A case report on the use of sustained release platelet-rich plasma for the treatment of chronic pressure ulcers

Abstract

Background/objectives: Chronic pressure ulcers affect patient health, emotional state, and quality of life, causing considerable morbidity and mortality in addition to contributing to significant health care costs from lengthy hospitalizations to advanced home care and surgical care costs. The conventional treatment of these wounds can be slow due to their chronic inflammatory state and the senescence of local reparative cells. Platelet-rich plasma (PRP) therapy has been growing as a viable treatment alternative for a number of clinical applications and has potential benefit for use in chronic wounds. The sustained release of large quantities of autologous growth factors, cytokines, and other mediators found in PRP plus the favorable mononuclear cell profile of PRP may help us to stimulate wound healing and resolve chronic inflammation.

Methods: Three veterans with spinal cord injury (SCI), presenting with chronic stage IV pressure ulcers, were treated with a sustained release PRP therapy to stimulate wound healing.

Results: PRP treatment consistently resulted in the formation of granulation tissue and improved vascularity for each of the three patients treated, while reducing the overall ulcer area and volume.

Conclusion: The controlled release of growth factors from PRP demonstrated a positive stimulatory effect on the healing rate of chronic pressure ulcers in individuals with SCI.     

A case report on the use of sustained release platelet-rich plasma for the treatment of chronic pressure ulcers

Background/objectives

Chronic pressure ulcers affect patient health, emotional state, and quality of life, causing considerable morbidity and mortality in addition to contributing to significant health care costs from lengthy hospitalizations to advanced home care and surgical care costs. The conventional treatment of these wounds can be slow due to their chronic inflammatory state and the senescence of local reparative cells. Platelet-rich plasma (PRP) therapy has been growing as a viable treatment alternative for a number of clinical applications and has potential benefit for use in chronic wounds. The sustained release of large quantities of autologous growth factors, cytokines, and other mediators found in PRP plus the favorable mononuclear cell profile of PRP may help us to stimulate wound healing and resolve chronic inflammation.

Methods

Three veterans with spinal cord injury (SCI), presenting with chronic stage IV pressure ulcers, were treated with a sustained release PRP therapy to stimulate wound healing.

Results

PRP treatment consistently resulted in the formation of granulation tissue and improved vascularity for each of the three patients treated, while reducing the overall ulcer area and volume.

Conclusion

The controlled release of growth factors from PRP demonstrated a positive stimulatory effect on the healing rate of chronic pressure ulcers in individuals with SCI.     

The growing evidence for the use of platelet‐rich plasma on diabetic chronic wounds: A review and a proposal for a new standard care

Nonhealing chronic wounds and exposed tendons, bones and joints are very challenging to cure specially for diabetic patients. Plastic surgeons have a new weapon to enhance wound healing with the use of autologous growth factors. Recently, the process of fabrication of platelet‐rich plasma (PRP) has been simplified. The goal of this literature review is to summarize the evidenced‐based body of knowledge regarding the treatment of diabetic chronic wounds by PRP. A PubMed and Cochrane search (1978–2015) was performed and all studies assessing the clinical effect of PRP on the healing of diabetic chronic wounds were included. The screening retrieved 7,555 articles and 12 studies were included. On six randomized studies included, five found significant benefits for the use of PRP on diabetic chronic foot ulcers and the sixth randomized study did not publish a statistical analysis but found favorable outcomes. The two other controlled studies included found significant benefits regarding the healing rate and the four uncontrolled studies included showed high rates of healing with the adjunction of PRP. Regarding the method of use, PRP was applied on the wound as a gel twice a week (41.7% of studies) or once a week (33.3% of studies). In conclusion, 87.5% of controlled studies found a significant benefit for the adjunction of PRP to treat chronic diabetic wounds. As PRP may be beneficial, we suggest using PRP on diabetic ulcers which remain unhealed after standard treatment.     

