Excision Wound Closure Research Articles

Nail unit incision lines: A tool to minimize nail unit scarring

Abstract Langer’s lines, lines of cleavage, and biodynamic excisional skin tension (BEST) lines have been defined for cutaneous surgery to ensure excisional wound closure with the least tension on any part of the body and minimize scarring. This article describes nail unit incision lines (NUIL) with a similar perspective. NUIL are followed by nail surgeons to help regrowth of a normal nail; however, they are not widely understood or respected during nail surgery. Within the anatomically small nail unit, the orientation of these lines varies depending on the area being operated upon. Nail bed incisions should be oriented longitudinally, while nail matrix incisions should be oriented horizontally. Being the germinative portion, nail matrix should be dealt with more cautiously, avoiding the lunular margin. Lateral nail fold incisions should be longitudinal, while proximal nail fold incisions should be radial. Distal nail fold (hyponychial) incisions should preferably be oriented parallel to the distal nail ridge. Knowledge and compliance with NUIL can help minimize scarring outcomes in nail surgery.

Selective Ablation of BCL11A in Epidermal Keratinocytes Alters Skin Homeostasis and Accelerates Excisional Wound Healing In Vivo.

Transcriptional regulator BCL11A plays a crucial role in coordinating a suite of developmental processes including skin morphogenesis, barrier functions and lipid metabolism. There is little or no reports so far documenting the role of BCL11A in postnatal adult skin homeostasis and in the physiological process of tissue repair and regeneration. The current study establishes for the first time the In Vivo role of epidermal BCL11A in maintaining adult epidermal homeostasis and as a negative regulator of cutaneous wound healing. Conditional ablation of Bcl11a in skin epidermal keratinocytes (Bcl11aep−/−mice) enhances the keratinocyte proliferation and differentiation program, suggesting its critical role in epidermal homeostasis of adult murine skin. Further, loss of keratinocytic BCL11A promotes rapid closure of excisional wounds both in a cell autonomous manner likely via accelerating wound re-epithelialization and in a non-cell autonomous manner by enhancing angiogenesis. The epidermis specific Bcl11a knockout mouse serves as a prototype to gain mechanistic understanding of various downstream pathways converging towards the manifestation of an accelerated healing phenotype upon its deletion.

Accelerated Wound Border Closure Using a Microemulsion Containing Non-Inhibitory Recombinant α1-Antitrypsin

Wound healing requires a non-compromising combination of inflammatory and anti-inflammatory processes. Human α1-antitrypsin (hAAT), a circulating glycoprotein that rises during acute-phase responses and during healthy pregnancies, is tissue-protective and tolerance-inducing; although anti-inflammatory, hAAT enhances revascularization. hAAT blocks tissue-degrading enzymes, including neutrophil elastase; it is, therefore, unclear how wound healing might improve under hAAT-rich conditions. Here, wound healing was examined in the presence of recombinant hAAT (hAATWT) and protease-inhibition-lacking hAAT (hAATCP). The impact of both hAAT forms was determined by an epithelial cell gap closure assay, and by excisional skin injuries via a microemulsion optimized for open wounds. Neutrophilic infiltration was examined after 8 h. According to results, both hAAT forms accelerated epithelial gap closure and excisional wound closure, particularly at early time points. Unlike dexamethasone-treated wounds, both resulted in closed borders at the 8-h time point. In untreated and hAATCP-treated wounds, leukocytic infiltrates were widespread, in hAATWT-treated wounds compartmentalized and in dexamethasone-treated wounds, scarce. Both hAAT forms decreased interleukin-1β and increased VEGF gene expression. In conclusion hAAT improves epithelial cell migration and outcomes of in vivo wounds irrespective of protease inhibition. While both forms of hAAT allow neutrophils to infiltrate, only native hAAT created discrete neutrophilic tissue clusters.

Accelerating the excisional wound closure by using the patterned microstructural nanofibrous mats/gentamicin-loaded hydrogel composite scaffold.

