Energy metabolism of experimental wounds at various oxygen environments.

Energy metabolism of healing tissue was studied in experimental wounds of rats chronically breathing 11% O2, air or 55% O2. Increasing oxygen supply elevated both PO2 and PCO2 in the wound tissue. At the early phases of healing hypoxic wounds contained less DNA than normoxic or hyperoxic tissues. In hypoxia the accumulation of wound collagen was clearly retarded. Furthermore, tissue taken from wounds healing in hypoxic environments and tested ex vivo in air showed decreased capacity for glucose utilization, lactate production and oxygen consumption. Concentrations of AMP, ADP and ATP in repair tissue increased as healing progressed. The more oxygen available the higher the amounts of ADP and ATP. The AMP content was not affected by changes in local oxygen tension. These results support the earlier concept that the supply of oxygen in healing tissue may be rate-limitimg. Reduction of available oxygen either by systemic hypoxia or by increased diffusion distance impedes healing.     

Tissue oxygenation, anemia, and perfusion in relation to wound healing in surgical patients.

Oxygen tension and collagen deposition were measured in standardized, subcutaneous wounds in 33 postoperative surgical patients. Pertinent clinical and wound parameters were analyzed by Pearson's correlation test and sequential linear regression analysis. Collagen deposition was directly and significantly proportional to wound oxygen tension and measures of perfusion. There were no significant correlations with hematocrit, estimated blood loss, length of operation, smoking, age, weight, sex, or urine output. This study in humans confirms animal experiments showing that collagen deposition and tensile strength in wounds are limited by perfusion and tissue oxygen tension. It appears unnecessary to maintain hemoglobin at normal levels to support repair, provided that peripheral perfusion can be maintained at a high level in compensation for anemia. These circumstances reflect the fact that although oxygen is essential to many aspects of healing, and must be delivered at adequate partial pressures, reparative tissue consumes relatively little of it.     

Hyperoxia and infection

Surgical wound infection remains a common and serious complication of surgery. Patient factors are a major determinant of wound outcome following surgery. Co-morbidities clearly contribute, but environmental stressors as well the individual response to stress may be equally important. In particular, wounds are exquisitely sensitive to hypoxia, which is both common and preventable. Perioperative management can promote postoperative wound healing and resistance to infection. Maintaining perfusion and oxygenation of the wound is paramount. Once perfusion is assured, addition of increased inspired oxygen substantially reduces surgical site infection in at risk patients. A greater degree of hyperoxemia, achievable with administration of hyperbaric oxygen, is useful as an adjunct to the treatment of serious soft tissue and bone infections in selected patients. This article will review the basic science underlying these observations, along with the clinical data that support the use of hyperoxia in preventing and treating infections.     

Oxygen tension in would tissues during healing

Transcutaneous strain of oxygen (TcPO2) was studied in tissues of 111 wounds in 110 patients. The uncomplicated course of the wound process was characterized by rapid normalization of the initially decreased TcPO2 in the wounds closed with sutures or in case of gradual approximation of their margins as well as by a slow elevation when the wounds were healing by second intention. High significance of measuring TcPO2 was shown for diagnosis of acute pyo-inflammatory diseases and wound complications. Great feed-back correlation was found between the degree of disjunction of the wound margins and TcPO2 of its tissues. A hypothesis is put forward on the dependence between the degree of tissue tension and the precapillary sphincter tone allowing an explanation of all the changes in TcPO2 of the wound tissues in the process of its healing.     

Hyperbaric oxygen and wound healing

Problem wounds, which fail to respond to traditional medical and surgical therapy, can be challenging to the plastic surgeon. Surgical, outpatient, and inpatient wound care costs can be exorbitant. Indirect costs, such as those related to patient productivity, disability, and premature death, can also be significant. The underlying problem in failure of a wound to heal is usually hypoxia and infection. HBO treatments in selected patients can facilitate healing by increasing tissue oxygen tension, thus providing the wound with a more favorable environment for repair. Therefore, HBO therapy can be an important component to any comprehensive wound care program.     

