International Wound Journal ISSN 1742-4801
INVITED REVIEW
Recent accomplishments in wound healing Elizabeth J Mudge Wound Healing Research Unit, Cardiff University School of Medicine, Cardiff, UK
Key words Chronic wound; Diagnostics; Scientific advancement; Wound healing practice
Mudge EJ. Recent accomplishments in wound healing. Int Wound J 2015; 12:4–9
Correspondence to EJ Mudge Wound Healing Research Unit Cardiff University School of Medicine Upper Ground Floor Room 21, Heath Park Cardiff CF14 4XN UK E-mail: [email protected]
The challenge to balance limited resources with infinite demand has encouraged an evolution in the way health care services are managed and operated. Chronic wound management is complex and prolonged, and places a considerable financial burden on health services. A typical driver of cost includes the necessity to change dressings on a regular basis. Over the last few decades, several scientific and biological advances have furthered the development of wound care products and facilitated wound management. This article investigates some of the major advancements that have occurred within the wound-care arena during the last 5 years and how these advancements are being translated to provide better delivery of clinical care to patients.
doi: 10.1111/iwj.12230
Abstract
Population change
The United Kingdom (UK) has a unique health care system that was founded in 1948 to provide equitable health care for everyone, irrespective of financial status. However, with increasing population growth, changing patient demographics, particularly in terms of an increasing elderly population, the obesity ‘epidemic’ and the dramatic rise in the number of people living with chronic diseases such as type 2 diabetes, coupled with rising public expectation; the challenge to balance limited resources with infinite demand is perhaps reaching a crisis point (1). In 2008 the Department of Health (DOH), under the guidance of Lord Darzi, published a report: ‘High quality care for all’, which stressed the need to accelerate change, improve quality standards and bring about cost savings (2). Initiatives, such as Commissioning for Quality and Innovation (CQUIN) (3), the Quality, Innovation, Productivity and Prevention (QIPP) programme (4), High Impact Actions (HIAs) (5) and Nurse Sensitive Indicators (NSIs) (6), evolved to promote efficacy and to underpin these changes and the Government’s White Paper, Equity and Excellence: Liberating the NHS , highlighted a need for radical reforms (7). The key messages underlined a necessity to change the culture within the NHS in order to provide quality service improvement frameworks that were patientcentred, efficient, improved health care outcomes, increased accountability and reduced bureaucracy. It acknowledged that in addition to health care-related reform there was also a necessity for greater patient empowerment; therefore, information generated by patients would also be critical to the process, and thus the use of Patient-Reported Outcome 4
Measures (PROMS), patient experience data and real-time feedback (7) were encouraged. Chronic wound management is complex and prolonged, and places a considerable financial burden on health services in terms of manpower requirement, equipment, specialist opinion and adjunct therapies. A typical driver of cost includes the necessity to change dressings on a regular basis. Furthermore, duration of treatment and management of complications, as a result of infection, ischaemia, neuropathy and immune compromise, significantly add to this cost (8). Over the last few decades, several scientific and biological advances have furthered the development of wound care products and facilitated wound management. This article will highlight how some of the more recent advancements have been translated to provide better delivery of clinical care to patients.
Key Messages • chronic ulcers represent a major health challenge in
clinical practice, impact on a persons’ quality of life and generate considerable health care costs • many scientific advancements have been made during the last 5 years, which have been successfully translated into clinical delivery with successful wound healing outcomes • a review of recent publications describes continual progress in wound healing knowledge and practice
© 2014 The Author International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd
E. J. Mudge
TIME
The TIME acronym (Tissue, Infection/Inflammation, Moisture balance and Edge of wound) was developed to provide a framework for a structured approach to wound bed preparation, as a basis for optimising the management of open chronic wound healing by secondary intention (9). In the intervening decade since its conception four key developments have emerged: recognition of the importance of biofilms, use of negative pressure wound therapy (NPWT), evolution of topical antiseptic therapy and expanded insight of the role of molecular biological processes in chronic wounds. Tissue: A major advance has been the recognition of the value of repetitive and maintenance debridement and wound cleansing. Infection/inflammation: Clinical recognition of infection and greater understanding of biofilm presence has led to a return to topical antiseptics to control bioburden in wounds, emphasised by the awareness of increasing antibiotic resistance. Moisture: The relevance of excessive or insufficient wound exudate and its molecular components has led to the development and use of a wide range of dressings to regulate moisture balance. Edge of wound : Several treatment modalities are being investigated and introduced to improve epithelial advancement, which can be regarded as the clearest sign of wound healing (10).