Ideal artificial tissue scaffolds should provide an in vitro microenvironment comparable to native human skin tissue to direct cell functions, regulate tissue homeostasis, and promote tissue regeneration. A sandwich-like composite scaffold consisting of a hydrogel layer and two aligned nanofibre layers was fabricated and applied as a wound-healing dressing. Gentamicin was preloaded into the hydrogel middle layer and naturally released for antibacterial activity during the healing period. Nanofibrous layers embedded on the top and bottom surfaces of the hydrogel improved the tensile strength fivefold (1560 ​kPa and 465% strain) while serving as a diffusion barrier to reduce the gentamicin initial burst release (30%–15%). Inspired by the extracellular matrix (ECM), the surface of nanofibre top layer was patterned with triangular microarrays using micro-moulding approach to reflect the multidimensional structure of ECM. Biocompatibility of the scaffold is proven from cytotoxicity and haemolysis studies. Fibroblast cells revealed a highly elongated and consistent alignment modulated by the micropatterned fibrous layer and directed their migration towards the wound area. Excisional wounds treated with the scaffold promoted 97.49% wound closure with low inflammation and rapid re-epithelialization and angiogenesis. This scaffold, with its tailored functionality capable of accelerating wound healing, has high potential in tissue engineering applications.

Lipin-1 integrates lipid metabolism with macrophage function to promote inflammation resolution

Abstract Free fatty acid accumulation in macrophages alters cellular metabolism, leading to failed inflammation resolution that contributes to cardiometabolic pathologies such as atherosclerotic cardiovascular disease. Free fatty acids are either broken down by β-oxidation, stored in glycerolipids, or incorporated into sphingolipids (e.g., ceramides). Ceramide synthesis inhibits several pro-resolving macrophage functions, such as β-oxidation and efferocytosis, needed for inflammation resolution. The regulatory signals that control free fatty acid incorporation into lipids (e.g., lipid channeling) for proper macrophage function are not well understood. Lipin-1 is a phosphatidic acid phosphatase with an independent transcriptional coregulatory activity that controls cellular lipid homeostasis. Using genetically engineered mice and bone marrow-derived macrophages, we investigated the contribution of lipin-1 on macrophage pro-resolving functions. Mice lacking myeloid-specific lipin-1 had defects in the clearance of apoptotic cells in a zymosan model of inflammation resolution, and these mice had increased atherosclerotic plaques and necrotic cores in a model of atherosclerosis and a delay excisional wound closure. Bone marrow-derived macrophages lacking lipin-1 showed a striking pattern of dysregulated lipid metabolism in which il-4 stimulation promoted ceramide synthesis over β-oxidation. Additionally, lipin-1 deficient macrophages had reduced phagocytosis of apoptotic cells. Our work provides evidence that lipin-1 promotes β-oxidation while inhibiting ceramide synthesis during free fatty acid accumulation in macrophages to allow for responses that promote inflammation resolution. Supported by grants from NIH (1 R01HL131844-04) and NIH (1P20GM134974-01A1)

Use of a Novel Adhesive Suture Retention Device in Lower Leg Excisional Wound Closure: A Retrospective Review

Introduction. Lower extremity excisional wound closures are associated with complications, including infection, delayed wound healing, skin tearing after suture placement, and dehiscence. Use of a novel adhesive suture retention device (ASRD) has previously been shown to support fragile skin under high tension and improve linear closure. Objective. A retrospective analysis of lower extremity excisional wounds was performed to investigate the effect of adopting ASRD on rate of wound closure and adverse events. Materials and Methods. A retrospective chart review from 2 Mohs surgical practices was conducted. The chart review assessed the differences before and after adopting ASRD in linear closure rates, wound healing, and dehiscence rates for lower extremity post-surgical full-thickness wounds of at least 1.0 cm diameter in patients aged 18 years or older. In all cases, the authors shared the same surgical techniques, including limited undermining and use of buried dermal polyglactin sutures. In all ASRD cases, the device was used with 2-0 nylon retention sutures. Results. Adoption of ASRD was associated with a significantly faster time to healing (P < .001). Dehiscence was significantly more commonly seen in the pre-ASRD cohort (24% vs 3%, P = .03). Infection was also more common in the pre-ASRD cohort; however, the difference was not statistically significant (18% vs 3%, P = .09). Conclusions. Utilization of ASRD decreased the incidence of lower extremity wound dehiscence and resulted in faster healing times after Mohs surgery.

