Rei Ogawa

The Most Current Algorithms for the Treatment and Prevention of Hypertrophic Scars and Keloids

Background: Previous reports on the treatment of hypertrophic scars and keloids have not described clear algorithms for multimodal therapies. This article presents an evidence-based review of previous articles and proposes algorithms for the treatment and prevention of hypertrophic scars and keloids. Methods: The methodologic quality of the clinical trials was evaluated, and the baseline characteristics of the patients and the interventions that were applied and their outcomes were extracted. Results: Important factors that promote hypertrophic scar/keloid development include mechanical forces on the wound, wound infection, and foreign body reactions. For keloids, the treatment method that should be used depends on whether scar contractures (especially joint contractures) are present and whether the keloids are small and single, or large and multiple. Small and single keloids can be treated radically by surgery with adjuvant therapy (which includes radiation or corticosteroid injections) or by nonsurgical monotherapy (which includes corticosteroid injections, cryotherapy, laser, and antitumor/immunosuppressive agents such as 5-fluorouracil). Large and multiple keloids are difficult to treat radically and are currently only treatable by multimodal therapies that aim to relieve symptoms. After a sequence of treatments, long-term follow-up is recommended. Conservative therapies, which include gel sheeting, taping fixation, compression therapy, external and internal agents, and makeup (camouflage) therapy, should be administered on a case-by-case basis. Conclusions: The increase in the number of randomized controlled trials over the past decade has greatly improved scar management, although these studies suffer from various limitations. The hypertrophic scar/keloid treatment algorithms that are currently available are likely to be significantly improved by future high-quality clinical trials.

Improved viability of random pattern skin flaps through the use of adipose-derived stem cells.

Background: Flap necrosis caused by inadequate blood supply is a common postoperative complication in reconstructive surgery. Because a putative stem cell population within the adipose tissue has been found to possess angiogenic potential, the authors sought to determine whether these cells might selectively induce neovascularization and increase the viability of random pattern skin flaps. Methods: Adipose-derived stem cells were isolated from the inguinal fat pads of ICR mice and expanded ex vivo for three passages. After the elevation of cranially based random pattern skin flaps (3 cm long and 1 cm wide), 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine (DiI)–labeled adipose-derived stem cells were then injected into the pedicle base (group A) or 1.5 cm distal to the pedicle (group B). Medium containing no adipose-derived stem cells, mature adipocytes, or basic fibroblast growth factor were injected in three other control groups separately. (n = 10 for each group). Millimetric measurements were taken at postoperative day 7 for evaluation of flap viability. Specimens were harvested for histologic analyses. Results: Adipose-derived stem cells led to a statistically significant increase in flap viability in both group A and group B compared with the control and the adipocyte groups. Histologic examination also demonstrated a statistically significant increase in capillary density in both group A and group B. Moreover, some of the endothelial cells were stained positively for DiI. Conclusions: These findings suggest that adipose-derived stem cells have a potential for enhancing the blood supply of random pattern skin flaps. This mechanism might be both the direct differentiation of adipose-derived stem cells into endothelial cells and the indirect effect of angiogenic growth factor released from adipose-derived stem cells.

Improvement of the Survival of Human Autologous Fat Transplantation by Using VEGF-Transfected Adipose-Derived Stem Cells

Background: The efficacy of autologous fat transplantation is reduced by fat absorption and fibrosis due to fat necrosis. Enhanced transplant neovascularization early after transplantation may reduce these outcomes. The authors asked whether cell and concomitant gene therapy using adipose-derived stem cells transduced with vascular endothelial growth factor (VEGF) improves fat transplant neovascularization and survival. Methods: Human adipose-derived stem cells were expanded ex vivo for three passages, labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine (DiI), and transduced with VEGF or left untransduced. Human fat tissues were then mixed with the DiI-labeled VEGF-transduced adipose-derived stem cells, the DiI-labeled adipose-derived stem cells, the known vascularization-promoting agent insulin, or medium alone, and 18 nude mice were injected subcutaneously with all four preparations, with each of the four designated spots receiving one of these four mixtures in a random fashion. Six months later, transplanted tissue volume and histology were evaluated and neovascularization was quantified by counting the capillaries. Results: Control transplant survival was 27.1 ± 8.2 percent, but mixture with the VEGF-transduced and VEGF-untransduced stem cells significantly increased transplant survival (74.1 ± 12.6 percent and 60.1 ± 17.6 percent, respectively). Insulin was less effective (37.7 ± 6.9 percent). Histological analysis revealed both types of transplants consisted predominantly of adipose tissue, unlike the control transplants, and had significantly less fat necrosis and fibrosis. The VEGF-transduced, adipose-derived stem cell–treated transplants had significantly higher capillary density than the other transplants and bore DiI-double-positive and CD31-double-positive cells (i.e., adipose-derived stem cell–derived endothelial cells). Conclusion: Adipose-derived stem cells together with VEGF transduction can enhance the survival and quality of transplanted fat tissues.