Predictors of ulceration
Comprehensive wound assessment is crucial in the prediction of ulcer risk. A large, prospective, observational study conducted in 14 European centres (11) investigated the characteristics of diabetic patients with a foot ulcer to assess which factors influenced management strategies in diabetic foot disease. The study followed up more than 1200 patients with a new diabetic foot ulcer (DFU) for 12 months (or until complete healing) to assess a wide variety of factors affecting healing. The mean minor amputation rate for all patients in the study was 18% and was mainly dependent on depth of the ulcer, presence of peripheral arterial disease (PAD) or infection and male gender. A 3-year prospective follow-up evaluation of patients who had completed the study (12) assessed the frequency of ulcer recurrence in patients with a healed DFU to identify the risk factors for recurrence. Incidence of ulcer recurrence was high (57·5%). The risk factor with the highest association with reulceration was plantar location of the initial ulcer. Radiographically diagnosed osteomyelitis was a strong predictor of ulcer recurrence. An elevated C-reactive protein (CRP) level at the time of enrolment in the study was an independent risk factor for reulceration, and the most sensitive CRP cut-off for predicting recurrence was above the upper normal range (>5 mg/l). Poor glycaemic control, defined as glycated haemoglobin (HbA1 c) > 7·5%, was also a significant risk factor for reulceration. It is possible that poor long-term glycaemic control may not only impair wound healing but may also reflect poorer patient compliance with various preventive
Recent accomplishments in wound healing
measures, such as self-monitoring of glycaemic control and adherence to treatment recommendations for DFU. The presence of PAD was not a predictor for ulcer recurrence. This study showed a high recurrence rate of DFU during 3-year follow-up period in patients with a primarily healed ulcer, despite regular follow-up and patient education. A cross-sectional study using administrative data from an outpatient practice (13) investigated predictor risk variables for venous leg ulceration (VLU). The authors reviewed the records of 12 650 patients and identified 581 (4·6%) who had a history of VLU. Venous insufficiency had the highest association with VLU with an odds ratio of more than 900. Decubitus ulceration also had a high association with an odds ratio of 2·66 (95% confidence interval: 1·74–4·07). Older age, female gender, previous hospitalisation, diabetes, renal insufficiency, peripheral vascular disease, congestive heart failure, depression, degenerative arthritis, peripheral neuropathy, hypothyroidism and falls were associated with VLU. However, marital status, hyperlipidaemia, hip fracture, chronic obstructive pulmonary disease, cancer and dementia were not associated with VLU. This study showed that the relationship between venous insufficiency and VLU appears to be very strong, as expected, given the aetiology of disease. Conditions such as vascular disease and vascular risk factors were also highly associated with ulceration. Despite the introduction of clinical practice guidelines and advances in medical technology, the prevalence of pressure ulcers (PUs) in hospitalised patients continues to remain unchanged. Currently, consensus is lacking on the most important risk factors for PU in critically ill patients, and no risk assessment scale exclusively for PUs in these patients is available. Cox (14) conducted a retrospective study to investigate which risk factors were most predictive of PU; 347 patients admitted to a medical-surgical intensive care unit were examined (14). Analyses demonstrated that age, length of stay, mobility, friction/shear, norepinephrine infusion and cardiovascular disease explained a major part of the variance in PUs. It was concluded that current risk assessment scales for the development of PUs may not include common risk factors in critically ill adults. Advanced wound diagnostics
With limited data to predict ulcer occurrence and reoccurrence, calls for better diagnostic tools to aid wound assessment were answered in 2012 with the launch of WOUNDCHEK™ Protease Status (www.Systagenix.com), the world’s first rapid, point-of-care diagnostic test developed specifically for chronic wounds. Able to detect elevated protease activity, WOUNDCHEK has the capacity to enable early, targeted intervention and cost-effective use of advanced therapies designed to modulate protease activity. Bioengineered skin substitutes
In the past decade, advances in stem cell research and biomimetic rational design of biomaterials have given rise to major breakthroughs in tissue engineering techniques, resulting in significant progress in the development of in
© 2014 The Author International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd
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vitro engineered skin substitutes that mimic human skin. But nowadays there are no models of bioengineered skin that completely replicate the nature of uninjured skin (15). However, as the technology advances and we gain new insights into the mechanisms that regulate cell–extracellular matrix interactions, there is a good possibility for the design of more sophisticated skin substitutes that may, in the near future, provide more effective therapies for patients. Another exciting prospect is that such substitutes may be further engineered to offer the complete regeneration of functional skin, including all the skin appendages and the establishment of a functional vascular and nerve network, with the surrounding host tissue allowing the cells to interact, so as to regenerate all the skin structures. Biofilms
Despite advances being made with the use of modern molecular microbiological techniques, consensus remains that common wound pathogens, such as Staphylococcus aureus, Pseudomonas aeruginosa and β-haemolytic streptococci, specifically cause delayed healing and infection in chronic wounds. Increasing data suggest that microorganisms in the biofilm form are among the leading agents of persistent infections of chronic wounds; however, microbial imbalances and synergistic relationships between bacteria in medically important biofilms are still not fully understood (16,17). Consequently, little is known about how synergy between bacteria may increase the net pathogenic effect of a biofilm in many diseases and infections, including chronic wounds. Microbial synergy and growth within a biofilm provide a competitive advantage to the microorganisms cohabiting in a wound, thereby promoting their survival and tolerance and resistance to antimicrobial agents (18). Topical antiseptics
Antimicrobial management is a major challenge that continues to require new solutions to combat microbes and their biofilms. Balancing antimicrobial potency and tolerability of antiseptic procedures is critical in wound management (19). The main arguments against using topical antiseptics are the lack of adequate proof of efficacy and residual concerns about their potential toxicity to healing wounds. However, there is little information on systemic absorption of antimicrobial agents, and evidence of clinical efficacy is meagre (20). In light of the size and importance of the problem of chronic wound infection, investigators are seeking other ways to deal with chronic wound infections, including various innovative non-antimicrobial approaches.
found to reduce the viability of the diabetic fibroblasts and collagen synthesis by 54–70% and 48–68%, respectively, and also to change the cell morphology significantly to decrease cell proliferation and collagen synthesis of diabetic fibroblasts. These results reinforced the recent controversy concerning silver dressings, adding to the evidence that they have significant toxic effects on morphology, proliferation and collagen synthesis of diabetic fibroblasts. However, evidence also exists to demonstrate that even the most potent modernday forms of silver, in terms of speed of bacterial kill, do not have a deleterious effect on similar cell types (22–24), and there is no evidence of haematological or biochemical indicators of toxicity associated with silver absorption (25). This poses conflicting evidence from the laboratory and preclinical studies to the wealth of positive experiences seen and reported with the use of silver. Consensus statements on antibacterials used in wound healing (26) put forward the view that silver has a place in the armamentarium of compounds available to combat not just infection but as a topical option in combating the threat of antibacterial resistance development associated with the management of at-risk wounds. It is necessary to take appropriate steps regarding the use of silver and silver-containing preparations, whose toxicity has been proved beyond doubt against the cells involved in the healing process, in light of availability of more potential and safe options. However, it should also be noted that cytotoxicity seen in the laboratory has not been reflected in clinical practice, and therefore silver should remain an integral component of topical antibacterial options available in managing at-risk or infected wounds.
