, andhyperemia. This construct serves well in considering any wound. Tissue inthe zone of necrosis is already lost, while tissue in the zone of stasis may besaved with good local and systemic care; otherwise, it is lost to infection,trauma, or dehydration. Tissue in the zone of hyperemia may become dam-

New Insights Into Oxygen Therapyfor Wound Healing

Daniel Ladizinsky, MD1 and David Roe, PhD2

WOUNDS 2010;22(12):294–300

From the 1Oregon Health SciencesUniversity, Portland, Oregon;2AcryMed, Inc, Beaverton, Oregon

Address correspondence to:David Roe, PhD9560 SW Nimbus Ave.Beaverton, OR 97008Phone: 503-624-9830Email: [email protected]

Disclosure: Dr. Roe is an employee ofAcrymed, Inc.

REVIEW

Abstract: Oxygen is a powerful substrate and signal. The ability tounderstand and control this vital substance will open new avenues oftherapy for multiple diseases. New insights into cutaneous oxygena-tion suggest that there may be a sound basis for topical oxygen ther-apy. The indications for systemic oxygen therapy are expanding aswell, as research delves into the role of oxygen in pathophysiologicconditions. Previous therapeutic approaches simply relied on provid-ing oxygen as a critical substrate for fundamental metabolic process-es. New therapies that also utilize oxygen as a needed signal will fur-ther expand the indications for oxygen therapy.

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Oxygen is a powerful substrate and signal. The ability to

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Oxygen is a powerful substrate and signal. The ability tounderstand and control this vital substance will open new avenues of

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understand and control this vital substance will open new avenues oftherapy for multiple diseases. New insights into cutaneous oxygena-

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therapy for multiple diseases. New insights into cutaneous oxygena-tion suggest that there may be a sound basis for topical oxygen ther-

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tion suggest that there may be a sound basis for topical oxygen ther-apy. The indications for systemic oxygen therapy are expanding as

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apy. The indications for systemic oxygen therapy are expanding aswell, as research delves into the role of oxygen in pathophysiologicRed

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well, as research delves into the role of oxygen in pathophysiologicconditions. Previous therapeutic approaches simply relied on provid-Red

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conditions. Previous therapeutic approaches simply relied on provid-ing oxygen as a critical substrate for fundamental metabolic process-Red

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ing oxygen as a critical substrate for fundamental metabolic process-

Ladizinsky and Roe

Vol. 22, No. 12 December 2010 295

aged or lost if problems arise in the zone of stasis.Recognizing that the key determinant of tissue survival isoxygenation, one can rephrase the burn zone paradigmas follows: zone of anoxia, zone of hypoxia, and zone ofnormoxia. In this oxygen-based paradigm, the woundhealer must focus on treating tissue in the zone of hypox-ia in order to preserve the maximum amount of viabletissue and encourage the healing process.

Oxygen levels in wounded tissue result from a bal-ance of supply and demand. Supply may be low due toproblems such as vascular disease, radiation (impaireddelivery), or edema (increased diffusion distance).Demand may be high as a result of metabolic needs ofspecific cells at various points within the wound healingsequence. White blood cells consume oxygen during therespiratory burst necessary for killing ingested bacte-ria.1–3 Fibroblasts require a critical level of oxygen inorder to secrete collagen and other extracellular matrixmolecules.4,5 This allows angiogenesis and granulation tis-sue formation to fill the wound.1,6 Hypoxic woundsdeposit collagen poorly and become infected easily.Epithelialization is a parallel process of resurfacing thewound that also proceeds optimally at high oxygen lev-els.7 Although the processes described may proceed opti-mally at elevated pO2 levels, they may still require somehypoxia as an intermittent signal.8

Oxygen as Substrate and SignalUntil recently, oxygen was simply viewed as “fuel for

the fire,” a vital metabolic substrate for a multitude ofimportant cellular functions. It was presumed that theeffect of a burst treatment of supplemental oxygen wasto allow those necessary reactions to proceed at higherrates, and that the effect would subside upon the cessa-tion of therapy. What we have learned recently is that theoxygen also provides an important signal that affectsmultiple cell behaviors long after the oxygen levelreturns to its pretreatment value. In the context of theimportant biological process of cutaneous wound heal-ing, oxygen functions as both a substrate and a signal(Table 1).

Clinical Relevance of Oxygen TherapyIt has been shown that vital cellular functions such

angiogenesis, fibroplasia, epithelialization, and bacterialkilling all proceed at a more rapid pace in response tohigher oxygen levels. In wound healing, bacterial burdenmust be removed and a preliminary matrix must beformed in order to allow fibrous tissue formation and

epithelial coverage. Oxygen hastens removal of bacterialbioburden, which allows resolution of inflammation andfacilitates matrix production, cell division, and ultimatewound closure. This is especially relevant in conditionswhere healing is impaired. Common impedimentsinclude diabetes, peripheral arterial or venous vasculardisease, radiation and other situations where reducedoxygenation and/or large bacterial bioburden may bepresent.