Wound healing essentials: Let there be oxygen

The state of wound oxygenation is a key determinant of healing outcomes. From a diagnostic standpoint, measurements of wound oxygenation are commonly used to guide treatment planning such as amputation decision. In preventive applications, optimizing wound perfusion and providing supplemental O₂ in the perioperative period reduces the incidence of postoperative infections. Correction of wound p O₂ may, by itself, trigger some healing responses. Importantly, approaches to correct wound p O₂ favorably influence outcomes of other therapies such as responsiveness to growth factors and acceptance of grafts. Chronic ischemic wounds are essentially hypoxic. Primarily based on the tumor literature, hypoxia is generally viewed as being angiogenic. This is true with the condition that hypoxia be acute and mild to modest in magnitude. Extreme near-anoxic hypoxia, as commonly noted in problem wounds, is not compatible with tissue repair. Adequate wound tissue oxygenation is required but may not be sufficient to favorably influence healing outcomes. Success in wound care may be improved by a personalized health care approach. The key lies in our ability to specifically identify the key limitations of a given wound and in developing a multifaceted strategy to specifically address those limitations. In considering approaches to oxygenate the wound tissue it is important to recognize that both too little as well as too much may impede the healing process. Oxygen dosing based on the specific need of a wound therefore seems prudent. Therapeutic approaches targeting the oxygen sensing and redox signaling pathways are promising.     

Effects of ischemia on ulcer wound healing: a new model in the rabbit ear

To study the effects of alteration of blood flow on wound healing in rabbit ear ulcers, two models were designed that produced maximum ischemia and maximum congestion, respectively, with complete survival of the ear by selective division of one or more of three arteries or veins and circumferential incisions. After selection of the best models from six variations, tissue perfusion was measured indirectly by venous oxygen tension, dermofluorometry, pulse oximetry, and skin temperature. Wound healing was measured seven days after creating 6-mm surgical ulcers. The tissue oxygen tension calculated from the venous oxygen tension fell to 30 mm Hg through days 1, 3, and 7 in the ischemic ears, and skin temperature and blood flow measured by dermofluorometry were similarly affected. However, there was no evidence of significant change in tissue perfusion except increased skin temperature in the congested ears. None of the ischemic wounds were epithelialized completely, but half of the control and congested wounds were. The granulation tissue formation was decreased (39% of the area versus 63% of the area) and the infection rate was increased (20% versus 2%) significantly in the ischemic wounds compared with the control wounds but not in the congested wounds. The ischemic ulcer model is reproducible and quantifiable and is potentially a useful model for examining agents to improve ulcer healing where blood flow is decreased. The congestion model showed no significant changes in blood flow or wound healing.     

Oxygen in Wound Healing and Infection

It is a fundamental clinical observation that wounds do not heal in tissue that does not bleed, and they almost always heal in tissue that bleeds extensively. Continuous supply of oxygen to the tissue through microcirculation is vital for the healing process and for resistance to infection. Evaluation of tissue perfusion and oxygenation is important in all types of wound patients. Monitoring systems should measure the hemodynamic situation and the ability of the cardiovascular system to deliver an adequate volume of oxygen to meet the metabolic demands of the peripheral tissue. Oxygen therapy is important in relation to both healing and resistance to infections. External factors have been shown to significantly decrease the peripheral oxygen supply, and supplementary perioperative oxygen to reduce the surgical wound infection rate by one- half in patients undergoing colorectal resection. Hyperbaric oxygen therapy may be beneficial in situations where the nutritive flow and oxygen supply to the healing tissue are compromised by local injury, and particularly if anaerobic infection is present. However, the definitive proof for the effect and indications of this therapy in wound healing still has to be established. It can be concluded that adequate delivery of oxygen to the wound tissue is vital for optimal healing and resistance to infection. Assessment of perfusion and oxygenation is essential for the wound patient, as well as the treating personnel. The indication for hyperbaric oxygen treatment still needs to be defined. During wound healing the continuity and function of the damaged tissue are re-established. This is only possible through a restoration of the microcirculation and thereby the nutrition to the tissue. The main component of the nutrition is oxygen, which is critically important for healing a wound by production of granulation tissue and for ensuring resistance against infection. This has been shown experimentally, but recently a short period of supplementary oxygen has been shown to decrease wound complications in clinical practice as well.     