Wound debridement
Wound debridement is an essential component of wound management, which underpins the concept of wound bed preparation. Several types of wound debridement techniques are used in clinical practice; yet there are limited data to recommend one method over another, and choice of debridement technique therefore tends to be decided by clinician preference, availability, patient tolerance, anatomical location and the extent of debridement required. However, recently developed products are beginning to challenge traditional techniques. Evidence is emerging that low-frequency ultrasound therapy may improve healing outcomes for patients with VLU and DFU. Furthermore, the monofilament polyester fibre pad and plasmamediated bipolar radiofrequency ablation have also attracted research interest recently, although further evidence is needed if these techniques are to be more widely adopted (27).
Silver
Negative pressure wound therapy
The use of silver to treat chronic wounds that are at risk of infection has had a high resurgence in the last decade because of its broad spectrum of antibacterial, antifungal and antiviral activities. However, the debate over the cytotoxicity of silver dressings on diabetic fibroblasts continues. Zou et al. (21) reported that all silver dressings tested in their study were
Research evidence for the effectiveness of many treatment modalities commonly used in the management of chronic wounds has fuelled debate in the wound-care arena, particularly in respect to the nature and quality of the research on which clinical recommendations have been made. This has been particularly evident in the field of NPWT where studies
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© 2014 The Author International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd
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using non-randomised designs or case series have been criticised for their high susceptibility to bias and possibility of false-positive results. A systemic review of NPWT in acute and chronic wounds (28) concluded that there is no worthwhile evidence to support the use of NPWT in various wounds. The authors noted selection bias, overestimation of treatment effect and various end points prohibiting a metaanalysis. Subsequently, a further Cochrane review by the same authors (29) concluded that the methodological quality of the trials was low with high susceptibility to bias and, as a result, the beneficial effect reported in some trials should be treated with caution. Despite lack of data NPWT is in widespread use and its role in wound care is expanding worldwide. More recently, a retrospective review (30) of 97 contaminated wounds managed with NPWT demonstrated a mean time to wound closure of 17 days (median 10 days). The authors concluded that NPWT appeared safe and effective in managing acute, contaminated wounds including patients meeting sepsis criteria. These findings provide evidence-based support for current worldwide empiric NPWT-related acute wound care. The Wound Union of Wound Healing Societies (WUWHS) consensus document for NPWT stated that NPWT therapy can have a positive impact on a patient’s quality of life (31). Patient’s experiences of NPWT have been investigated by a number of authors and demonstrate that NPWT can lead to faster wound healing (32) and can reduce frequency of dressing change (33) and hospital stay (34), but there are still a number of challenges such as pain, anxiety, embarrassment, restriction in patient’s wider social life, negative self-image and low self-esteem (35). Changing outcomes
PUs represent the class of wounds with the highest prevalence among patients with advanced illness, where the life expectancy is generally less than 6 months (36). Goal setting is challenging in this context. Although complete wound healing is the most coveted target, clinicians should neither discount nor marginalise the value of achieving other significant outcomes. The concept of wound maintenance has been defined in both patients with advanced illness as well as non-terminally ill patients (37). In addition to optimal wound palliation (wound-related pain and symptom management or palliative wound care), it is also imperative to provide health care that is patient-centred/patient-empowered, while promoting the best achievable levels of health-related quality of life and well-being. With comprehensive wound management, the majority of PUs (92·87%) in patients with advanced illness achieve either wound maintenance or some degree of wound healing (36). A combination of high levels of wound maintenance together with modest levels of wound healing and low levels of wound deterioration, within the most compromised patients within health care, must be recognised as successful outcomes in wound management. The current PU debate
The profile of PUs has risen dramatically around the world as they are increasingly used as a quality indicator. This
Recent accomplishments in wound healing
has led to much debate around definitions; most importantly the categorisation of damage, the avoidability of occurrence and the attribution of where damage occurred (38, 39). Prevention of pressure damage has attracted payment as part of large-scale quality initiatives but has also resulted in loss of income/fines and in some case large lawsuits against organisations. Organisations strive to provide protocols for management by the use of care bundles and as numbers of PUs remain constant despite increasing use of specialist equipment (40) they seek alternative actions to supplement standard protocols for prevention such as the use of dressings (41) and focussing on particular groups of PUs, for example, those related to the use of medical devices.
Health-related quality of life (HRQoL)
There is increasing recognition that HRQoL is a valuable outcome measure in wound care and should be included in reviews of new and existing therapies ensuring that importance is placed on the impact of health services on the patient experience. There is also a growing body of evidence that demonstrates a patient’s psychological/mood state and in particular psychological stress (42,43) is negatively related to wound healing outcomes. Providing health care within a socially supportive environment can increase well-being and contribute to positive health experiences. This may have a profound effect on how services are provided, and may lead to an increased collaboration between health and social care services to provide patients with access to both social and emotional support, whilst receiving wound care. Last year an international consensus on optimising wellbeing in patients living with a chronic wound was published (44). This consensus document aimed to increase stakeholders’ understanding of the impact of living with a wound; it discusses factors affecting well-being, investigates the assessment and measurement of quality of life and well-being and suggests strategies for optimising well-being for effective wound management.