Of particular note, chronic venous leg ulcers are oftencolonized with anaerobic bacteria which impede thehealing process.9 In this setting oxygen therapy canchange the wound microenvironment to a more aerobicmilieu, which will inhibit anaerobe proliferation. It hasbeen demonstrated that hyperbaric oxygen therapyimproved the healing of chronic venous ulcers in a con-trolled randomized clinical trial.10 As more is learnedabout bacterial resistance to antimicrobial therapy, alter-nate methods of antibacterial control such as oxygentherapy become more relevant. Bacteria do not developresistance to oxygen therapy in the same manner as theydo to antibiotic therapy. Oxygen may offer a novel thera-peutic strategy against biofilm forming bacteria, wheresuch microbes can greatly increase their resistance toantibiotics.11

Another problem with chronic wounds is that there ispoor quality of healing after a prolonged period ofinflammation. For example, burns that are not closedwithin a 3-week period have a 70% chance of developingexcessive fibrotic hypertrophic scars.12 Similarly, chronicleg ulcers often heal with unstable, brittle fibrotic skinthat is prone to recurrent ulceration. If better woundoxygenation yields a faster exit from the inflammatorystate, then perhaps an increase of healing by regenera-tion and less by fibrosis will result in higher quality andmore durably healed tissue.

Tissue oxygen levels have also been measured as pre-dictors of clinical outcome. For example, limb amputa-tions at the below knee level have been shown to heal inonly 11% of patients with an oxygen partial pressure of< 20 mmHg at the amputation site, heal in 46% at 20mmHg–30 mmHg, and to heal at 97% at ≥ 30 mmHg.13

Oxygen as signal

ATP production Macrophage VEGF secretionRespiratory burst PDGF receptor increaseProtein synthesis Cell proliferation increase

Table 1. Functions of oxygen.

Oxygen as substrate

Do tion of therapy. What we have learned recently is that the

Do tion of therapy. What we have learned recently is that theoxygen also provides an important signal that affects

Do oxygen also provides an important signal that affectsmultiple cell behaviors long after the oxygen level

Do multiple cell behaviors long after the oxygen levelreturns to its pretreatment value. In the context of theDo returns to its pretreatment value. In the context of theimportant biological process of cutaneous wound heal-Do important biological process of cutaneous wound heal-ing, oxygen functions as both a substrate and a signalDo ing, oxygen functions as both a substrate and a signal

Not the fire,” a vital metabolic substrate for a multitude of

Not the fire,” a vital metabolic substrate for a multitude ofimportant cellular functions. It was presumed that the

Not important cellular functions. It was presumed that theeffect of a burst treatment of supplemental oxygen was

Not effect of a burst treatment of supplemental oxygen wasto allow those necessary reactions to proceed at higher

Not to allow those necessary reactions to proceed at higherrates, and that the effect would subside upon the cessa-Not rates, and that the effect would subside upon the cessa-tion of therapy. What we have learned recently is that theNot tion of therapy. What we have learned recently is that theoxygen also provides an important signal that affectsNot oxygen also provides an important signal that affects

Copy Although the processes described may proceed opti-

Copy Although the processes described may proceed opti-

levels, they may still require some

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Oxygen as Substrate and Signal

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or wound that also proceeds optimally at high oxygen lev- or wound that also proceeds optimally at high oxygen lev-Although the processes described may proceed opti- or Although the processes described may proceed opti-

milieu, which will inhibit anaerobe proliferation. It has

or milieu, which will inhibit anaerobe proliferation. It hasbeen demonstrated that hyperbaric oxygen therapyor been demonstrated that hyperbaric oxygen therapyimproved the healing of chronic venous ulcers in a con-or improved the healing of chronic venous ulcers in a con-trolled randomized clinical trial.or trolled randomized clinical trial.

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epithelial coverage. Oxygen hastens removal of bacterial

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epithelial coverage. Oxygen hastens removal of bacterialbioburden, which allows resolution of inflammation and

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facilitates matrix production, cell division, and ultimate

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ributefacilitates matrix production, cell division, and ultimate

wound closure. This is especially relevant in conditions

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where healing is impaired. Common impediments

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where healing is impaired. Common impedimentsinclude diabetes, peripheral arterial or venous vascular

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include diabetes, peripheral arterial or venous vasculardisease, radiation and other situations where reduced

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disease, radiation and other situations where reducedoxygenation and/or large bacterial bioburden may be

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oxygenation and/or large bacterial bioburden may be

Of particular note, chronic venous leg ulcers are often

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Of particular note, chronic venous leg ulcers are oftencolonized with anaerobic bacteria which impede the

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colonized with anaerobic bacteria which impede thehealing process.Red

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healing process.9Redist

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change the wound microenvironment to a more aerobicRedist

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change the wound microenvironment to a more aerobicmilieu, which will inhibit anaerobe proliferation. It hasRed

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milieu, which will inhibit anaerobe proliferation. It hasRedist