Exploration of the role of a lithophytic fern, Pteris vittata L. in wound tissue regeneration and remodelling of genes in hyperglycaemic rat model

BackgroundIn hyperglycemic conditions like diabetes, impaired wound healing occurs due to endothelial damage, dysfunction of leukocyte, decreased phagocytosis and secondary infection which may lead to amputation and debility. Ethnomedicinally, Pteris vittata L. (PV) is used for wound healing. This fern is arsenic hyper-accumulator but its therapeutic aspect is still unexplored. Hence, the present study was put forth to study its aqueous extract and ethanolic extract in diabetic wound healing.MethodsRats were divided into diabetic control, povidine iodine (PI) treated, ethanolic and aqueous extracts of PV treated groups (n = 6). Circular excision wound closure was observed for 15 days with and without treatment. After study completion, skin was divided into four sections wherein first section was homogenized for collagen, hydroxyproline and hexosamine assay. Second, third and fourth sections were used for antioxidant assay, gene expression and histopathology. Column purified fraction of ethanolic extract of PV was subjected to High Performance Liquid Chromatography, Fourier-transform infrared spectroscopy, Nuclear Magnetic Resonance and Mass spectroscopy. Data obtained were analyzed using one way analysis of variance and expressed as Mean ± SD.ResultsThe percentage difference in wound area of day 15 to day 0 showed 65% wound contraction in diabetic control rats. The percentage reduction in wound area showed by PI and extracts of PV were 79% and 85% respectively. Statistical significant increase in collagen, hydroxyproline and hexosamine was observed in the test groups as compared to disease control and PI treated rats. Similarly, statistical significant increases in antioxidant enzymes were observed in the treated groups with decrease in lipid peroxidation. Treatment of rats with PI and two extracts of PV up-regulated Matrix Metalloprotein-9, Collagenase-2 and VEGF-1 and down regulated Tumor Necrosis Factor- α and Interleukin-6. Histopathology in diabetic rats showed incomplete scab formation with haemorrhages which were absent in treated rats. Spectral data showed presence of polyphenolic compounds, fatty acids and ascorbic acid.ConclusionAlternative and complimentary management based on herbal biotherapy which can promote angiogenesis, increase collagen and lower the levels of reactive oxygen species are warranted for healing of wounds in hyperglycaemic conditions which were achieved by two extracts of PV.

Cell-specific expression of the transcriptional regulator RHAMM provides a timing mechanism that controls appropriate wound re-epithelialization

Prevention of aberrant cutaneous wound repair and appropriate regeneration of an intact and functional integument require the coordinated timing of fibroblast and keratinocyte migration. Here, we identified a mechanism whereby opposing cell-specific motogenic functions of a multifunctional intracellular and extracellular protein, the receptor for hyaluronan-mediated motility (RHAMM), coordinates fibroblast and keratinocyte migration speed and ensures appropriate timing of excisional wound closure. We found that, unlike in WT mice, in Rhamm-null mice, keratinocyte migration initiates prematurely in the excisional wounds, resulting in wounds that have re-surfaced before the formation of normal granulation tissue, leading to a defective epidermal architecture. We also noted aberrant keratinocyte and fibroblast migration in the Rhamm-null mice, indicating that RHAMM suppresses keratinocyte motility but increases fibroblast motility. This cell context-dependent effect resulted from cell-specific regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) activation and expression of a RHAMM target gene encoding matrix metalloprotease 9 (MMP-9). In fibroblasts, RHAMM promoted ERK1/2 activation and MMP-9 expression, whereas in keratinocytes, RHAMM suppressed these activities. In keratinocytes, loss of RHAMM function or expression promoted epidermal growth factor receptor-regulated MMP-9 expression via ERK1/2, which resulted in cleavage of the ectodomain of the RHAMM partner protein CD44 and thereby increased keratinocyte motility. These results identify RHAMM as a key factor that integrates the timing of wound repair by controlling cell migration.

Periostin and CCN2 Scaffolds Promote the Wound Healing Response in the Skin of Diabetic Mice.

Nonhealing skin wounds remain a significant burden on health care systems, with diabetic patients 20 times as likely to undergo a lower extremity amputation due to impaired healing. Novel treatments that suppress the proinflammatory signature and induce the proliferative and remodeling phases are needed clinically. We demonstrate that the addition of periostin and CCN2 in a scaffold form increases closure rates of full-thickness skin wounds in diabetic mice, concomitant with enhanced angiogenesis. Our results demonstrate the efficacy of periostin- and CCN2-containing biomaterials to stimulate wound closure, which could represent a novel method for the treatment of diabetic skin wounds.