Social media
There is a global recognition that the methods for communication with patients are changing; today social media networks such as Facebook and Twitter are commonplace in everyday life for public connection and as a forum for sharing experiences. In health care, individuals, especially patients with chronic conditions, can feel isolated and alone. This often drives such individuals to Internet-based resources to inform, educate and engage, but without professional regulation such resources may also misinform and confuse (45). Recently, two exciting social media-based approaches have been introduced in the wound-care arena. These are The Welsh Wound Community (www.welshwoundcommunity.com) and the Diabetic Foot Canada Community (www.diabeticfootcommunity.ca). These sites represent the first truly interactive private communities focused on wounds and their prevention and treatment. The sites provide a significant resource to all involved
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in the care of patients with wounds and allow members to not only communicate privately but also to exchange relevant documents and to share information. These private networks allow access to the many assets required to provide effective, evidence-based management and prevention in the area of DFUs and chronic wound management (46). Digital technology
It is important that all clinical information is recorded and evaluated. The last few years have seen a significant development in the capture and use of clinical and research data. Digital pen and paper technology, which converts analogue information (created using a pen and paper) directly into a digital data package, represents a major technological advancement in the area of wound healing. By enabling handwritten data to be instantly uploaded to a computer and used in various applications, it thus has the potential to save valuable research time and money. Furthermore, the creation of a wound registry allows the capture and more importantly the use of data as validation of a clinical approach. Data stored in a registry can be examined for a variety of parameters, including usage statistics, adverse event reporting and successful outcome data, which are essential for effective evidence-based decision making leading to the adoption of cost-effective wound prevention and treatment solutions and planning for service delivery in the future (47). Conclusion
Many advances have been made during the last few years to meet some of the challenges of chronic wound management. There have been exciting innovations in the area of diagnostics and bioengineering and also in respect to how we communicate and use technology. Debate on the management of microbes continues, as does agreement on relevant research outcomes and predictors for ulceration. The evidence base for chronic wound management continues to grow and thus presents positive impact for better clinical outcomes. References 1. Coombes R. The NHS debate. BMJ 2008;337:a628. DOI: 10.1136/bmj.a1628. 2. Darzi A. High quality care for all: NHS Next Stage Review final report [Online]. London: Department of Health, 2008, 192. URL http://webarchive.nationalarchives.gov.uk/+/www.dh.gov.uk/en/ healthcare/highqualitycareforall/index.htm [accessed on 16 April 2013] 3. DOH. NHS 2010-2015: from good to great. Preventative, peoplecentred, productive [Online]. London: Department of Health, 2009. URL www.official-documents.gov.uk/document/cm77/7775/ 7775.pdf [accessed on 16 April 2013] 4. DOH. NHS Chief Executive’s Annual Report for 2008-09 [Online]. London: Department of Health, 2009. URL http://www. healthcaretoday.co.uk/doclibrary/documents/pdf/215_the_year_200809.pdf [accessed on 16 April 2013] 5. Dowsett C, White R. Delivering quality and high impact actions. Br J Healthcare Manage 2010;16:92–3. 6. Negus J, Howat M. Linking indicators and metrics to patient experience. Wounds UK 2010;6:125–6. 8
7. DOH. Equity and excellence: liberating the NHS [Online]. London: Department of health, 2010. URL https://www.gov.uk/ government/ . . . /liberating-the-nhs-white-paper [accessed on 16 April 2013] 8. Dowsett C, Davis L, Henderson V, Searle R. The economic benefits of negative pressure wound therapy in community-based wound care in the NHS. Int Wound J 2012;9:544–52. DOI: 10.1111/j.17421481X.2011.00913.x. 9. Schultz GS, Sibbald RG, Falanga V, Ayello EA, Dowsett C, Harding K, Romanelli M, Stacey MC, Teot L, Vanscheidt W. Wound bed preparation: a systematic approach to wound management. Wound Repair Regen 2003;11:1–28. 10. Leaper DJ, Schultz G, Carville K, Fletcher J, Swanson T, Drake R. Extending the TIME concept: what have we learned in the past 10 years? Int Wound J 2012;9(Suppl 2):1–19. 11. Prompers L, Schaper N, Apelqvist J, Edmonds M, Jude E, Mauricio D, Uccioli L, Urbancic V, Bakker K, Holstein P, Jirkovska A, Piaggesi A, Ragnarson-Tennvall G, Reike H, Spraul M, Van Acker K, Van Baal J, Van Merode F, Ferreira I, Huijberts M. Prediction of outcome in individuals with diabetic foot ulcers: focus on the differences between individuals with and without peripheral arterial disease. The EURODIALE Study. Diabetologia 2008;51: 747–55. 12. Dubsk´y M, Jirkovska A, Bem R, Fejfarov´a V, Skibov´a J, Schaper NC, Lipsky BA. Risk factors for recurrence of diabetic foot ulcers: prospective follow-up analysis in the Eurodiale subgroup. Int Wound J 2013;10:555–61. 13. Takahashi PY, Kiemele L, Cha SS, Chandra A. A cross-sectional evaluation of the association between lower extremity venous ulceration and predictive risk factors. Wounds 2009;21:290–6. 14. Cox J. Predictors of pressure ulcers in adult critical care patients. Am J Crit Care 2011;20:364–75. 15. Lu G, Huang S. Bioengineered skin substitutes: key elements and novel design for biomedical applications. Int Wound J 2013;10: 365–71. 16. Thomson CH. Biofilms: do they affect wound healing? Int Wound J 2011;8:63–7. 17. Junka A, Bartoszewicz M, Smutnicka D, Secewicz A, Szymczyk P. Efficacy of antiseptics containing povidone-iodine, octenidine dihydrochloride and ethacridine lactate against biofilm formed by Pseudomonas aeruginosa and Staphylococcus aureus measured with the novel biofilm-oriented antiseptics test. Int Wound J 2013. DOI: 10.1111/iwj.12057. 18. Percival SL, Thomas JG, Williams DW. Biofilms and bacterial imbalances in chronic wounds: anti-Koch. Int Wound J 2010;7:169–75. 19. Daeschlein G. Antimicrobial and antiseptic strategies in wound management. Int Wound J 2013;10(S1):9–14. 20. Lipsky BA, Hoey C. Topical antimicrobial therapy for treating chronic wounds. Clin Infect Dis 2009;49:1541–9. 21. Zou SB, Yoon WY, Han SK, Jeong SH, Cui ZJ, Kim WK. Cytotoxicity of silver dressings on diabetic fibroblasts. Int Wound J 2013;10:306–12. 22. Roberts C. Reply to cytotoxicity of silver dressings – time to think and react by Nagoba et al. Int Wound J 2013;10:617. 23. Le Duc Q, Breetveld M, Middlekoop E, Scheper RJ, Ulrich MMW, Gibbs S. A cytotoxic analysis of antiseptic medication on skin substitutes and autografts. Br J Dermatol 2007;157:33–40. 24. Wright BJ, Lam K, Buret AG, Olson M, Burrell RE. Early healing events in a porcine model of contaminated wounds; effects of nanocrystalline silver on matrix metalloproteases, cell apoptosis and healing. Wound Repair Regen 2007;10:141–51. 25. Vlachou E, Chipp E, Shale E, Wilson YT, Papini R, Moiemen NS. Safety of nanocrystalline silver dressings on burns; a study of systemic silver absorption. Burns 2007;33:979–85. 26. International consensus. Appropriate use of silver dressings in wounds. An expert working group consensus. London: Wounds InternationalURL www.woundsinternational.com, 2012.
