Treatment Of Chronic Venous Ulcers Research Articles

Innovative Therapies in Wound Healing

Background: Apligraf is a bioengineered skin product composed of neonatal fibroblasts and keratinocytes. The FDA has approved Apligraf for the treatment of chronic venous ulcers and diabetic ulcers. Objective: We review the development of bioengineered skin, examine the cellular activities of various growth factors that may facilitate wound healing, and discuss the results of clinical trials with a particular construct, Apligraf, as proof of principle. Conclusion: Bioengineered skin acts as a “smart” delivery system for growth factors and other stimulatory substances. Not only does it present a novel treatment for chronic and diabetic ulcers, but it could also be considered for application to other types of acute wounds.

Innovative Therapies in Wound Healing

Apligraf is a bioengineered skin product composed of neonatal fibroblasts and keratinocytes. The FDA has approved Apligraf for the treatment of chronic venous ulcers and diabetic ulcers. We review the development of bioengineered skin, examine the cellular activities of various growth factors that may facilitate wound healing, and discuss the results of clinical trials with a particular construct, Apligraf, as proof of principle. Bioengineered skin acts as a "smart" delivery system for growth factors and other stimulatory substances. Not only does it present a novel treatment for chronic and diabetic ulcers, but it could also be considered for application to other types of acute wounds.

Expression of cyclooxygenase isoforms in normal human skin and chronic venous ulcers.

Chronic venous ulcers are an example of abnormal wound healing showing chronic inflammation which together with the underlying vascular pathology results in delayed healing. Prostaglandins are among the most important mediators of inflammation. They have proinflammatory effects, predominantly by affecting the vasculature. Cyclooxygenase (COX) is the rate-limiting enzyme in prostanoid synthesis. It is present in two isoforms: COX-1 (constitutive cyclooxygenase) which is produced in the body to maintain normal haemostatic functions, and COX-2 (inducible cyclooxygenase), which is induced during inflammation in response to cytokines. Using immunoenzymatic labelling and western blot analysis, this study has shown that both COX-1 and COX-2 were up-regulated in chronic venous leg ulcers by comparison with normal human skin. De novo appearance of COX-2 in chronic venous ulcers was demonstrated, which is not seen in normal human skin. The main cellular sources of both COX isoforms are macrophages and endothelial cells. COX-2 is also produced by mast cells and fibroblasts. A COX radioimmunoassay showed up-regulation of COX activity in chronic venous ulcers compared with normal skin (p<0.05). Up-regulation of COX-1 in chronic venous leg ulcers could produce prostacyclin, which contributes to angiogenesis. Thus, inhibition of COX-1 by non-steroidal anti-inflammatory drugs (NSAIDs) could increase the local ischaemia and hypoxia associated with chronic venous ulcers. On the other hand, up-regulation of COX-2 is most likely responsible for the persistent inflammation in chronic venous leg ulcers. COX-2 selective inhibitors could therefore be effective in the treatment of chronic venous ulcers.

Investigation and treatment of chronic venous ulcer disease.

The investigation and treatment of chronic venous ulceration continues to present many difficulties for the clinician. The uncertainties relate to the appropriate use of different forms of investigation and whether conservative treatment or surgical treatment should be used. A comprehensive search was undertaken of published literature on venous ulceration. The extent of investigations is largely determined by the type of treatment that the patient is either fit to undertake or is prepared to undertake. When conservative treatment only is to be used, detailed investigation of the venous system is not required. The role of surgery to the veins remains unproven in improving the healing of venous ulcers. Surgery to prevent ulcer recurrence has been demonstrated to be of benefit only in patients who have normal deep veins. Investigations performed on the venous system should be determined by the planned treatment. Many of the operations that have been performed on the venous system still remain unproven in providing a benefit to the healing of venous ulcers and in preventing venous ulcer recurrence.