1312 Nrf2 activation enhances the healing of cutaneous wounds through the activation of hair follicle stem cells

The transcription factor Nrf2 is a key regulator of the cellular stress response through the regulation of antioxidant enzymes, cytoprotective proteins and various transporters. Strong genetic activation of Nrf2 in keratinocytes leads to a pilosebaceous phenotype, characterized by hyperplasia of the sebaceous glands and infundibula, hyperkeratosis, and seborrhea, implicating Nrf2 in several other key processes in the epidermis. Here we show that Nrf2 activation in keratinocytes promotes the proliferation and expansion of the junctional zone (JZ) and upper isthmus (UI) hair follicle stem cells, while bulge stem cells are only mildly affected. This was observed to be functionally important for wound repair, since Nrf2 activation also led to the faster closure of excisional wounds through the formation of a longer and larger wound epithelium. This however, was neither due to changes in proliferation or apoptosis of keratinocytes in the wound epithelium, nor their migration as measured in vitro. Instead, an increased number and proliferation of follicular JZ and UI stem cells were observed peripheral to the wound. An enhancement of wound healing in Nrf2 transgenic mice following tape stripping of the epidermis revealed a functional link between the Nrf2-mediated expansion of hair follicles stem cells and accelerated re-epithelialization. The effect of Nrf2 activation on JZ and UI stem cells resulted from the Nrf2-mediated up-regulation of the EGF family member Epigen and subsequent EGF receptor activation. These results suggest pharmacological Nrf2 activation as a promising approach for the enhancement of wound healing through expansion of hair follicle stem cell pools.

Administration of Curcuma longa Extract Topically does not Accelerate Skin Excision Wound Closure in Alloxan-Induced Diabetic Mice Model

Administration of Curcuma longa Extract Topically does not Accelerate Skin Excision Wound Closure in Alloxan-Induced Diabetic Mice Model

Biodynamic excisional skin tension lines for surgical excisions: untangling the science.

Objective There remains confusion between Langer's lines and wrinkle lines with respect to the optimal orientation of elliptical excisions on the trunk. This study sought to determine the directions of wound closure that would result in least wound tension after skin lesion excisions. Materials and methods Some 1181 consecutive skin lesion excisions were investigated (age range 13-95 years, median 64 years) using a tensiometer to determine directions of least wound tension. These lines were mapped. Skin tension measurements were taken during the procedure and analysed. The clear majority of excisions were for skin cancer and the others were for cysts or dysplastic naevi. Lesions such as lipomas, which entail incisional rather than excisional surgery (i.e. where overlying skin was not excised) were excluded. All lesions were cut out in a circular fashion following tension measurements. Closure was undertaken in the direction of least tension (biodynamic excisional skin tension line) and this was illustrated. This process was repeated in all cases where body site and direction of closure was mapped. Statistical analyses were undertaken on a series on the scalp and lower limb. Results Biodynamic excisional skin tension lines have a clear directional preference: scalp-coronal direction, limbs--vertical orientation of ellipses and trunk - mostly horizontal except oblique at the shoulder and scapular regions. Discussion Skin cancer excisions often end up with poor cosmetic results, owing to inconsistency in identifying the correct excisional wound closure lines. This has not been helped by the (hitherto) lack of large in vivo biomechanical studies, and because incisional lines and excisional lines have not been considered separately in surgical practice. Orientating ellipses or wound closures using biodynamic excisional skin tension lines offers a guide to reducing wound tension and minimising wound complications or scarring after cutaneous surgery.