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Cell proliferation increase

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Cell proliferation increase


Physiology of Oxygen DeliveryHow does the body normally deliver oxygen to those

tissues that vitally need it? First, oxygen in the atmos-phere enters the lungs during respiration. There, thegaseous oxygen must cross from the air spaces (alveoli)of the lung into the fluid spaces (capillaries). Oxygenmust become dissolved in the fluid state in order to doso. In other words, gaseous oxygen may not enter the tis-sues until it first becomes dissolved oxygen. This dis-solved oxygen then moves across the alveolar membraneinto the lung capillaries where it then enters the blood-stream. Oxygen movement from alveolar air space intothe capillary liquid space is dependent on surface area.The human lungs are optimally designed for this pur-pose. They provide a total surface area of 70 squaremeters for gas exchange across the very thin alveolarmembrane (thickness < 1 µm).14 Note that even with thishuge surface area available for gas exchange, only about50% of the inspired gaseous oxygen actually traversesthe alveolar membrane. Oxygen moves by diffusion, fromareas of high concentration to low concentration. Thesize of the diffusion gradient (the difference betweenhigh and low concentration) determines the amount ofdiffused oxygen that may move into the low concentra-tion area. As shown below, the amount of oxygen isreduced as it diffuses out of the bloodstream and reach-es the peripheral tissues.

Once in the peripheral tissues, movement of oxygen isdriven by a gradient, where it travels from regions of high-er concentration to lower concentration (Figure 2). Uponentering the bloodstream, oxygen is carried in its dis-solved form, either bound to hemoglobin within the redblood cell or free in an unbound form within the plasma.When the richly oxygenated blood approaches theperipheral tissue capillaries, the dissolved oxygen beginsto move again by the diffusion gradient, away from theoxygen rich capillary to the oxygen poor tissues. The firstoxygen to leave the capillaries is the free or unbound oxy-gen within the plasma. When the plasma oxygen concen-tration lowers, hemoglobin begins to unload its boundoxygen into the plasma and this oxygen also diffuses intothe tissues. Ultimately, the dissolved oxygen is taken up bythe peripheral tissue cells and is consumed. Tissue factorssuch as edema may limit cellular oxygen uptake due tohigh diffusion distance from the capillary to the cell.Normal gradients cannot drive oxygen very far into thetissues if there is significant edema. The oxygen-depletedplasma returns via the venous system to reload with oxy-gen in the lungs for the next cycle.

Delivering Oxygen From the “Inside Out”:pO2 vs. O2 Content

Oxygenation of the skin may occur by two routes:delivery from the “inside out” via the circulation or deliv-ery from the “outside in” via the atmosphere. Once bloodis oxygenated and travels through the body, dissolvedplasma oxygen diffuses into peripheral tissues such asthe skin. The oxygen moves by gradient from the capil-laries into the interstitial space and ultimately to the skincells. Note the amount of dissolved oxygen in the bloodis described by its partial pressure or pO2 (expressed inmmHg). Note also that the total O2 content includes thedissolved as well as the hemoglobin-bound oxygen. AsHunt speculated, pO2 may be more important than O2

content in terms of delivery of oxygen to the skin andwound.15 Hopf16 provided further support for this viewand found normal levels of subcutaneous tissue pO2 at ahemoglobin level of 5 g/dL in normal healthy volunteerswho allowed phlebotomy with crystalloid substitution.16

Note that the oxygen content in a person with a hemo-globin level of 5 g/dL is 9 g/100 mL O2 content, com-pared to a hemoglobin level of 14 g/dL (normal) with 20g/100 mL O2 content. This indicates that the dissolvedoxygen segment may be more important in driving dif-fusion into the tissues than the hemoglobin-bound seg-ment, and that O2 is carried in the blood greatly in excess

Figure 2. Diagram of the oxygen partial pressurechanges from air to tissue. Note, the solid line depictsthe hypothetical perfect situation and the broken linedepicts hypoventilation. (Figure used withpermission).14

Ladizinsky and Roe

Do peripheral tissue capillaries, the dissolved oxygen begins

Do peripheral tissue capillaries, the dissolved oxygen beginsto move again by the diffusion gradient, away from the

Do to move again by the diffusion gradient, away from theoxygen rich capillary to the oxygen poor tissues. The first

Do oxygen rich capillary to the oxygen poor tissues. The firstoxygen to leave the capillaries is the free or unbound oxy-Do oxygen to leave the capillaries is the free or unbound oxy-Do gen within the plasma. When the plasma oxygen concen-Do gen within the plasma. When the plasma oxygen concen-tration lowers, hemoglobin begins to unload its boundDo tration lowers, hemoglobin begins to unload its bound

Not er concentration to lower concentration (Figure 2). Upon

Not er concentration to lower concentration (Figure 2). Uponentering the bloodstream, oxygen is carried in its dis-

Not entering the bloodstream, oxygen is carried in its dis-solved form, either bound to hemoglobin within the red

Not solved form, either bound to hemoglobin within the redblood cell or free in an unbound form within the plasma.