Transcutaneous oxygen measurements predict a beneficial response to hyperbaric oxygen therapy in patients with nonhealing wounds and critical limb ischemia.

Hyperbaric oxygen (HBO) therapy may be a useful adjunct in the treatment of patients with wounds associated with critical limb ischemia. These patients either cannot undergo a successful bypass or may not heal after vascular reconstruction alone. Identification of patients likely to benefit from HBO is essential before treatment, as this therapy is time-consuming, costly, and not without risk. Transcutaneous oxygen measurements (TCOM) can be used to evaluate the degree of hypoxia in ischemic tissue. In this study we evaluated whether TCOM could be used to identify those patients who would or would not benefit from HBO therapy. Our hypothesis is that a difference in transcutaneous oxygen tension readings measured near the ischemic lesion with the patient breathing room air and while breathing 100 per cent oxygen at ambient pressure may be predictive of wound healing with adjunctive hyperbaric oxygen therapy. Thirty-six patients with critical limb ischemia and nonhealing ulcers were referred for HBO therapy. They were deemed either nonreconstructible from a vascular surgical viewpoint, had failed prior revascularization attempts, or could not achieve complete wound healing even after a successful revascularization. Pretreatment assessment included a room air and post-100 per cent-O2 challenge TCOM reading obtained in the vicinity of the open wound. Hyperbaric oxygen treatments at 2.0 to 2.5 atm were then administered until healing occurred or failure was confirmed. All patients undergoing HBO had a baseline TCOM of <40 torr. Twenty-seven patients had an increase in TCOM of >10 torr with oxygen inhalation at initial evaluation. Of these patients, 19 (70%) healed their wounds with HBO therapy. Conversely the increase in TCOM was <10 torr in nine patients, and only one of these patients (11%) ultimately healed (P < 0.01). Patients with nonhealing ischemic extremity wounds may heal with adjunctive HBO therapy. We can predictably identify patients who are likely to benefit from this modality using TCOM at the time of initial evaluation. An increase of tissue O2 tension of > or =10 torr when breathing pure O2 suggests that the patient may benefit from HBO therapy. Those patients with an increase of <10 torr are unlikely to receive benefit from this treatment modality.     

Regulation of wound-healing angiogenesis-effect of oxygen gradients and inspired oxygen concentration

Tissue hypoxia is a well-known stimulus to angiogenesis. The central dead space in healing wounds has been shown to be hypoxic (PO2 = 1 to 10). Angiogenesis is a necessary component of all healing wounds. Rabbit ear chambers were used to explore the contribution of O2 gradients and various inspired oxygen concentrations on wound healing and angiogenesis. These experiments demonstrate that: (1) A hypoxic tissue gradient is mandatory for wound-healing angiogenesis, (2) when the hypoxic gradient is destroyed capillary growth cases, and (3) inspired oxygen concentrations affect the rate and density of capillary growth.     

Cigarette smoking decreases tissue oxygen

Subcutaneous wound-tissue oxygen (PsqO2) tension in eight volunteers fell rapidly and significantly in response to smoking, and remained low for 30 to 50 minutes. Sham "smoking" had no effect. These data suggest that a typical "pack-per-day" smoker experiences tissue hypoxia during a significant portion of each day. The degree of hypoxia found in these subjects has been associated with poor wound healing in animal and human studies. The onset and duration of tissue hypoxia paralleled the well-established plasma pharmacokinetics of nicotine. This suggests that peripheral vasoconstriction, induced by the adrenergic effects of nicotine, may contribute to the observed decrease in PsqO2.     