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27. Madhok B, Vowden K, Vowden P. New techniques for wound debridement. Int Wound J 2013;10:247–51. 28. Ubbink DT, Westerbos SJ, Nelson EA, Vermeulen H. A systematic review of topical negative pressure therapy for acute and chronic wounds. Br J Surg 2008;95:685–92. 29. Ubbink DT, Westerbos SJ, Evans D, Land L, Vermeulen H. Topical negative pressure for treating chronic wounds (Review). Cochrane review [Online], 2011:1–25. URL http://onlinelibrary. wiley.com/doi/10.1002/14651858.CD001898.pub2/pdf/standard [accessed on 14 April 2013] 30. Sheweiki E, Gallagher KE. Negative pressure wound therapy in acute, contaminated wounds: documenting its safety and efficacy to support current global practice. Int Wound J 2013;10:13–43. 31. WUWHS. Vacuum assisted closure: recommendations for use. A consensus document. Int Wound J 2008;5(Suppl 4):iii–19. DOI: 10.1111/j.1742-1481X.2008.00537.x. 32. Mendonca DA, Papini R, Price PE. Negative-pressure wound therapy: a snapshot of the evidence. Int Wound J 2006;3:261–71. 33. Searle R, Milne J. Tools to compare the cost of NPWT with advanced wound care: an aid to clinical decision-making. Wounds UK 2010;6:106–9. 34. Kaplan M, Daly D, Stemkowski S. Early intervention of negative pressure wound therapy using vacuum-assisted closure in trauma patients: impact on hospital length of stay and cost. Adv Skin Wound Care 2009;22:128–32. DOI: 10.1097/1001.ASW.0000305451.718 11.d5. 35. Abbotts J. Patients’ views on topical negative pressure: ’effective but smelly’. Br J Nurs 2010;19:S37–41. 36. Maida V, Ennis M, Corban J. Wound outcomes in patients with advanced illness. Int Wound J 2012;9:683–92. 37. Maida V, Corban J. Wound healing isn’t everything. Int Wound J 2013;10:117. 38. Baharestani MM, Black JM, Carville K, Clark M, Cuddigan JE, Dealey C, Defloor T, Harding KG, Lahmann NA, Lubbers MJ,
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INVITED REVIEW
Recent accomplishments in wound healing Elizabeth J Mudge Wound Healing Research Unit, Cardiff University School of Medicine, Cardiff, UK
Key words Chronic wound; Diagnostics; Scientific advancement; Wound healing practice
Mudge EJ. Recent accomplishments in wound healing. Int Wound J 2015; 12:4–9
Correspondence to EJ Mudge Wound Healing Research Unit Cardiff University School of Medicine Upper Ground Floor Room 21, Heath Park Cardiff CF14 4XN UK E-mail: [email protected]
The challenge to balance limited resources with infinite demand has encouraged an evolution in the way health care services are managed and operated. Chronic wound management is complex and prolonged, and places a considerable financial burden on health services. A typical driver of cost includes the necessity to change dressings on a regular basis. Over the last few decades, several scientific and biological advances have furthered the development of wound care products and facilitated wound management. This article investigates some of the major advancements that have occurred within the wound-care arena during the last 5 years and how these advancements are being translated to provide better delivery of clinical care to patients.
doi: 10.1111/iwj.12230
Abstract
Population change
The United Kingdom (UK) has a unique health care system that was founded in 1948 to provide equitable health care for everyone, irrespective of financial status. However, with increasing population growth, changing patient demographics, particularly in terms of an increasing elderly population, the obesity ‘epidemic’ and the dramatic rise in the number of people living with chronic diseases such as type 2 diabetes, coupled with rising public expectation; the challenge to balance limited resources with infinite demand is perhaps reaching a crisis point (1). In 2008 the Department of Health (DOH), under the guidance of Lord Darzi, published a report: ‘High quality care for all’, which stressed the need to accelerate change, improve quality standards and bring about cost savings (2). Initiatives, such as Commissioning for Quality and Innovation (CQUIN) (3), the Quality, Innovation, Productivity and Prevention (QIPP) programme (4), High Impact Actions (HIAs) (5) and Nurse Sensitive Indicators (NSIs) (6), evolved to promote efficacy and to underpin these changes and the Government’s White Paper, Equity and Excellence: Liberating the NHS , highlighted a need for radical reforms (7). The key messages underlined a necessity to change the culture within the NHS in order to provide quality service improvement frameworks that were patientcentred, efficient, improved health care outcomes, increased accountability and reduced bureaucracy. It acknowledged that in addition to health care-related reform there was also a necessity for greater patient empowerment; therefore, information generated by patients would also be critical to the process, and thus the use of Patient-Reported Outcome 4
Measures (PROMS), patient experience data and real-time feedback (7) were encouraged. Chronic wound management is complex and prolonged, and places a considerable financial burden on health services in terms of manpower requirement, equipment, specialist opinion and adjunct therapies. A typical driver of cost includes the necessity to change dressings on a regular basis. Furthermore, duration of treatment and management of complications, as a result of infection, ischaemia, neuropathy and immune compromise, significantly add to this cost (8). Over the last few decades, several scientific and biological advances have furthered the development of wound care products and facilitated wound management. This article will highlight how some of the more recent advancements have been translated to provide better delivery of clinical care to patients.