Not blood cell or free in an unbound form within the plasma.When the richly oxygenated blood approaches theNot When the richly oxygenated blood approaches theperipheral tissue capillaries, the dissolved oxygen beginsNot peripheral tissue capillaries, the dissolved oxygen beginsto move again by the diffusion gradient, away from theNot to move again by the diffusion gradient, away from the

Copy diffused oxygen that may move into the low concentra-

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tion area. As shown below, the amount of oxygen is

Copy tion area. As shown below, the amount of oxygen is

reduced as it diffuses out of the bloodstream and reach-

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or high and low concentration) determines the amount of or high and low concentration) determines the amount ofdiffused oxygen that may move into the low concentra- or diffused oxygen that may move into the low concentra- Delivering Oxygen From the “Inside Out”:or Delivering Oxygen From the “Inside Out”:or

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Figure 2.

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Figure 2. Diagram of the oxygen partial pressure

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Diagram of the oxygen partial pressurechanges from air to tissue. Note, the solid line depicts

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changes from air to tissue. Note, the solid line depictsthe hypothetical perfect situation and the broken line

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the hypothetical perfect situation and the broken line

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depicts hypoventilation. (Figure used withRedist

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depicts hypoventilation. (Figure used withpermission).Red

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permission).

Vol. 22, No. 12 December 2010 297

of the skin and subcutaneous tissue needs. However, onemust be cautious in treating sick patients with these lowhemoglobin levels, as there are tissues that may havegreater oxygen demand (muscle, nerve) or be in a condi-tion of increased oxygen demand (sepsis, shock). Undernormal conditions pO2 is 55 mmHg–70 mmHg in thesubcutaneous chest tissue of a healthy subject breathingroom air, but this level varies in different regions of thebody.16

Delivering Oxygen From the “Outside In”:The Role of Skin Permeability

Oxygen can diffuse through any gas permeable sur-face, and can therefore enter the skin. However, the skinis a limited surface for oxygen exchange as the total sur-face area of the human skin is relatively small (slightlygreater than 1 m2 compared to the lungs 70 m2) and itsthickness is a significant barrier to oxygen diffusion (epi-dermis up to 1.5 mm thick and dermis up to 3 mm thick,compared to the lungs < 1 µm). It has been long knownthat the skin is capable of gas exchange. In 1851, whenGerlach17 secured a varnished horse bladder to his skinfor 24 hours and measured the gas content before andafter, he observed a decrease in O2 and an increase inCO2. The skin can exchange 80 mL–100 mL O2/m2, orprovide about 1%–2% of the total O2 exchange surfaceneeded by the body.18 Though the skin’s gas exchange isnot systemically significant, it is locally important. Recentadvances in the technology of cutaneous oxygen meas-urement have changed quite a few long held beliefs

about how the skin receives its oxygen supply. It hadbeen observed that oxygen will pass through the stratumcorneum in vitro as well as 0.30 mm down into thesuperficial dermis,19,20 but advances in oxygen measure-ment technology have produced in-vivo data as well.Two investigators have demonstrated that the atmos-pheric ambient O2 almost exclusively supplies the outer0.25 mm–0.40 mm of the skin.15,21 A nadir of pO2 occursat 0.1 mm below the skin surface (Figure 3).5

It was previously believed that poorly diffusing oxy-gen was further limited in its penetration of the skin bystratified epithelium, and that all O2 delivered to the skinoccurred via the capillary beds. However, oxygen levelsin the superficial dermis and epithelium are well main-tained even in the setting of cuff occlusion of limb arte-rial inflow.22 The oxygen is therefore concluded to havebeen directly absorbed from the ambient atmosphericO2, rather than from the capillary beds by diffusion.Interestingly, when an experimental wound surface wasdeprived of atmospheric oxygen by substituting anatmosphere of pure nitrogen, wound surface pO2

dropped to 4 mmHg–5 mmHg, indicating that was thelevel achievable via diffusion from the underlying circu-lation alone.23 Another recent study using oxygenatedwater (dissolved oxygen) on porcine skin noted pene-tration of the skin by oxygen that was enhanced whentape stripping of the epidermis was performed.24

Hyperbaric Oxygen Therapy and itsEfficacy

Hyperbaric oxygen therapy (HBOT) has been in usefor many years and its clinical indications continue toincrease. It is known from experimental and clinical evi-dence that HBOT can accelerate healing throughincreased angiogenesis.25 Hyperbaric oxygen will sub-stantially increase the amount of dissolved oxygen in theblood, since at a pO2 of 100 mmHg, hemoglobin is near-ly fully saturated. These changes can have a significantimpact on healing tissues through a combination of sub-strate and signaling roles. Hyperbaric oxygen therapycreates a large (pO2 > 2000 mmHg) driving gradientsfrom the high systemic O2 concentration in the blood-stream, which allows better tissue penetration as long asthe vasculature can deliver the oxygenated blood to thetarget tissue.