Autologous platelet‐rich plasma for healing chronic venous leg ulcers: Clinical efficacy and potential mechanisms

The overall quality of evidence of autologous platelet‐rich plasma (PRP) for treating chronic wounds remains low. While further well‐designed clinical studies are clearly required to convincingly demonstrate the efficacy of autologous PRP in improved healing of venous leg ulcers (VLUs) and other chronic wounds, there is also an increasing need to better define the underlying mechanisms of action and whether positive outcomes can be predicted based on the analysis of PRP. This brief review will discuss the current understanding of autologous PRP in VLUs and whether molecular evaluation of PRP at the time of collection could potentially be informative to clinical outcomes. Benefits of the autologous PRP treatment strategy include that PRP is easily accessible and is relatively inexpensive and safe. Better understanding of the mechanisms involved could improve treatment, enable supplementation, and/or lead to gains in product development. Analysis of PRP could also add value to future clinical trials on efficacy and potentially personalised treatment regimens.     

The effectiveness of intralesional injection of platelet‐rich plasma in accelerating the healing of chronic ulcers: an experimental and clinical study

The purpose of this prospective experimental and clinical study is to evaluate the effectiveness of the intralesional injection of platelet‐rich plasma (PRP), in the management of non‐healing chronic wounds. Skin defects were created in the ears of 20 white New Zealand rabbits. In the study group, autologous PRP was injected intralesionally. The control group was treated conservatively. Nineteen out of 20 cases of the study group healed within a mean time of 24·9 days. In the control group, seven defects healed within a mean period of 26·7 days, seven ulcers did not heal at day 28 and in six cases a full thickness ear defect was recorded. For a 3‐year period, 26 patients with chronic ulcers underwent surgical debridement and intralesional injection of PRP. A histological study was performed before and 7 days after PRP injection. Ten patients healed within a mean period of 7 weeks. In 16 cases, PRP prepared the wound bed for the final and simpler reconstructive procedure. Intralesional injection is a newly described method for application of PRP and represents an effective therapeutic option when dealing with non‐healing wounds.     

Topically applied rhGM-CSF for the wound healing: a systematic review

The process of wound healing involves a complex interplay of cells, mediators, growth factors and cytokines. GM-CSF has been shown to be involved in a number of processes essential in this event. Topically applied rhGM-CSF has been reported to successfully treat wounds with diverse etiology, including burns, chronic venous leg ulcers, pressure ulcers, and leprosy ulcers, both in animal experiments and clinical studies. To evaluate the effect of the rhGM-CSF on wound healing, 8 RCT studies and 23 clinical studies and case reports are collected for analysis of the evidence. The overall effects of rhGM-CSF on the healing of wound are diverse. Topically applied rhGM-CSF is beneficial for deep partial-thickness burn wounds, chronic leg ulcers, and leprosy ulcers. rhGM-CSF may have a positive effect on other type of chronic ulcers such as pressure ulcers and cancer related ulcers, but the evidence is not sufficient for generalised use at present. rhGM-CSF is suggested have no accelerating effect on the healing of healthy wounds or surgical incisions.     

Epidemiology of chronic wounds in Germany: Analysis of statutory health insurance data

Epidemiologic analyses in routine care of chronic wounds are scarce, and published studies show wide variations. This study analyzes the population‐based prevalence and incidence of chronic wounds in Germany. Secondary analyses of data from a German statutory health insurance with about 9 million insured persons were examined (2010 to 2012). Internal diagnostic validations were used to control for different inclusion criteria. In 2012, 1.04% (95% CI 1.03–1.05) of insured patients had a wound diagnosis, including 0.70% with leg ulcers and 0.27% with diabetic ulcers. Wound treatment was received by 0.43% (0.43–0.44) of patients. Prevalence and incidence increased over 3 years. Extrapolated to the German population, there were 786,407 prevalent and 196,602 incident chronic wounds, including 326,334/172,026 patients who underwent wound‐relevant treatment in 2012. There is an annually increasing frequency of chronic wounds in Germany. Chronic wound epidemiology is sensitive to wound treatment as a filter criterion.     