Key Messages • chronic ulcers represent a major health challenge in
clinical practice, impact on a persons’ quality of life and generate considerable health care costs • many scientific advancements have been made during the last 5 years, which have been successfully translated into clinical delivery with successful wound healing outcomes • a review of recent publications describes continual progress in wound healing knowledge and practice
© 2014 The Author International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd
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TIME
The TIME acronym (Tissue, Infection/Inflammation, Moisture balance and Edge of wound) was developed to provide a framework for a structured approach to wound bed preparation, as a basis for optimising the management of open chronic wound healing by secondary intention (9). In the intervening decade since its conception four key developments have emerged: recognition of the importance of biofilms, use of negative pressure wound therapy (NPWT), evolution of topical antiseptic therapy and expanded insight of the role of molecular biological processes in chronic wounds. Tissue: A major advance has been the recognition of the value of repetitive and maintenance debridement and wound cleansing. Infection/inflammation: Clinical recognition of infection and greater understanding of biofilm presence has led to a return to topical antiseptics to control bioburden in wounds, emphasised by the awareness of increasing antibiotic resistance. Moisture: The relevance of excessive or insufficient wound exudate and its molecular components has led to the development and use of a wide range of dressings to regulate moisture balance. Edge of wound : Several treatment modalities are being investigated and introduced to improve epithelial advancement, which can be regarded as the clearest sign of wound healing (10).
Predictors of ulceration
Comprehensive wound assessment is crucial in the prediction of ulcer risk. A large, prospective, observational study conducted in 14 European centres (11) investigated the characteristics of diabetic patients with a foot ulcer to assess which factors influenced management strategies in diabetic foot disease. The study followed up more than 1200 patients with a new diabetic foot ulcer (DFU) for 12 months (or until complete healing) to assess a wide variety of factors affecting healing. The mean minor amputation rate for all patients in the study was 18% and was mainly dependent on depth of the ulcer, presence of peripheral arterial disease (PAD) or infection and male gender. A 3-year prospective follow-up evaluation of patients who had completed the study (12) assessed the frequency of ulcer recurrence in patients with a healed DFU to identify the risk factors for recurrence. Incidence of ulcer recurrence was high (57·5%). The risk factor with the highest association with reulceration was plantar location of the initial ulcer. Radiographically diagnosed osteomyelitis was a strong predictor of ulcer recurrence. An elevated C-reactive protein (CRP) level at the time of enrolment in the study was an independent risk factor for reulceration, and the most sensitive CRP cut-off for predicting recurrence was above the upper normal range (>5 mg/l). Poor glycaemic control, defined as glycated haemoglobin (HbA1 c) > 7·5%, was also a significant risk factor for reulceration. It is possible that poor long-term glycaemic control may not only impair wound healing but may also reflect poorer patient compliance with various preventive
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measures, such as self-monitoring of glycaemic control and adherence to treatment recommendations for DFU. The presence of PAD was not a predictor for ulcer recurrence. This study showed a high recurrence rate of DFU during 3-year follow-up period in patients with a primarily healed ulcer, despite regular follow-up and patient education. A cross-sectional study using administrative data from an outpatient practice (13) investigated predictor risk variables for venous leg ulceration (VLU). The authors reviewed the records of 12 650 patients and identified 581 (4·6%) who had a history of VLU. Venous insufficiency had the highest association with VLU with an odds ratio of more than 900. Decubitus ulceration also had a high association with an odds ratio of 2·66 (95% confidence interval: 1·74–4·07). Older age, female gender, previous hospitalisation, diabetes, renal insufficiency, peripheral vascular disease, congestive heart failure, depression, degenerative arthritis, peripheral neuropathy, hypothyroidism and falls were associated with VLU. However, marital status, hyperlipidaemia, hip fracture, chronic obstructive pulmonary disease, cancer and dementia were not associated with VLU. This study showed that the relationship between venous insufficiency and VLU appears to be very strong, as expected, given the aetiology of disease. Conditions such as vascular disease and vascular risk factors were also highly associated with ulceration. Despite the introduction of clinical practice guidelines and advances in medical technology, the prevalence of pressure ulcers (PUs) in hospitalised patients continues to remain unchanged. Currently, consensus is lacking on the most important risk factors for PU in critically ill patients, and no risk assessment scale exclusively for PUs in these patients is available. Cox (14) conducted a retrospective study to investigate which risk factors were most predictive of PU; 347 patients admitted to a medical-surgical intensive care unit were examined (14). Analyses demonstrated that age, length of stay, mobility, friction/shear, norepinephrine infusion and cardiovascular disease explained a major part of the variance in PUs. It was concluded that current risk assessment scales for the development of PUs may not include common risk factors in critically ill adults. Advanced wound diagnostics