The effectiveness of HBOT has been studied exten-sively in many different clinical settings. Although HBOTtreatments are brief, subcutaneous oxygen tensions areelevated for several hours.26,27 One effect has been to

Figure 3. Oxygen partial pressure measured by a needleelectrode inserted perpendicularly into the skin. (Figure used with permission).5

Ladizinsky and Roe

Do face area of the human skin is relatively small (slightly

Do face area of the human skin is relatively small (slightlygreater than 1 m

Do greater than 1 m2

Do 2 compared to the lungs 70 m

Do compared to the lungs 70 mthickness is a significant barrier to oxygen diffusion (epi-

Do thickness is a significant barrier to oxygen diffusion (epi-dermis up to 1.5 mm thick and dermis up to 3 mm thick,Do dermis up to 1.5 mm thick and dermis up to 3 mm thick,compared to the lungs < 1 µm). It has been long knownDo compared to the lungs < 1 µm). It has been long knownthat the skin is capable of gas exchange. In 1851, whenDo that the skin is capable of gas exchange. In 1851, when

Not Delivering Oxygen From the “Outside In”:

Not Delivering Oxygen From the “Outside In”:The Role of Skin Permeability

Not The Role of Skin Permeability

Oxygen can diffuse through any gas permeable sur-

Not Oxygen can diffuse through any gas permeable sur-face, and can therefore enter the skin. However, the skin

Not face, and can therefore enter the skin. However, the skinis a limited surface for oxygen exchange as the total sur-Not is a limited surface for oxygen exchange as the total sur-face area of the human skin is relatively small (slightlyNot face area of the human skin is relatively small (slightly

compared to the lungs 70 mNot compared to the lungs 70 m

Copy tion of increased oxygen demand (sepsis, shock). Under

Copy tion of increased oxygen demand (sepsis, shock). Under

is 55 mmHg–70 mmHg in the

Copy is 55 mmHg–70 mmHg in the

subcutaneous chest tissue of a healthy subject breathing

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room air, but this level varies in different regions of the

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room air, but this level varies in different regions of the

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or greater oxygen demand (muscle, nerve) or be in a condi- or greater oxygen demand (muscle, nerve) or be in a condi-tion of increased oxygen demand (sepsis, shock). Under or tion of increased oxygen demand (sepsis, shock). Under

atmosphere of pure nitrogen, wound surface pO

or atmosphere of pure nitrogen, wound surface pOdropped to 4 mmHg–5 mmHg, indicating that was theor dropped to 4 mmHg–5 mmHg, indicating that was thelevel achievable via diffusion from the underlying circu-or level achievable via diffusion from the underlying circu-lation alone.or lation alone.

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Two investigators have demonstrated that the atmos-

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Two investigators have demonstrated that the atmos-almost exclusively supplies the outer

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almost exclusively supplies the outerA nadir of pO

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A nadir of pO2

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2 occurs

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occursat 0.1 mm below the skin surface (Figure 3).

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It was previously believed that poorly diffusing oxy-

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gen was further limited in its penetration of the skin by

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stratified epithelium, and that all O

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stratified epithelium, and that all O2

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2 delivered to the skin

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delivered to the skinoccurred via the capillary beds. However, oxygen levels

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occurred via the capillary beds. However, oxygen levels

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in the superficial dermis and epithelium are well main-

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in the superficial dermis and epithelium are well main-tained even in the setting of cuff occlusion of limb arte-

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tained even in the setting of cuff occlusion of limb arte-The oxygen is therefore concluded to have

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The oxygen is therefore concluded to havebeen directly absorbed from the ambient atmospheric

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been directly absorbed from the ambient atmospheric, rather than from the capillary beds by diffusion.

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, rather than from the capillary beds by diffusion.Interestingly, when an experimental wound surface wasRed

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Interestingly, when an experimental wound surface wasdeprived of atmospheric oxygen by substituting anRed

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deprived of atmospheric oxygen by substituting anatmosphere of pure nitrogen, wound surface pORed

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atmosphere of pure nitrogen, wound surface pO


improve angiogenesis and tissue transcutaneous oxygentension in a diabetic foot wound and irradiated tis-sue.28,29 The success of HBOT has been seen in a prospec-tive study of chronic leg wounds.10 Patients receivingHBOT treatment had a significant reduction in woundsize (35.7%) at 6 weeks compared to control patients(2.7%). Similarly, an extensive retrospective analysis ofpatients with intractable wounds evidenced a 70%–90%success rate.30,31 It should also be mentioned that peri-operative normobaric supplemental oxygen breathing(FIO2 of 80%) reduced the incidence of surgical woundinfections.32

Topical Oxygen Therapy and its Efficacy:Gaseous vs. Dissolved

Many wound patients cannot tolerate systemic HBOTside effects, afford HBOT, or gain access to a hyperbaricchamber. Sometimes the patient’s cardiovascular systemis inadequate for carrying the oxygenated blood to thewounded tissue, or the tissue is so edematous that theoxygen cannot reach the wound well. Topical oxygentherapies are designed to allow oxygen to enter thewound or skin via the external surface of the body ratherthan from capillaries within. The oxygen is thereforedelivered directly to the wound and the systemic sideeffects are eliminated.