Clinical Experience with a Novel Topical Adhesive for Dermatologic Excisional Wound Closure: A Case-Series

Background. The topical adhesive, 2-octyl cyanoacrylate, has been used as an alternative to sutures for closure of skin in a variety of surgical procedures. While potential benefits exist, reports of allergic contact dermatitis and exothermic reactions have been a barrier to widespread adoption by dermatologic surgeons. Objective. To describe our experience using a novel formulation of 2-octyl cyanoacrylate for skin closure after surgical excision of cutaneous lesions. Methods. We describe the results of 9 office-based dermatologic excisions in 8 patients utilizing a novel formulation of 2-octyl cyanoacrylate for skin closure. At two weeks of follow-up, all incisions were examined for cosmetic result and signs of infection as per the office’s standard of care. Results. At follow-up, there were no signs of infection. One wound demonstrated mild tissue hypertrophy, while another showed very minimal skin separation (< 1mm) that did not require reintervention. No incidences of contact dermatitis, application discomfort, or burns were noted. Patient satisfaction was high. Conclusion. A novel formulation of 2-octyl cyanoacrylate topical adhesive demonstrates feasibility as a potential alternative to the use of sutures for skin closure following dermatologic excisions. Larger studies are imperative to fully describe the outcomes associated with use of this new preparation.

Constitutive overexpression of periostin delays wound healing in mouse skin.

Periostin is a matricellular protein involved in development, maintenance, and regulation of tissues and organs via by binding to cell surface integrin receptors. Pathologically, periostin plays an important role in the process of wound healing: as a deficiency of the Postn gene delays wound closure and periostin is consistently up-regulated in response to injury and skin diseases. However, the functional role of elevated periostin in the process of wound healing has not been tested. In this study, we generated Postn-transgenic mice under the control of the CAG promoter/enhancer to investigate the effects of constitutive overexpression of full length periostin during its pathophysiological roles. Transgenic mice showed significant overexpression of periostin in skin, lung, and heart, but no morphological changes were observed. However, when these transgenic mice were injured, periostin overexpression delayed the closure of excisional wounds. Expression of IL-1β and TNFα, pro-inflammatory cytokines important for wound healing, was significantly decreased in the transgenic mice, prior to delayed healing. Infiltration of neutrophils and macrophages, the main sources of IL-1β and TNFα, was also down-regulated in the transgenic wound sites. From these data, we conclude that enforced expression of periostin delays wound closure due to reduced infiltration of neutrophils and macrophages followed by down-regulation of IL-1β and TNFα expression. This suggests that regulated spatiotemporal expression of periostin is important for efficient wound healing and that constitutive periostin overexpression interrupts the normal process of wound closure.

Pilot Study Assessing the Efficacy of a Novel Topical Adhesive for Dermatologic Excisional Wound Closure

Abstract Not Available

EPR monitoring of wound oxygenation as a biomarker of response to gene therapy encoding hCAP-18/LL37 peptide.

To investigate the value of electron paramagnetic resonance oximetry to follow oxygenation in wounds treated by a plasmid-encoding host defense peptide hCAP-18/LL37. Flaps were created on diabetic mice (7- or 12-week-old db/db mice) presenting different levels of microangiopathy. The hCAP-18/LL37-encoding plasmids were administered in wounds by electroporation. Low-frequency electron paramagnetic resonance oximetry using lithium phthalocyanine as the oxygen sensor was used to monitor wound oxygenation in flaps during the healing process. Flaps were analyzed by immunohistochemistry to assess hypoxia and cell proliferation. Kinetics of closure was also assessed in excisional skin wounds. A reoxygenation of the flap was observed during the healing process in the 7-week-old db/db treated mice, but not in the untreated mice and the 12-week-old mice. Histological studies demonstrated less hypoxic regions and higher proportion of proliferating cells in hCAP-18/LL37-treated flaps in the 7-week-old db/db treated mice compared with untreated mice. Consistently, the kinetics of excisional wound closure was improved by hCAP-18/LL37 treatment in the 7-week-old db/db but not in the 12-week-old mice. Oxygenation measured by electron paramagnetic resonance oximetry is a promising biomarker of response to treatments designed to modulate wound oxygenation. Magn Reson Med 79:3267-3273, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Compromised Wound Healing in Ischemic Type 2 Diabetic Rats.