With limited data to predict ulcer occurrence and reoccurrence, calls for better diagnostic tools to aid wound assessment were answered in 2012 with the launch of WOUNDCHEK™ Protease Status (www.Systagenix.com), the world’s first rapid, point-of-care diagnostic test developed specifically for chronic wounds. Able to detect elevated protease activity, WOUNDCHEK has the capacity to enable early, targeted intervention and cost-effective use of advanced therapies designed to modulate protease activity. Bioengineered skin substitutes
In the past decade, advances in stem cell research and biomimetic rational design of biomaterials have given rise to major breakthroughs in tissue engineering techniques, resulting in significant progress in the development of in
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vitro engineered skin substitutes that mimic human skin. But nowadays there are no models of bioengineered skin that completely replicate the nature of uninjured skin (15). However, as the technology advances and we gain new insights into the mechanisms that regulate cell–extracellular matrix interactions, there is a good possibility for the design of more sophisticated skin substitutes that may, in the near future, provide more effective therapies for patients. Another exciting prospect is that such substitutes may be further engineered to offer the complete regeneration of functional skin, including all the skin appendages and the establishment of a functional vascular and nerve network, with the surrounding host tissue allowing the cells to interact, so as to regenerate all the skin structures. Biofilms
Despite advances being made with the use of modern molecular microbiological techniques, consensus remains that common wound pathogens, such as Staphylococcus aureus, Pseudomonas aeruginosa and β-haemolytic streptococci, specifically cause delayed healing and infection in chronic wounds. Increasing data suggest that microorganisms in the biofilm form are among the leading agents of persistent infections of chronic wounds; however, microbial imbalances and synergistic relationships between bacteria in medically important biofilms are still not fully understood (16,17). Consequently, little is known about how synergy between bacteria may increase the net pathogenic effect of a biofilm in many diseases and infections, including chronic wounds. Microbial synergy and growth within a biofilm provide a competitive advantage to the microorganisms cohabiting in a wound, thereby promoting their survival and tolerance and resistance to antimicrobial agents (18). Topical antiseptics
Antimicrobial management is a major challenge that continues to require new solutions to combat microbes and their biofilms. Balancing antimicrobial potency and tolerability of antiseptic procedures is critical in wound management (19). The main arguments against using topical antiseptics are the lack of adequate proof of efficacy and residual concerns about their potential toxicity to healing wounds. However, there is little information on systemic absorption of antimicrobial agents, and evidence of clinical efficacy is meagre (20). In light of the size and importance of the problem of chronic wound infection, investigators are seeking other ways to deal with chronic wound infections, including various innovative non-antimicrobial approaches.
found to reduce the viability of the diabetic fibroblasts and collagen synthesis by 54–70% and 48–68%, respectively, and also to change the cell morphology significantly to decrease cell proliferation and collagen synthesis of diabetic fibroblasts. These results reinforced the recent controversy concerning silver dressings, adding to the evidence that they have significant toxic effects on morphology, proliferation and collagen synthesis of diabetic fibroblasts. However, evidence also exists to demonstrate that even the most potent modernday forms of silver, in terms of speed of bacterial kill, do not have a deleterious effect on similar cell types (22–24), and there is no evidence of haematological or biochemical indicators of toxicity associated with silver absorption (25). This poses conflicting evidence from the laboratory and preclinical studies to the wealth of positive experiences seen and reported with the use of silver. Consensus statements on antibacterials used in wound healing (26) put forward the view that silver has a place in the armamentarium of compounds available to combat not just infection but as a topical option in combating the threat of antibacterial resistance development associated with the management of at-risk wounds. It is necessary to take appropriate steps regarding the use of silver and silver-containing preparations, whose toxicity has been proved beyond doubt against the cells involved in the healing process, in light of availability of more potential and safe options. However, it should also be noted that cytotoxicity seen in the laboratory has not been reflected in clinical practice, and therefore silver should remain an integral component of topical antibacterial options available in managing at-risk or infected wounds.
Wound debridement
Wound debridement is an essential component of wound management, which underpins the concept of wound bed preparation. Several types of wound debridement techniques are used in clinical practice; yet there are limited data to recommend one method over another, and choice of debridement technique therefore tends to be decided by clinician preference, availability, patient tolerance, anatomical location and the extent of debridement required. However, recently developed products are beginning to challenge traditional techniques. Evidence is emerging that low-frequency ultrasound therapy may improve healing outcomes for patients with VLU and DFU. Furthermore, the monofilament polyester fibre pad and plasmamediated bipolar radiofrequency ablation have also attracted research interest recently, although further evidence is needed if these techniques are to be more widely adopted (27).