Topical oxygen therapy may be delivered to the exter-nal surfaces of the body in a gaseous or dissolved form.However, the administered oxygen must be transformedfrom the gaseous to the dissolved form to become bio-logically available to the target cells being treated.

Topical gaseous “oxygen boot” systems have been pro-posed since 1932 with refinements since. Treatmentmethods that deliver gaseous oxygen include enclosuresaround a limb or wound site that are flushed with puregaseous oxygen, or machines that generate gaseous oxy-gen at the wound surface.33 A recent review discusses theevidence based recommendations for topical oxygentherapy.34

For oxygen to be transferred from a gas bubble to anindividual cell, several independent partial resistancesmust be overcome including35:

• resistance within the gas film to the phase boundary• penetration of the phase boundary between gas

bubble and liquid• transfer from the phase boundary to the liquid • movement within the nutrient solution• transfer to the surface of the cell.These intrinsic issues limit the efficacy of gaseous

topical oxygen systems; yet, topical low-pressure oxygentherapy has shown some encouraging results in prelim-inary studies. One hundred percent oxygen is adminis-tered at atmospheric or slightly greater pressure with-out a hyperbaric chamber via an enclosure that sur-rounds the affected area. It is inexpensive and can beprovided in the home environment. It has been shownto promote wound angiogenesis and healing in animalstudies as well as in human clinical studies.36–38 A topicaldevice that administers a stream of 100% oxygen bub-bles to the wound surface has been shown to improveepithelial healing.39

Methods that deliver topical dissolved oxygen includethose which catalytically produce dissolved oxygen atthe wound surface, those which contain diffusible dis-solved oxygen bound to a carrier such as a fluorocarbon,or those which allow a reservoir of gaseous oxygen todiffuse through the vehicle. There have been difficultiesreported in creating stable fluorocarbon emulsions, how-ever some promising early results have been reported.

Recent experimental data on a set of devices thatdeliver unbound dissolved oxygen have demonstratedsignificant oxygen penetration through viable humanskin samples.40 Levels of transcutaneous oxygen 4–6times normal subcutaneous oxygen (250 mmHg) wereobserved after topical dissolved oxygen treatment ofskin samples with or without a stratum corneum epi-dermal layer present. This level of penetration achievedwas twice the depth of that noted in previous studies ofskin exposed to hyperbaric gaseous oxygen.20 Anotherrecent study demonstrated penetration of topical dis-solved oxygen through both intact (with epidermis)and tape striped (epidermis removed) viable porcineskin samples.24

There appears to be a significant advantage to deliv-ering oxygen topically in its dissolved form, as it is bio-logically available immediately upon administration. Thefundamental challenge to topical oxygenation methodsis to create a large enough driving oxygen gradient toallow oxygen delivery into zones of tissue hypoxia. If thiscan be achieved clinically, topical tissue oxygenation pro-cedures will become complementary to systemic meth-ods of oxygenation and will allow the treating physiciangreater therapeutic versatility in treating wounds.

The ability to control duration and depth of topicaloxygen delivery into human tissue will allow new strate-gies in individualizing patient therapy. A deeper under-standing into the pharmacokinetics of topical oxygenadministration will allow manipulation of specific healing

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Do around a limb or wound site that are flushed with pure

Do around a limb or wound site that are flushed with puregaseous oxygen, or machines that generate gaseous oxy-

Do gaseous oxygen, or machines that generate gaseous oxy-gen at the wound surface.

Do gen at the wound surface.evidence based recommendations for topical oxygenDo evidence based recommendations for topical oxygentherapy. Do therapy.34 Do

34

For oxygen to be transferred from a gas bubble to anDo For oxygen to be transferred from a gas bubble to an

Not from the gaseous to the dissolved form to become bio-

Not from the gaseous to the dissolved form to become bio-logically available to the target cells being treated.

Not logically available to the target cells being treated.

Topical gaseous “oxygen boot” systems have been pro-

Not Topical gaseous “oxygen boot” systems have been pro-posed since 1932 with refinements since. Treatment

Not posed since 1932 with refinements since. Treatmentmethods that deliver gaseous oxygen include enclosuresNot methods that deliver gaseous oxygen include enclosuresaround a limb or wound site that are flushed with pureNot around a limb or wound site that are flushed with puregaseous oxygen, or machines that generate gaseous oxy-Not gaseous oxygen, or machines that generate gaseous oxy-

Copy than from capillaries within. The oxygen is therefore

Copy than from capillaries within. The oxygen is therefore

delivered directly to the wound and the systemic side

Copy delivered directly to the wound and the systemic side

Topical oxygen therapy may be delivered to the exter-

Copy

Topical oxygen therapy may be delivered to the exter-nal surfaces of the body in a gaseous or dissolved form.

Copy

nal surfaces of the body in a gaseous or dissolved form.However, the administered oxygen must be transformedCop

y However, the administered oxygen must be transformedfrom the gaseous to the dissolved form to become bio-Cop

y from the gaseous to the dissolved form to become bio-logically available to the target cells being treated. Cop

y logically available to the target cells being treated.