The relationship between skin stretching/contraction and pathologic scarring: The important role of mechanical forces in keloid generation

Keloids tend to occur on highly mobile sites with high tension. This study was designed to determine whether body surface areas exposed to large strain during normal activities correlate with areas that show high rates of keloid generation after wounding. Eight adult Japanese volunteers were enrolled to study the skin stretching/contraction rates of nine different body sites. Skin stretching/contraction was measured by marking eight points on each region and measuring the change in location of the marked points after typical movements. The distribution of 1,500 keloids on 483 Japanese patients was mapped. The parietal region and anterior lower leg were associated with the least stretching/contraction, while the suprapubic region had the highest stretching/contraction rate. With regard to keloid distribution, there were 733 on the anterior chest region (48.9%) and 403 on the scapular regions (26.9%). No keloids were reported on the scalp or anterior lower leg. Because these sites are rarely subjected to skin stretching/contraction, it appears that mechanical force is an important trigger that drives keloid generation even in patients who are genetically predisposed to keloids. Thus, mechanotransduction studies are useful for developing clinical approaches that reduce the skin tension around wounds or scars for the prevention and treatment of not only keloids but also hypertrophic scars.

The relationship between keloid growth pattern and stretching tension: visual analysis using the finite element method.

Background:Keloids grow and spread horizontally, like malignant tumors, for reasons that remain unknown. Yet, stretching tension is clearly associated with keloid generation, as keloids tend to occur on high tension sites such as the anterior chest and scapular region. Thus, we analyzed the relationship between keloid growth patterns and stretching tension using a visualized finite element study. Materials and Methods:Keloids, normal skin, and fat structures were reproduced using DISCUS software. The contours were transferred to ADINA analytical software to rebuild and mesh volumes. Results:(1) High tension was observed at the edges, and not in the entire region, of stretched keloids. (2) Keloid centers were regions of low tension, which helps to explain the healing that generally occurs in the central regions of keloids. (3) Expansion of a keloid occurred in the direction in which it was pulled. (4) The “crabs claw”-shaped invasion occurred in response to increased stretching tension. (5) Skin stiffness in the circumference of a keloid was associated with greatly increased tension. (6) Fat hardness and thickness did not influence the amount of tension. (7) Adhesion with subcutaneous hard tissue greatly increased the tension in the keloid. Conclusion:These stretching results have advanced understanding of keloid formation under various conditions. Our results suggest that stretching tension is an important condition associated with keloid growth.

Is Radiation Therapy for Keloids Acceptable? The Risk of Radiation-Induced Carcinogenesis

Background: Keloids have been treated by using radiation for over a century, and it is currently suggested that keloids are best treated by a combination of surgery and postoperative radiation therapy, although randomized controlled trials testing this are still lacking. However, plastic surgeons tend to avoid radiation therapy for keloids for fear of inducing malignant tumors. Thus, the authors searched for previous reports of associations between carcinogenesis and keloid radiation therapy, and examined the evidence-based opinions of radiation oncologists regarding the acceptability of using radiation to treat keloids. Methods: A computerized literature search was carried out using PubMed that included citations from MEDLINE and PubMed Central between 1901 and March of 2009. The following search terms were used: “keloid(s),” “hypertrophic scar(s),” “radiation,” “radiation therapy,” “radiotherapy,” “carcinogenesis,” “carcinoma,” “cancer,” “complications,” and “side effects.” Moreover, the references for each report were also retrieved. Results: The authors located five cases of carcinogenesis (i.e., fibrosarcoma, basal cell carcinoma, thyroid carcinoma, and breast carcinoma) that were associated with radiation therapy for keloids. However, it was unclear whether an appropriate dose of radiation was used and whether sufficient protection of surrounding tissues was provided. Moreover, a questionnaire study of radiation oncologists around the world revealed that approximately 80 percent considered radiation to be acceptable for treating keloids. Conclusions: The authors conclude that the risk of carcinogenesis attributable to keloid radiation therapy is very low when surrounding tissues, including the thyroid and mammary glands, especially in children and infants, are adequately protected, and that radiation therapy is acceptable as a keloid treatment modality.