rbFGF、VSD结合局部氧疗对深Ⅱ度烧伤创面愈合及时长的影响

目的探讨重组牛碱性成纤维细胞生长因子(recombinant bovine basic fibroblast growth factor,rbFGF)、封闭负压引流(vacuum sealing drainage,VSD)结合局部氧疗治疗深Ⅱ度烧伤创面的愈合效果及时长。方法自2018年1月至2019年4月,黄石市第五医院烧伤外科对就诊的92例深Ⅱ度烧伤患者采用随机双盲法分为对照组(46例)和观察组(46例)。对照组采用VSD结合局部氧疗进行治疗;观察组在对照组基础上增用rbFGF。并对两组临床疗效、恢复情况、氧环境、愈合后瘢痕情况以及并发症情况进行比较。结果观察组治疗总有效率高于对照组(P<0.05)。观察组创面愈合时间、换药次数、住院时间、愈合后瘢痕量表各维度评分均低于对照组。观察组治疗3周后创面愈合率、肉芽组织生长面积均高于对照组(P<0.05)。观察组乳酸脱氢酶(lactate dehydrogenase,LDH)水平低于对照组;琥珀酸脱氢酶(succinate dehydrogenase,SDH)水平高于对照组(P<0.05)。两组并发症总发生率比较,其差异无统计学意义(P>0.05)。结论采用rbFGF、VSD结合局部氧疗治疗深Ⅱ度烧伤可以改善创面组织的缺氧状态,促进创面愈合,缩短住院时间,并有助于减少愈合后瘢痕形成,且安全性较高,值得临床推广。     

Supplemental Postoperative Oxygen and Tissue Oxygen Tension in Morbidly Obese Patients

Background  

Subcutaneous tissue oxygen tension (PsqO₂) is a major predictor for wound healing and the occurrence of wound infections. Perioperative subcutaneous wound and tissue oxygen tension is significantly reduced in morbidly obese patients. Even during intraoperative supplemental oxygen administration, PsqO₂ remains low. Tissue hypoxia is pronounced during surgery and might explain the substantial increase in infection risk in obese patients. It remains unknown whether long-term supplemental postoperative oxygen augments tissue oxygen tension. Consequently, we tested the hypothesis that 80% inspired oxygen administration during 12–18 postoperative hours significantly increases PsqO₂ compared to 30% inspired oxygen fraction.     

Topical oxygen therapy & micro/nanobubbles: a new modality for tissue oxygen delivery

Up to 15 billion dollars of US health care expenditure each year is consumed by treatment of poorly healing wounds whose etiologies are often associated with aberrancies in tissue oxygenation. To address this issue, several modes of tissue oxygen delivery systems exist, including Hyperbaric Oxygen Therapy (HBOT) and Topical Oxygen Therapy (TOT), but their efficacies have yet to be fully substantiated. Micro/nanobubbles (MNBs), which range anywhere from 100 μm to <1 μm in diameter and are relatively stable for hours, offer a new mode of oxygen delivery to wounds. The aim of this article is to systematically review literature examining the use of TOT for wound healing and use of MNBs for tissue oxygenation using the MEDLINE database. The search yielded 87 articles (12 MNB articles and 75 TOT articles), of which 52 met the inclusion criteria for this literature review (12 MNB articles and 40 TOT articles). Additionally, we present an analysis on the efficacy of our MNB generating technology and propose its use as a wound healing agent.     

Regional disturbances in blood flow and metabolism in equine limb wound healing with formation of exuberant granulation tissue

As in other fibroproliferative disorders, hypoxia has been suggested to play a key role in the pathogenesis of exuberant granulation tissue (EGT). The purpose of this study was to investigate metabolism and blood flow locally in full‐thickness wounds healing with (limb wounds) and without (body wounds) formation of EGT. Microdialysis was used to recover endogenous metabolites from the wounds, and laser Doppler flowmetry was used to measure blood flow. Measurements were performed before wounding and 1–28 days after wounding. Blood flow was consistently lower in limb wounds than in body wounds throughout the study period with no change over time. After wounding and throughout the study period, the glucose concentration was significantly lower in limb wounds than in body wounds, whereas the lactate level showed a significantly higher concentration in limb wounds. The lactate/glucose ratio displayed a significant difference between body and limb wounds. In conclusion, the metabolic disturbances may suggest an inadequate oxygen supply during the wound healing process in equine limb wounds healing with EGT. This may be related to the inherently decreased perfusion in the wound bed of limb wounds.     

