Skin substitutes to enhance wound healing

Biologically-based skin substitutes have developed as commercial products over the last 5 years. The first generation includes the collagen-based synthetic device, Integra, and Alloderm, which is based on devitalised and cross-linked human dermis. These are used as dermal replacements for third degree burns. Within the last year, the tissue-engineered product, Dermagraft-TC^®, has become available. While originally intended as a temporary covering for severe burns, Dermagraft-TC^® has proved to markedly improve the healing of deep second degree burns. The earliest living skin substitutes used autologous keratinocytes expanded in vitro. Two new products containing living cells, Dermagraft^® and Apligraf, are expected to be approved shortly for diabetic foot ulcers and venous stasis ulcers, respectively. Dermagraft^® is produced by growing human fibroblasts on a three-dimensional scaffold. The cells actively proliferate and lay down extracellular matrix to generate a papillary dermis-like device that shows a combination of angiogenic, growth factor and cell adhesion properties that enhance healing in diabetic foot ulcers. The production of Apligraf includes casting human fibroblasts in collagen, in order to generate a dermal equivalent on which is grown an epidermis. The structure is akin to a skin graft and is so applied. Despite Dermagraft^® and Apligraf being of allogeneic origin, rejection has not been an issue in clinical trials and possible contamination by pathogens has been eliminated as a concern through extensive testing. These developments represent a new concept and are expected to revolutionise wound care. They may also provide a platform for gene therapy applications.     

PTEN: a promising pharmacological target to enhance epithelial wound healing

PI3Ks (phosphoinositide-3 kinases) produce PIP3 (phosphatidylinositol(3,4,5)-trisphosphate) which mediates signals for cell survival and proliferation. The tumour suppressor PTEN (phosphatase and tensin homologue) dephosphorylates PIP3 and is a key negative regulator of PI3K signalling. Recent research highlighted important roles for PI3K/PTEN in cell polarization and directional cell migration, pointing to a significant role for PTEN in wound healing where spatially organized tissue growth is essential. Lai et al. (in this issue of British Journal of Pharmacology) have moved a step closer in utilizing PTEN for wound healing through pharmacological inhibition. Two vanadium derivative inhibitors targeting PTEN significantly elevated the level of phosphorylated Akt (protein kinase B) and nearly doubled the wound healing rate in monolayer cultures of lung and airway epithelial cells. Damage to airway and lung epithelia underlies a wide spectrum of significant clinical conditions. With further experiments, this promising approach may find potential clinical use in situations where enhanced wound healing of pulmonary and other epithelia is important.     

Protein-energy malnutrition and involuntary weight loss: nutritional and pharmacological strategies to enhance wound healing

Clinically significant involuntary weight loss (IWL) is defined as a loss of 4.5 kg or > 5% of the usual body weight over a period of 6 - 12 months, especially when progressive. Weight loss of > 10% of normal body weight is considered to represent protein-energy malnutrition (PEM). Despite progress in our understanding of the aetiology and pathophysiology of IWL and PEM, these conditions remain frequent and serious problems in several high-risk populations in both acute and long-term care facilities. In patients with IWL and PEM, nonhealing wounds signal a catabolic process that requires prompt nutritional intervention. Aggressive nutritional therapy that provides adequate protein, calories and micronutrients, combined with an anabolic agent such as oxandrolone, may provide the most optimal environment for restoration of lean body mass and body weight and in turn, promote wound healing. More research, however, is needed to define optimal nutritional and anabolic therapies for these patients given the associated high morbidity and cost of care.     

Protein-energy malnutrition and involuntary weight loss: nutritional and pharmacological strategies to enhance wound healing

Clinically significant involuntary weight loss (IWL) is defined as a loss of 4.5 kg or > 5% of the usual body weight over a period of 6 – 12 months, especially when progressive. Weight loss of > 10% of normal body weight is considered to represent protein-energy malnutrition (PEM). Despite progress in our understanding of the aetiology and pathophysiology of IWL and PEM, these conditions remain frequent and serious problems in several high-risk populations in both acute and long-term care facilities. In patients with IWL and PEM, nonhealing wounds signal a catabolic process that requires prompt nutritional intervention. Aggressive nutritional therapy that provides adequate protein, calories and micronutrients, combined with an anabolic agent such as oxandrolone, may provide the most optimal environment for restoration of lean body mass and body weight and in turn, promote wound healing. More research, however, is needed to define optimal nutritional and anabolic therapies for these patients given the associated high morbidity and cost of care.     