Compression Treatment of Chronic Venous Ulceration: A Review

Objective: To review the recent medical literature with regard to the use of compressive therapy in healing and preventing the recurrence of venous ulceration. Methods: Searches of Medline and Embase medical literature databases. Appropriate non-indexed journals and textbooks were also reviewed. Synthesis: Elastic compression therapy is regarded as the ‘gold standard’ treatment for venous ulceration. The benefits of elastic compression therapy in the treatment of venous ulceration may be mediated through favourable alterations in venous haemodynamics, micro-circulatory haemodynamics and/or improvement in subcutaneous Starling forces. Available data indicate compressive therapy is highly effective in healing of the large majority of venous ulcers. Elastic compression stockings, Unna boots, as well as multi-layer elastic wraps, have all been noted to achieve excellent healing rates for venous ulcers. In compliant patients it appears that approximately 75% of venous ulcers can be healed by 6 months, and up to 90% by 1 year. Non-healing of venous ulcers is associated with lack of patient compliance with treatment, large and long-standing venous ulceration and the coexistence of arterial insufficiency. Recurrence of venous ulceration is, however, a significant problem after healing with compressive therapy, even in compliant patients; approximately 20-30% of venous ulcers will recur by 2 years. Conclusions: Compressive therapy is capable of achieving high rates of healing of venous ulceration in compliant patients. Various forms of compression, including elastic, rigid and multi-layer dressings, are available depending on physician preference, the clinical situation and the needs of the individual patient. Compressive therapy, while effective, remains far from ideal. The future goals are to achieve faster healing of venous ulceration, less painful healing and freedom from ulcer recurrence.

Compression Treatment of Chronic Venous Ulceration: A Review

Compression Treatment of Chronic Venous Ulceration: A Review

Nonoperative Management of Venous Leg Ulcers: Evolving Role of Skin Substitutes

Chronic venous leg ulcers markedly influence the physical, financial, and psychologic wellbeing of patients and result in an estimated 2 million lost workdays annually. Despite a wide variety of therapeutic options, venous leg ulcers remain a substantial management challenge to health care professionals. Although no consensus on compression therapy exists, it remains a primary treatment of edema and ulceration secondary to venous disease. Recently, biotechnology-derived skin substitutes have been developed to help stimulate local wound healing. These range in composition from an epidermal or dermal layer to a complete, bilayered living skin construct. This review focuses on nonoperative treatment options for venous ulcers, particularly the evolving roles of newer treatment options including skin substitutes and growth factor/cytokine preparations. The development and characteristics of these emerging therapies as well as clinical experience with and options for their use in the treatment of chronic venous ulcers are reviewed.

Low‐frequency ultrasound treatment of chronic venous ulcers

In a randomized controlled clinical trial, the properties of low-frequency ultrasound in the treatment of chronic venous ulcers were investigated. Thirty-eight patients with chronic ulcerations of the legs caused by chronic venous insufficiency were randomly assigned to receive either conventional therapy alone or conventional therapy plus additional 30 kHz ultrasound treatment. Patients with other conditions that may impair wound healing such as diabetes mellitus or arterial disease were excluded. The ultrasound treatment consisted of 10 minutes of foot bathing with application of 30 kHz ultrasound 100 mW/cm(2) three times a week. Response was evaluated with the use of planimetry of the ulcer area and compared with controls after 3 and 8 weeks. After 3 weeks of treatment (and to a greater extent after 8 weeks of treatment) the ultrasound group showed a markedly better response than the control group. Although the control group showed a mean decrease of 11% in the ulcerated area after 8 weeks, in the ultrasound group the mean ulcerated area decreased by 41% (p < 0.05). There were only mild side effects in some of the patients treated with ultrasound. In conclusion, application of low-frequency ultrasound may be a helpful treatment option in chronic venous leg ulcers.

Treatment of Chronic Venous Ulcers Using Sequential Gradient Intermittent Pneumatic Compression

Objective: To determine if a limited regimen of sequential gradient intermittent pneumatic compression (‘HomeRx’: HRx) is as effective in promoting the healing of chronic venous stasis ulcers as is the Unna's boot (UB), considered the ‘gold standard’ in compression therapy. Design: Fifty-three patients, aged 31–85 years, with ulcers ranging up to 31.8 cm2 (mean 9.9, SE 1.1) were Prospectively randomized to treatments with UB or HRx and followed weekly for 180 days or until healing was complete, whichever came first. The HRx group wore graduated compression stockings, which were removed only while intermittent pneumatic compression was applied bilaterally at home for 1 h each morning and 2 h each evening. The UB was re-applied at least weekly. The two groups were equivalent in their use of hydrocolloid dressings and periods of leg elevation. Setting: Therapy performed at home, with weekly visits to an outpatient clinic. Main outcome measures: Complete ulcer healing and the rate of healing, based on area and perimeter changes; amounts of wound exudate and pain. Results: Complete healing was achieved in 20 of 28 Patients (71%) in the HRx group, compared with 15 of 25 (60%) treated with UB. Three patients had an adverse reaction to UB, one had cellulitis and five were non-compliant. Correcting for these withdrawn patients by life table analysis, healing rates were 76% and 64%, respectively. Healing rates did not correlate with haemodynamic measurements made prior to treatment. Conclusions: Using HRx for just a few hours daily to supplement graduated elastic compression heals venous ulcers at least as well as does the UB, without its disadvantages (e.g. the need for frequent re-application by qualified personnel, difficulty bathing), affording patients greater convenience during treatment.