Silver
Negative pressure wound therapy
The use of silver to treat chronic wounds that are at risk of infection has had a high resurgence in the last decade because of its broad spectrum of antibacterial, antifungal and antiviral activities. However, the debate over the cytotoxicity of silver dressings on diabetic fibroblasts continues. Zou et al. (21) reported that all silver dressings tested in their study were
Research evidence for the effectiveness of many treatment modalities commonly used in the management of chronic wounds has fuelled debate in the wound-care arena, particularly in respect to the nature and quality of the research on which clinical recommendations have been made. This has been particularly evident in the field of NPWT where studies
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using non-randomised designs or case series have been criticised for their high susceptibility to bias and possibility of false-positive results. A systemic review of NPWT in acute and chronic wounds (28) concluded that there is no worthwhile evidence to support the use of NPWT in various wounds. The authors noted selection bias, overestimation of treatment effect and various end points prohibiting a metaanalysis. Subsequently, a further Cochrane review by the same authors (29) concluded that the methodological quality of the trials was low with high susceptibility to bias and, as a result, the beneficial effect reported in some trials should be treated with caution. Despite lack of data NPWT is in widespread use and its role in wound care is expanding worldwide. More recently, a retrospective review (30) of 97 contaminated wounds managed with NPWT demonstrated a mean time to wound closure of 17 days (median 10 days). The authors concluded that NPWT appeared safe and effective in managing acute, contaminated wounds including patients meeting sepsis criteria. These findings provide evidence-based support for current worldwide empiric NPWT-related acute wound care. The Wound Union of Wound Healing Societies (WUWHS) consensus document for NPWT stated that NPWT therapy can have a positive impact on a patient’s quality of life (31). Patient’s experiences of NPWT have been investigated by a number of authors and demonstrate that NPWT can lead to faster wound healing (32) and can reduce frequency of dressing change (33) and hospital stay (34), but there are still a number of challenges such as pain, anxiety, embarrassment, restriction in patient’s wider social life, negative self-image and low self-esteem (35). Changing outcomes
PUs represent the class of wounds with the highest prevalence among patients with advanced illness, where the life expectancy is generally less than 6 months (36). Goal setting is challenging in this context. Although complete wound healing is the most coveted target, clinicians should neither discount nor marginalise the value of achieving other significant outcomes. The concept of wound maintenance has been defined in both patients with advanced illness as well as non-terminally ill patients (37). In addition to optimal wound palliation (wound-related pain and symptom management or palliative wound care), it is also imperative to provide health care that is patient-centred/patient-empowered, while promoting the best achievable levels of health-related quality of life and well-being. With comprehensive wound management, the majority of PUs (92·87%) in patients with advanced illness achieve either wound maintenance or some degree of wound healing (36). A combination of high levels of wound maintenance together with modest levels of wound healing and low levels of wound deterioration, within the most compromised patients within health care, must be recognised as successful outcomes in wound management. The current PU debate
The profile of PUs has risen dramatically around the world as they are increasingly used as a quality indicator. This
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has led to much debate around definitions; most importantly the categorisation of damage, the avoidability of occurrence and the attribution of where damage occurred (38, 39). Prevention of pressure damage has attracted payment as part of large-scale quality initiatives but has also resulted in loss of income/fines and in some case large lawsuits against organisations. Organisations strive to provide protocols for management by the use of care bundles and as numbers of PUs remain constant despite increasing use of specialist equipment (40) they seek alternative actions to supplement standard protocols for prevention such as the use of dressings (41) and focussing on particular groups of PUs, for example, those related to the use of medical devices.
Health-related quality of life (HRQoL)
There is increasing recognition that HRQoL is a valuable outcome measure in wound care and should be included in reviews of new and existing therapies ensuring that importance is placed on the impact of health services on the patient experience. There is also a growing body of evidence that demonstrates a patient’s psychological/mood state and in particular psychological stress (42,43) is negatively related to wound healing outcomes. Providing health care within a socially supportive environment can increase well-being and contribute to positive health experiences. This may have a profound effect on how services are provided, and may lead to an increased collaboration between health and social care services to provide patients with access to both social and emotional support, whilst receiving wound care. Last year an international consensus on optimising wellbeing in patients living with a chronic wound was published (44). This consensus document aimed to increase stakeholders’ understanding of the impact of living with a wound; it discusses factors affecting well-being, investigates the assessment and measurement of quality of life and well-being and suggests strategies for optimising well-being for effective wound management.
Social media
There is a global recognition that the methods for communication with patients are changing; today social media networks such as Facebook and Twitter are commonplace in everyday life for public connection and as a forum for sharing experiences. In health care, individuals, especially patients with chronic conditions, can feel isolated and alone. This often drives such individuals to Internet-based resources to inform, educate and engage, but without professional regulation such resources may also misinform and confuse (45). Recently, two exciting social media-based approaches have been introduced in the wound-care arena. These are The Welsh Wound Community (www.welshwoundcommunity.com) and the Diabetic Foot Canada Community (www.diabeticfootcommunity.ca). These sites represent the first truly interactive private communities focused on wounds and their prevention and treatment. The sites provide a significant resource to all involved
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in the care of patients with wounds and allow members to not only communicate privately but also to exchange relevant documents and to share information. These private networks allow access to the many assets required to provide effective, evidence-based management and prevention in the area of DFUs and chronic wound management (46). Digital technology
It is important that all clinical information is recorded and evaluated. The last few years have seen a significant development in the capture and use of clinical and research data. Digital pen and paper technology, which converts analogue information (created using a pen and paper) directly into a digital data package, represents a major technological advancement in the area of wound healing. By enabling handwritten data to be instantly uploaded to a computer and used in various applications, it thus has the potential to save valuable research time and money. Furthermore, the creation of a wound registry allows the capture and more importantly the use of data as validation of a clinical approach. Data stored in a registry can be examined for a variety of parameters, including usage statistics, adverse event reporting and successful outcome data, which are essential for effective evidence-based decision making leading to the adoption of cost-effective wound prevention and treatment solutions and planning for service delivery in the future (47). Conclusion
Many advances have been made during the last few years to meet some of the challenges of chronic wound management. There have been exciting innovations in the area of diagnostics and bioengineering and also in respect to how we communicate and use technology. Debate on the management of microbes continues, as does agreement on relevant research outcomes and predictors for ulceration. The evidence base for chronic wound management continues to grow and thus presents positive impact for better clinical outcomes. References 1. Coombes R. The NHS debate. BMJ 2008;337:a628. DOI: 10.1136/bmj.a1628. 2. Darzi A. High quality care for all: NHS Next Stage Review final report [Online]. London: Department of Health, 2008, 192. URL http://webarchive.nationalarchives.gov.uk/+/www.dh.gov.uk/en/ healthcare/highqualitycareforall/index.htm [accessed on 16 April 2013] 3. DOH. NHS 2010-2015: from good to great. Preventative, peoplecentred, productive [Online]. London: Department of Health, 2009. URL www.official-documents.gov.uk/document/cm77/7775/ 7775.pdf [accessed on 16 April 2013] 4. DOH. NHS Chief Executive’s Annual Report for 2008-09 [Online]. London: Department of Health, 2009. URL http://www. healthcaretoday.co.uk/doclibrary/documents/pdf/215_the_year_200809.pdf [accessed on 16 April 2013] 5. Dowsett C, White R. Delivering quality and high impact actions. Br J Healthcare Manage 2010;16:92–3. 6. Negus J, Howat M. Linking indicators and metrics to patient experience. Wounds UK 2010;6:125–6. 8
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