Studies on wound healing

Factors affecting the rate of healing of experimental skin wounds in rats have been investigated. The effectiveness of healing was measured by determining the tensile strengths of the incised skin after various time intervals. When the skin histamine content was lowered by treatment with polymyxin B or with compound 48/80, retardation of the healing process was evident from the reduced tensile strengths. When the skin 5-hydroxytryptamine content was lowered by treatment with reserpine, retardation of healing was also found. Heparin increased the rate of healing and more rapid healing was obtained by giving histamine before each dose of heparin. On the other hand, some glucocorticoids markedly inhibited the healing process. Of the constituents of the tissue mast cells, heparin appears to be more important than histamine and 5-hydroxytryptamine in promoting the healing of experimental skin wounds in rats.     

Targeting matrix metalloproteases to improve cutaneous wound healing

Wound repair is a physiological event in which tissue injury initiates a repair process leading to restoration of structure and function of the tissue. Cutaneous wound repair can be divided into a series of overlapping phases including formation of fibrin clot, inflammatory response, granulation tissue formation incorporating re-epithelialisation and angiogenesis and finally, matrix formation and remodelling. Matrix metalloproteases (MMPs) are a family of neutral proteases that play a vital role throughout the entire wound healing process. They regulate inflammation, degrade the extracellular matrix (ECM) to facilitate the migration of cells and remodel the new ECM. However, excessive MMP activity contributes to the development of chronic wounds. Selective control of MMP activity may prove to be a valuable therapeutic approach to promote healing of chronic ulcers. Recent evidence indicates that the anticoagulant, activated protein C may be useful in the treatment of non-healing wounds by preventing excessive protease activity through inhibition of inflammation and selectively increasing MMP-2 activity to enhance angiogenesis and re-epithelialisation.     

Targeting matrix metalloproteases to improve cutaneous wound healing

Wound repair is a physiological event in which tissue injury initiates a repair process leading to restoration of structure and function of the tissue. Cutaneous wound repair can be divided into a series of overlapping phases including formation of fibrin clot, inflammatory response, granulation tissue formation incorporating re-epithelialisation and angiogenesis and finally, matrix formation and remodelling. Matrix metalloproteases (MMPs) are a family of neutral proteases that play a vital role throughout the entire wound healing process. They regulate inflammation, degrade the extracellular matrix (ECM) to facilitate the migration of cells and remodel the new ECM. However, excessive MMP activity contributes to the development of chronic wounds. Selective control of MMP activity may prove to be a valuable therapeutic approach to promote healing of chronic ulcers. Recent evidence indicates that the anticoagulant, activated protein C may be useful in the treatment of non-healing wounds by preventing excessive protease activity through inhibition of inflammation and selectively increasing MMP-2 activity to enhance angiogenesis and re-epithelialisation.     

Xanthinol nicotinate and wound healing

In an experimental study the local effect of i.v. applied xantinol-nicotinate (Complamin) on healing skin incisions in rats was studied. In conclusion, there was a higher ultimate tensile strength of wounds treated by the agent, based on the increased synthesis of collagen fibres. This statement was proved by the alteration of free hydroxyproline in serum. Histologically, there was an intensive vascularization of the wound healing area. Concerning the elastic behaviour we found a more rigid regenerative tissue in the early phases of healing on account of the enhanced thickness of the wound area.     

Endothelin and hepatic wound healing

Liver wound healing is a coordinated response to injury caused by infections (hepatitis) or toxins (alcohol) or other processes where activation of hepatic stellate cells are a central component. During stellate cell activation, a major phenotypic transformation occurs which leads to increased production of increased extracellular matrix proteins and smooth muscle α-actin the results is organ dysfunction due to gross architectural disruption and impaired blood flow.Endothelin-1 (ET-1) is produced in increased amounts and the cellular source of ET-1 shifts from endothelial cells to stellate cells during liver injury thus setting a feedback loop which accentuates further activation, stellate cell proliferation, and production of extracellular matrix proteins. Therapy directed at intervening the ET-1 signaling pathway has significant therapeutic potential in patients with liver disease.     

芍药苷促进糖尿病创面愈合

目的研究芍药苷(paeoniflorin,PA)对糖尿病创面愈合作用及作用机制。方法采用糖尿病小鼠全层皮肤切除夹板模型,HE染色及Masson染色观察创面组织形态改变;免疫荧光法检测血管新生。PA干预人脐静脉内皮细胞(human umbilical vein endothelial cells,HUVECs)和小鼠成纤维细胞(fibroblast,FB),MTS、Brd U和划痕实验检测细胞增殖和迁移能力; Matrigel实验检测HUVECs成管能力,q PCR检测FB中CollagenⅢ、Fibronectin、α-SMA mRNA的变化;免疫荧光法观察α-SMA在FB中的表达部位及表达量的变化。结果与db/db模型组相比,PA组创面肉芽组织,胶原形成和新生毛细血管密度明显增加(P <0. 01)。PA对HUVECs增殖无影响,可明显促进HUVECs迁移和成管的能力(P <0. 05,P <0. 01)。PA可明显增加FB增殖和迁移的能力,明显增加CollagenⅢ、α-SMA mRNA的表达(P <0. 05,P <0. 01),对Fibronectin mRNA的表达无影响,同时可增加α-SMA的荧光强度。结论芍药苷可能通过促进细胞外基质生成和血管新生,促进糖尿病创面愈合。     