Angiogenesis in Wounds Treated by Microdeformational Wound Therapy

BACKGROUND Mechanical forces play an important role in tissue neovascularization and are a constituent part of modern wound therapies. The mechanisms by which vacuum assisted closure (VAC) modulates wound angiogenesis are still largely unknown. OBJECTIVE To investigate how VAC treatment affects wound hypoxia and related profiles of angiogenic factors as well as to identify the anatomical characteristics of the resultant, newly formed vessels. METHODS Wound neovascularization was evaluated by morphometric analysis of CD31-stained wound cross-sections as well as by corrosion casting analysis. Wound hypoxia and mRNA expression of HIF-1α and associated angiogenic factors were evaluated by pimonidazole hydrochloride staining and quantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively. Vascular endothelial growth factor (VEGF) protein levels were determined by western blot analysis. RESULTS VAC-treated wounds were characterized by the formation of elongated vessels aligned in parallel and consistent with physiological function, compared to occlusive dressing control wounds that showed formation of tortuous, disoriented vessels. Moreover, VAC-treated wounds displayed a well-oxygenated wound bed, with hypoxia limited to the direct proximity of the VAC-foam interface, where higher VEGF levels were found. By contrast, occlusive dressing control wounds showed generalized hypoxia, with associated accumulation of HIF-1α and related angiogenic factors. CONCLUSIONS The combination of established gradients of hypoxia and VEGF expression along with mechanical forces exerted by VAC therapy was associated with the formation of more physiological blood vessels compared to occlusive dressing control wounds. These morphological changes are likely a necessary condition for better wound healing.

Postoperative Radiation Protocol for Keloids and Hypertrophic Scars : Statistical Analysis of 370 Sites Followed for Over 18 Months

Background:Before 2002, keloids and intractable hypertrophic scars were treated at our facility with postoperative irradiation of 15 Gy (the traditional protocol). Analysis of the therapeutic outcomes of patients treated with this protocol showed that the recurrence rates of keloids and intractable hypertrophic scars in the anterior chest wall, as well as the scapular and suprapubic regions, were statistically higher than at other sites, while the recurrence rates in earlobes were lower. Thus, we customized doses for various sites. This report describes our trial of postoperative radiation therapy. Methods:Between January 2002 and September 2004, 109 patients with 121 keloid and intractable hypertrophic scar sites were treated with surgical excision following the new protocol: electron-beam irradiation at total doses of 10, 15, or 20 Gy, depending on the site. The recurrence rates and toxicities were historically followed in 218 patients with 249 keloid and intractable hypertrophic scar sites treated with the old protocol of surgical removal followed by irradiation at 15 Gy (without variation by site). The minimal follow-up time was 18 months. Statistical analysis was performed using Fisher exact probability test. Results:Total recurrence rates were 29.3% before 2002 and 14.0% after 2003. The recurrence rate in the anterior chest wall was statistically reduced. Outcomes of earlobe did not differ between irradiation with 15 Gy or 10 Gy. Conclusions:Keloids and intractable hypertrophic scars should be treated with dose protocols customized by site. Our results suggest that keloid and intractable hypertrophic scar sites with a high risk of recurrence should be treated with 20 Gy in 4 fractions over 4 days and that earlobe should be treated with 10 Gy in 2 fractions over 2 days.

Keloid and hypertrophic scarring may result from a mechanoreceptor or mechanosensitive nociceptor disorder

Keloid and hypertrophic scars (HSs) are fibroproliferative diseases (FPDs) of the skin. It is well known that stretching tension of skin, in other words mechanical force (mechanical loading, mechanical stress) on the skin, is an important factor that promotes their growth. Currently, the widely held view is that while mechanical force is a factor that aggravates keloid/HS growth after their induction, it is not a causative factor. However, there is no evidence that supports this view and recent observations from studies of keloids/HSs suggest that mechanical force in fact not only promotes the growth of such scars, it also drives their generation. Here, I hypothesize that FPDs of the skin, including keloids and HSs, are the result of an excessive responsiveness or functional failure of either dermal cell mechanoreceptors (mechanosensors) or mechanosensitive nociceptors of sensory fibers in the skin. In other words, FPDs of the skin are mechanoreceptor/mechanosensor or mechanosensitive nociceptor (mechanosensory) disorders, respectively. Moreover, by examining the site specificity of keloids, I show that stretching tension may be a major mechanical force that drives their generation. While further experimental studies of signaling pathways related to mechanotransduction, mechanosensitive (MS) channels, cell adhesion molecules, and cytoskeleton dynamics are needed, this hypothesis may provide new insights into the etiology and pathology of FPDs of the skin such as keloids and HSs.

A review of the role of mechanical forces in cutaneous wound healing.

Cutaneous wound healing is a complex process with many types of mechanical forces regulating the quality and speed of healing. The role of mechanical forces in regulating tissue growth, repair and remodelling was recognised more than a century ago. Such forces influence gene expression, the synthesis of growth factors and inflammatory mediators and cellular processes like proliferation of many load-sensitive cells. However, the exact mechanisms by which these forces interact with cells and ways to use them to stimulate tissues are still active research fronts. This article sets to review the literature on mechanical forces and their role in cutaneous wound healing.