Early wound healing exhibits cytokine surge without evidence of hypoxia

OBJECTIVE: To ascertain the spatial and temporal relation of wound hypoxia to the cell types involved, expression of selected angiogenic cytokines, the proliferative status of cells in the wound site, and angiogenesis. SUMMARY BACKGROUND DATA: Hypoxia is considered to drive the angiogenic response by upregulating angiogenic cytokines observed during wound healing. But this correlation has not been shown on a cell-to-cell basis in vivo because of limitations in measuring tissue PO2 at the cellular level. METHODS: Using punch biopsy wounds in rats as a wound healing model, the distributions of vascular endothelial growth factor, transforming growth factor-beta, tumor necrosis factor-alpha, and pimonidazole adducts (as a hypoxia marker) were followed immunohistochemically during the healing process. RESULTS: Hypoxia was absent on day 1 after wounding, even though angiogenesis and maximal expression of cytokines were observed in the wounds. Hypoxia peaked in the granulation tissue stage at day 4 and correlated with increased cellularity and cellular proliferation. Hypoxia started to decrease after day 4 and was limited to the remnant blood vessels and epithelial layer in the scar tissue. CONCLUSIONS: Induction of angiogenic cytokines early during wound healing may be due to triggering mechanisms other than hypoxia. Alternatively, the unique pattern of development and decline of cellular hypoxia as wound cellularity and proliferation regress suggest its involvement in initiating vascular regression during the later stages of healing.     

Microfluidic wound bandage: Localized oxygen modulation of collagen maturation

Restoring tissue oxygenation has the potential to improve poorly healing wounds with impaired microvasculature. Compared with more established wound therapy using hyperbaric oxygen chambers, topical oxygen therapy has lower cost and better patient comfort, although topical devices have provided inconsistent results. To provide controlled topical oxygen while minimizing moisture loss, a major issue for topical oxygen, we have devised a novel wound bandage based on microfluidic diffusion delivery of oxygen. In addition to modulating oxygen from 0 to 100% in 60 seconds rise time, the microfluidic oxygen bandage provides a conformal seal around the wound. When 100% oxygen is delivered, it penetrates wound tissues as measured in agar phantom and in vivo wounds. Using this microfluidic bandage, we applied the oxygen modulation to 8 mm excisional wounds prepared on diabetic mice. Treatment with the microfluidic bandage demonstrated improved collagen maturity in the wound bed, although only marginal differences were observed in total collagen, microvasculature, and external closure rates. Our results show that proper topical oxygen can improve wound parameters underneath the surface. Because of the ease of fabrication, the oxygen bandage represents an economical yet practical method for oxygen wound research.     

The effect of topical hyperalimentation on wound healing rate and granulation tissue formation of experimental deep second degree burns in guinea-pigs

Revital , a product containing 19 amino acids, was applied to experimental deep second degree burns in guinea-pigs for 24 days, in order to assess the effect of this form of hyperalimentation on the healing process. Silver sulphadiazine cream served as the contralateral control standard. Epithelialization was faster in the silver sulphadiazine treated burn wounds, while contraction of both tested wounds proceeded at a similar rate. Revital significantly enhanced the formation of granulation and scar tissue in this burn wound model. These observations indicate that topical wound hyperalimentation promotes granulation tissue formation of experimental deep second degree burns in guinea-pigs.     

The science of wound bed preparation

The concept of wound bed preparation (WBP) heralded a new era in terms of how we treat wounds. It emphasized the difference between acute and chronic wounds, and it cemented the idea that the processes involved in the healing of acute wounds do not apply completely to the healing of chronic wounds. The arbitrary division of the normal healing process into the phases of hemostasis, inflammation, proliferation, and maturation addresses the events in acute wound healing. We have realized that the impediments to healing in chronic wounds lead to a failure to progress through these phases and are independent factors that make the chronic wound a much more complex condition. A major advance in resolving or addressing the chronic wound has been the concept of WBP. WBP allows us to address the problems of wound healing individually-the presence of necrotic tissue, hypoxia, high bacterial burden, corrupt matrix, and senescent cells within the wound bed. In WBP we can optimize our therapeutic agents to accelerate endogenous healing or to increase the effectiveness of advanced therapies.