Ischemia is one of the main epidemic factors and characteristics of diabetic chronic wounds, and exerts a profound effect on wound healing. To explore the mechanism of and the cure for diabetic impaired wound healing, we established a type 2 diabetic rat model. We used an 8weeks high fat diet (HFD) feeding regimen followed by multiple injections of streptozotocin (STZ) at a dose of 10mg/kg to induce Wister rat to develop type 2 diabetes. Metabolic characteristics were assessed at the 5th week after the STZ injections to confirm the establishment of diabetes mellitus on the rodent model. A bipedicle flap, with length to width ratio 1.5, was performed on the back of the rat to make the flap area ischemic. Closure of excisional wounds on this bipedicle flap and related physiological and pathological changes were studied using histological, immunohistochemical, real time PCR and protein immunoblot approaches. Our results demonstrated that a combination of HFD feeding and a low dose of STZ is capable of inducing the rats to develop type 2 diabetes with noticeable insulin resistance, persistent hyperglycemia, moderate degree of insulinemia, as well as high serum cholesterol and high triglyceride levels. The excision wounds on the ischemic double pedicle flap showed deteriorative healing features comparing with non-ischemic diabetic wounds, including: delayed healing, exorbitant wound inflammatory response, excessive and prolonged ROS production and excessive production of MMPs. Our study suggested that HFD feeding combined with STZ injection could induce type 2 diabetes in rat. Our ischemic diabetic wound model is suitable for the investigation of human diabetic related wound repair; especically for diabetic chronic wounds.

Do not be alarmed: understanding IL33-ST2 signalling in wound repair.

Do not be alarmed: understanding IL33-ST2 signalling in wound repair.

Promotion of Wound Healing by an Agonist of Adenosine A2A Receptor Is Dependent on Tissue Plasminogen Activator.

Impaired wound healing, as it occurs in diabetes mellitus or long-term corticoid treatment, is commonly associated with disability, diminished quality of life, and high economic costs. Selective agonists of the A2A receptor subtype of adenosine, an endogenous regulator of inflammation, promote tissue repair in animal models, both healthy and with impaired healing. Plasmin-mediated proteolysis of fibrin and other matrix proteins is essential for cell migration at sites of injury. Since adenosine A2A receptor activation increases plasminogen activator release from macrophages and mast cells, we studied the effect of a selective agonist, CGS-21680, on full-thickness excisional wound closure in wild-type, urokinase plasminogen activator (uPA)-deficient, and tissue plasminogen activator (tPA)-deficient mice. Wound closure was impaired in tPA- and uPA-deficient mice as compared with wild-type mice, and topical application of CGS-21680 significantly increased the rate at which wounds closed in wild-type mice and uPA-deficient mice, but not in tPA-deficient mice. Immunostaining of tissue sections showed that tPA was present in endothelial cells and histiocytes by day 3 post-wound and also by day 6. In contrast, uPA was more prominent in these cell types only by day 6 post-wound. Our results confirm that plasminogen activation contributes to wound repair and are consistent with the hypothesis that adenosine A2A receptor activation promotes wound closure by a mechanism that depends upon tPA, but not uPA. Moreover, our results suggest that topical adenosine A2A receptor agonists may be useful in promotion of wound closure in patients with impaired wound healing.

Global Deletion of Ankrd1 Results in a Wound-Healing Phenotype Associated with Dermal Fibroblast Dysfunction

The expression of ankyrin repeat domain protein 1 (Ankrd1), a transcriptional cofactor and sarcomeric component, is strongly elevated by wounding and tissue injury. We developed a conditional Ankrd1(fl/fl) mouse, performed global deletion with Sox2-cre, and assessed the role of this protein in cutaneous wound healing. Although global deletion of Ankrd1 did not affect mouse viability or development, Ankrd1(-/-) mice had at least two significant wound-healing phenotypes: extensive necrosis of ischemic skin flaps, which was reversed by adenoviral expression of ANKRD1, and delayed excisional wound closure, which was characterized by decreased contraction and reduced granulation tissue thickness. Skin fibroblasts isolated from Ankrd1(-/-) mice did not spread or migrate on collagen- or fibronectin-coated surfaces as efficiently as fibroblasts isolated from Ankrd1(fl/fl) mice. More important, Ankrd1(-/-) fibroblasts failed to contract three-dimensional floating collagen gels. Reconstitution of ANKRD1 by adenoviral infection stimulated both collagen gel contraction and actin fiber organization. These invitro data were consistent with invivo wound closure studies, and suggest that ANKRD1 is important for the proper interaction of fibroblasts with a compliant collagenous matrix both invitro and invivo.