Topical gaseous “oxygen boot” systems have been pro-Cop

y

Topical gaseous “oxygen boot” systems have been pro-

or wound or skin via the external surface of the body rather or wound or skin via the external surface of the body ratherthan from capillaries within. The oxygen is therefore or than from capillaries within. The oxygen is therefore

Recent experimental data on a set of devices that

or Recent experimental data on a set of devices that

deliver unbound dissolved oxygen have demonstratedor deliver unbound dissolved oxygen have demonstratedsignificant oxygen penetration through viable humanor significant oxygen penetration through viable humanskin samples.or skin samples.

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rounds the affected area. It is inexpensive and can be

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rounds the affected area. It is inexpensive and can beprovided in the home environment. It has been shown

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provided in the home environment. It has been shownto promote wound angiogenesis and healing in animal

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to promote wound angiogenesis and healing in animalstudies as well as in human clinical studies.

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ributestudies as well as in human clinical studies.36–38

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ribute36–38 A topical

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device that administers a stream of 100% oxygen bub-

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ributedevice that administers a stream of 100% oxygen bub-

bles to the wound surface has been shown to improve

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ributebles to the wound surface has been shown to improve

Methods that deliver topical dissolved oxygen include

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Methods that deliver topical dissolved oxygen includethose which catalytically produce dissolved oxygen at

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those which catalytically produce dissolved oxygen atthe wound surface, those which contain diffusible dis-

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the wound surface, those which contain diffusible dis-solved oxygen bound to a carrier such as a fluorocarbon,

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solved oxygen bound to a carrier such as a fluorocarbon,or those which allow a reservoir of gaseous oxygen to

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or those which allow a reservoir of gaseous oxygen to

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diffuse through the vehicle. There have been difficulties

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diffuse through the vehicle. There have been difficultiesreported in creating stable fluorocarbon emulsions, how-Red

istrib

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reported in creating stable fluorocarbon emulsions, how-ever some promising early results have been reported.Red

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ever some promising early results have been reported.Recent experimental data on a set of devices thatRed

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Recent experimental data on a set of devices that

Vol. 22, No. 12 December 2010 299

processes (Table 2). Targeted oxygen therapies will bebased on pharmacokinetics that will control oxygen tis-sue penetration depth, with degree and duration of oxy-genation. New insights into oxygen’s ability to penetrateintact skin may prove therapeutic in other conditionsbesides wounds, where inflammatory or degenerativeconditions of the skin require repair and rejuvenation.

ConclusionOxygen is a powerful and multifunctional substrate

and signal. The ability to understand and control this vitalsubstance may open new avenues of treatment in multi-ple disease states. Oxygen based treatment strategies forwounded soft tissues can be designed on an understand-ing of the zones of anoxia, hypoxia, and normoxia.Recent insights into cutaneous oxygenation suggest thatthere may be a sound basis for topical tissue oxygenationprocedures. Recent technological developments nowallow delivery of biologically available dissolved oxygendirectly to the wound and skin. The ability to drive oxy-gen deep into zones of tissue hypoxia will lead to bettermetabolic support of cellular function, more rapid clear-ance of bacteria and resolution of inflammation, and ulti-mately faster and better tissue preservation and healing.

References1. Stücker M, Steinbrügge J, Ihrig C, et al. Rhythmical varia-

tions of hemoglobin oxygenation in cutaneous capillar-

ies. Acta Derm Venereol. 1998;78(6):408–411.

2. Wang W. Oxygen partial pressure in outer layers of skin:

simulation using three-dimensional multilayered models.

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O2 treatment strategy

Epithelialization continuous, low dose, shallowAngiogenesis intermittent, high dose, deepGranulation tissue formation intermittent, high dose, deepCollagenesis intermittent, high dose, deepBacteria killing continuous, high dose, deep

Table 2. Theoretical examples of targeted oxygen therapy.

Biological process

Ladizinsky and Roe

Do References

Do References1. Stücker M, Steinbrügge J, Ihrig C, et al. Rhythmical varia-

Do 1. Stücker M, Steinbrügge J, Ihrig C, et al. Rhythmical varia-

tions of hemoglobin oxygenation in cutaneous capillar-

Do tions of hemoglobin oxygenation in cutaneous capillar-

ies. Do ies. Acta Derm VenereolDo Acta Derm Venereol

2. Wang W. Oxygen partial pressure in outer layers of skin:Do 2. Wang W. Oxygen partial pressure in outer layers of skin:

simulation using three-dimensional multilayered models.Do simulation using three-dimensional multilayered models.

Not gen deep into zones of tissue hypoxia will lead to better

Not gen deep into zones of tissue hypoxia will lead to bettermetabolic support of cellular function, more rapid clear-

Not metabolic support of cellular function, more rapid clear-ance of bacteria and resolution of inflammation, and ulti-

Not ance of bacteria and resolution of inflammation, and ulti-mately faster and better tissue preservation and healing.

Not mately faster and better tissue preservation and healing.