Age-related changes in wound healing

Evidence for age-related effects on wound healing have been derived for the most part from empirical observations without adjustment for confounders other than age. Age-related changes in the structure and function of the skin do occur. Some of these changes result from chronic solar radiation exposure rather than chronological age per se. The tensile strength of wounds, accumulation of wound healing factors and rate of wound closure have all been examined in relation to chronological aging. However, the clinical impact of these changes in acute wound healing appears to be small. Poor healing in chronic wounds is more often related to comorbid conditions rather than age alone. Since the majority of these chronic wounds occur in elderly populations, this has contributed to the conclusion that aging itself may influence healing. Progress in understanding the role that growth factors play in wound healing and the ability to synthesise adequate quantities of these factors for clinical use has led to clinical trials evaluating their use in wound healing. The results of these studies, with the possible exception of those in diabetic wounds, have been disappointing. Insight into the wound healing process indicates that growth factors interact during wound healing in a sequential and orderly process. Improved wound healing may require different clinical designs or the use of these factors in a precisely timed sequential administration.     

Gamma-irradiation of lyophilised wound healing wafers

Lyophilised wafers are being developed as drug delivery systems that can be applied directly to the surface of suppurating wounds. They are produced by the freeze-drying of polymer solutions and gels. This study investigates the possibility of sterilising these glassy, solid dosage forms with gamma-irradiation and determining the rheological properties of rehydrated wafers post-irradiation. One series of wafers was formulated using sodium alginate (SA) modified with increasing amounts of methylcellulose (MC), the other being composed of xanthan gum (XG) and MC. Batches were divided into three lots, two of which were exposed to 25 and 40 kGrays (kGy) of Cobalt-60 gamma-irradiation, respectively, the third being retained as a non-irradiated control. Apparent viscosities of solutions/gels resulting from the volumetric addition of distilled water to individual wafers were determined using continuous shear, flow-rheometry. Flow behaviour on proprietary suppurating surfaces was also determined. Large reductions in viscosity were apparent for irradiated SA samples while those of XG appeared to be largely unaffected. In addition, an increase in the yield stress of xanthan formulations was observed. Xanthan wafers appeared to withstand large doses of irradiation with no detrimental effect on the rheology of reconstituted gels. This offers the possibility of manufacturing sterilisable delivery systems for wounds.     

Ischemic wound healing and possible treatments

The present review describes the major steps in wound healing, the factors that clinically cause ischemia including the changes found in diabetes mellitus and the possible interventions and treatments of ischemic wounds. The number of randomized, double-blind, controlled clinical trials is scarce, especially on the healing of chronic ischemic soft tissue wounds. Experimental and clinical studies to date have demonstrated that hyperbaric oxygen may be an effective treatment of chronic hypoxic wounds and that certain growth factors (e.g., recombinant platelet-derived growth factor-BB) are likely to enhance the healing of such wounds. Other treatments are discussed, among them vasoactive drugs (e.g., pentoxifylline), occlusive dressings and surgical treatment, including delayed primary closure of acute ischemic wounds.     

Antiviral medications and corneal wound healing

Masked controlled rabbit studies were done to determine the toxic effects on corneal wound healing of the antiviral ointments 0.5% idoxuridine, 3% Ara A, and 3% acyclovir, and the antiviral drops 0.1% idoxuridine, 3% Ara AMP, and 1% trifluridine. Ara A, acyclovir, trifluridine and idoxuridine drops had no significant effects on the rate of closure of epithelial wounds. Idoxuridine ointment given 5 times a day significantly retarded the rate of epithelial wound closure, but not when given 4 times a day. Only Ara AMP caused a retardation of epithelial healing and an actual increase in the defect after 4 days of treatment. Histopathologically all drugs, except acyclovir, showed a toxic effect on the regenerating epithelium. All drugs, except acyclovir, showed retarded stromal wound healing with reduced bursting strength and collagen content. Ara AMP had increased bursting strength and collagen content possibly because of greater inflammation. Acyclovir, in comparison to all the other medications studied, appeared to have minimal to no toxic effects on experimental epithelial and stromal wound healing, and on this basis is the agent of choice for use in herpes simplex stromal keratitis with ulceration and as a prophylactic agent for long-term use after penetrating keratoplasty.