Hypoglycaemia and Golytely in Distal Intestinal Obstruction Syndrome

immunosuppression. Meshing the dermis allows a larger surface area to be grafted and allows simultaneous grafting with cultured keratinocytes. Unfortunately, the demand for cadaver skin greatly outstrips supply and there is a need for a connective tissue component (dermal substitute) that can be produced in the laboratory. Various techniques have been tried leading to the formation of a number of composite skin grafts or 'artificial skin substitutes'. Collagen gels contracted by incorporation of fibroblasts have had keratinocytes cultured on the surface to form a composite culture graft4 and a combination of bovine collagen and shark chondroitin-6sulphate has been overlaid with sheets of Silastic in an attempt to produce a stable skin substitute5. In fact, a number of complex culture systems exist, containing substrates of human, rat or bovine collagen some cross linked with glycoproteins and others containing fibroblasts. Unfortunately, many groups have reported poor handling with these systems6 and dermo-epidermal separation remains a problem. Certainly, at present, intact whole dermis appears to be the best substrate available. References 1 Rheinwald JG, Green H. Serial cultivation of strains of human keratinocytes: the formation in keratinising colonies from single cells. Cell 1975;6:331-44 2 Leigh IM, Navsaria H, Purkis PE, McKay I. Clinical Practice and Biological Effects of Keratinocyte Grafting. Ann Acad Med Singapore 1991;20(4):549-55 3 Leigh IM, Purkis PE, Navsaria H, Phillips TA. Treatment of chronic venous ulcers with sheets of cultured allogenic keratinocytes. Br J Dermatol 1987;117:591-7 4 Bell E, Sher S, Hull B, Merrill C, Rosen S, Chamsen A, et al. The reconstruction of living skin. J Invest Dermatol 1983;81:2s-lOs 5 Burke JF, Yannas IV, Quinby WC, Bondoc CC, Jung WK. Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury. Ann Surg 1981; 194:413-28 6 Nanchahal J, Davies D. Cultured composite skin grafts for burns. BMJ 1990;301:1342-3

Venous ulceration: factors influencing recurrence after standard surgical procedures

Ninety patients with chronic venous ulceration were investigated to determine the extent of the incompetence of the venous valves. They were then treated by established surgical methods to control reflux. All wore fitted compression stockings and were regularly followed up. Forty-two patients had valvular incompetence confined to the perforating and superficial veins. All their ulcers healed and only one developed a minor recurrence during the three year follow-up. Nineteen patients had additional but limited incompetence of the deep veins; all their ulcers healed, but three developed a recurrence. Twenty-nine patients had extensive deep vein valvular incompetence including incompetence of the popliteal valve; in 12 of these patients either the ulcer failed to heal or the patient developed a recurrent ulcer within 18 months. Thirty-two other patients developed further venous reflux from the opening of new channels, including the perforating veins of the foot, and required sclerosants or local ligation. It was concluded that established surgical techniques, thoroughly performed, were very effective for the treatment of chronic venous ulceration provided the popliteal valves were competent. When the popliteal valves were incompetent the recurrence rate was unacceptably high and additional methods, including vein valve transplants, excision of the ulcer with skin grafting and lumbar sympathectomy, were considered. Nine of 11 patients who received a vein valve transplant had falls in their ambulant venous pressures, improvement in the nutrition of their skin and healing of their recurrent ulcers.

Treatment of chronic venous ulcers with sheets of cultured allogenic keratinocytes

Cultured keratinocytes were used as allografts to treat 51 patients with chronic venous ulceration or rheumatoid ulcers unresponsive to all previous conventional treatments including split skin grafts. Although early epithelialization could be seen in the centre of some ulcers, a major effect appeared to be healing from the previously indolent edge. This treatment appears to provide some clinical benefit in healing of chronic ulceration.

Plastic surgery treatment of chronic venous ulcers of the leg.

The treatment of 113 patients with a total of 178 chronic venous leg ulcers is described. After early radical excision of the ulcer the defect was covered with large split thickness skin grafts, in most cases after a delay which allows for granulation formation. The series has been followed for 3-18 years after treatment and 93 patients with 152 ulcers have been traced. The results were excellent in 62.5%, good in 15.8% and poor in 21.7%. The general treatment as well as the surgical principles used are presented and the results are discussed.