1. Stücker M, Steinbrügge J, Ihrig C, et al. Rhythmical varia-Not 1. Stücker M, Steinbrügge J, Ihrig C, et al. Rhythmical varia-

Copy ing of the zones of anoxia, hypoxia, and normoxia.

Copy ing of the zones of anoxia, hypoxia, and normoxia.

Recent insights into cutaneous oxygenation suggest that

Copy Recent insights into cutaneous oxygenation suggest that

there may be a sound basis for topical tissue oxygenation

Copy there may be a sound basis for topical tissue oxygenation

procedures. Recent technological developments now

Copy

procedures. Recent technological developments nowallow delivery of biologically available dissolved oxygen

Copy

allow delivery of biologically available dissolved oxygendirectly to the wound and skin. The ability to drive oxy-Cop

y directly to the wound and skin. The ability to drive oxy-gen deep into zones of tissue hypoxia will lead to betterCop

y gen deep into zones of tissue hypoxia will lead to bettermetabolic support of cellular function, more rapid clear-Cop

y metabolic support of cellular function, more rapid clear-ance of bacteria and resolution of inflammation, and ulti-

Copy

ance of bacteria and resolution of inflammation, and ulti-

or wounded soft tissues can be designed on an understand- or wounded soft tissues can be designed on an understand-ing of the zones of anoxia, hypoxia, and normoxia. or ing of the zones of anoxia, hypoxia, and normoxia.


or 11. Stewart PS, Costerton JW. Antibiotic resistance of bacteria

in biofilms. or in biofilms.

12. Velasco MG, Mutch D, Surkes N, Williams HB.or 12. Velasco MG, Mutch D, Surkes N, Williams HB.

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. 1948;89(Pt 2):187–196.

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. 1948;89(Pt 2):187–196.


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ME, O’Neal LW, Bowker JH, eds.

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ributeME, O’Neal LW, Bowker JH, eds. The Diabetic Foot

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ributeThe Diabetic Foot

ed. St. Louis, MO: Mosby Year Book; 1993:305–319.

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ributeed. St. Louis, MO: Mosby Year Book; 1993:305–319.

8. Sheikh AY, Gibson JJ, Rollins MD, Hopf HW, Hussain Z,

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ribute8. Sheikh AY, Gibson JJ, Rollins MD, Hopf HW, Hussain Z,


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growth factor levels in a wound model.

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growth factor levels in a wound model.

2000;135(11):1293–1297.

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2000;135(11):1293–1297.


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bic cocci in impaired human wound healing.

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bic cocci in impaired human wound healing.

Repair Regen

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ribute

Repair Regen

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. 2002;10(6):346–353.

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. 2002;10(6):346–353.


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sizes of chronic leg ulcers: a randomized double-blindRedist

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sizes of chronic leg ulcers: a randomized double-blind

study. Redist

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study. Plast Reconstr SurgRedist

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Plast Reconstr Surg

11. Stewart PS, Costerton JW. Antibiotic resistance of bacteriaRedist

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Ladizinsky and Roe


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Do 34. Gordillo GM, Sen CK. Evidence-based recommendations

Do 34. Gordillo GM, Sen CK. Evidence-based recommendations

for the use of topical oxygen therapy in the treatment of

Do for the use of topical oxygen therapy in the treatment of

lower extremity wounds.

Do lower extremity wounds.

Do 2009;8(2):105–111.Do 2009;8(2):105–111.

35. Pumphrey B, Christian J. Do 35. Pumphrey B, Christian J.

Netherlands: New Brunswick Scientific (UK) Ltd andDo Netherlands: New Brunswick Scientific (UK) Ltd and

Not N Engl J Med

Not N Engl J Med


Not 33. Wang Y, Cohen J, Boron WF, Schulten K, Takjhorshid E.


Not Exploring gas permeability of cellular membranes and

membrane channels with molecular dynamics.

Not membrane channels with molecular dynamics.

. 2007;157(3):534–544.Not . 2007;157(3):534–544.

34. Gordillo GM, Sen CK. Evidence-based recommendationsNot 34. Gordillo GM, Sen CK. Evidence-based recommendations

for the use of topical oxygen therapy in the treatment ofNot for the use of topical oxygen therapy in the treatment of

Copy 31. Oriani G. Diabetic foot and hyperbaric oxygen therapy: a

Copy 31. Oriani G. Diabetic foot and hyperbaric oxygen therapy: a

J Hyperbaric Med

Copy J Hyperbaric Med.

Copy .


Copy


perioperative oxygen to reduce the incidence of surgicalCopy

perioperative oxygen to reduce the incidence of surgical

N Engl J Med Copy

N Engl J Med. 2000;342(3):161–167.Copy

. 2000;342(3):161–167.

33. Wang Y, Cohen J, Boron WF, Schulten K, Takjhorshid E.Copy


Exploring gas permeability of cellular membranes andCop

y


or Hyperbaric oxygen in the treatment of diabetic foot or Hyperbaric oxygen in the treatment of diabetic foot

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gen penetrates skin: model and method.

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gen penetrates skin: model and method. J Surg Res

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J Surg Res

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