Platelet-rich plasma versus platelet-poor plasma in the management of chronic diabetic foot ulcers: a comparative study

Non healing diabetic foot ulcers and the resulting potential amputations present significant costs to the health care system and reduce patient quality of life. The goal of diabetic foot ulcer treatment is to obtain wound closure as expeditiously as possible. The use of platelet-rich plasma (PRP) to enhance wound healing has increased dramatically over the last decade. However, controversies exist in the literature regarding the added benefit of this procedure. The aim of this study is to investigate the efficiency of platelet releasate on the healing of chronic diabetic ulcers in comparison with platelet-poor plasma (PPP). This study included 24 patients with chronic diabetic ulcers. They were systematically randomised into two groups: PRP group (n = 12) and PPP group (n = 12). The results showed that healing in PRP group was significantly faster (P < 0·005). PRP enhances healing of chronic diabetic foot ulcers.     

In vitro multispecies Lubbock chronic wound biofilm model

Multispecies biofilms are becoming increasingly recognized as the naturally occurring state in which bacteria reside. One of the primary health issues that is now recognized to be exacerbated by biofilms are chronic, nonhealing wounds such as venous leg ulcers, diabetic foot ulcers, and pressure ulcers. Arguably three of the most important species associated with multispecies biofilms that our group sees clinically are Pseudomonas aeruginosa, Enterococcus faecalis, and Staphylococcus aureus. This study was conducted to address the need for a chronic pathogenic biofilm laboratory model that allows for cooperative growth of these three organisms. We have developed a novel media formulation, simple laboratory system, quantitative polymerase chain reaction for monitoring population dynamics, and methods for objectively and subjectively measuring biofilm formation. The Lubbock chronic wound pathogenic biofilm withstood treatment with a 50‐fold higher concentration of bleach than that which was completely bacteriocidal for fully turbid planktonic cultures. The Lubbock chronic wound pathogenic biofilm when treated with biofilm effectors such as gallium nitrate and triclosan responded with selective inhibition of Pseudomonas aeruginosa or Staphylococcus aureus, respectively, as has been reported in the literature. The ability of this 24‐hour model to react as predicted using known biofilm effectors suggests that it will lend itself to future work in the development and testing of first‐generation chronic wounds pathogenic biofilm therapeutics. We have defined a realistic in vitro multispecies biofilm model simulating the functional characteristics of chronic pathogenic biofilms and developed effective tools for its characterization and analyses.     

Platelet-rich fibrin matrix improves wound angiogenesis via inducing endothelial cell proliferation

The economic, social, and public health burden of chronic ulcers and other compromised wounds is enormous and rapidly increasing with the aging population. The growth factors derived from platelets play an important role in tissue remodeling including neovascularization. Platelet-rich plasma (PRP) has been utilized and studied for the last four decades. Platelet gel and fibrin sealant, derived from PRP mixed with thrombin and calcium chloride, have been exogenously applied to tissues to promote wound healing, bone growth, hemostasis, and tissue sealing. In this study, we first characterized recovery and viability of as well as growth factor release from platelets in a novel preparation of platelet gel and fibrin matrix, namely platelet-rich fibrin matrix (PRFM). Next, the effect of PRFM application in a delayed model of ischemic wound angiogenesis was investigated. The study, for the first time, shows the kinetics of the viability of platelet-embedded fibrin matrix. A slow and steady release of growth factors from PRFM was observed. The vascular endothelial growth factor released from PRFM was primarily responsible for endothelial mitogenic response via extracellular signal-regulated protein kinase activation pathway. Finally, this preparation of PRFM effectively induced endothelial cell proliferation and improved wound angiogenesis in chronic wounds, providing evidence of probable mechanisms of action of PRFM in healing of chronic ulcers.     

Marjolin ulcer: an overlooked entity

Marjolin ulcer is a well-defined, but uncommon malignant ulcer that occurs in chronic wounds and cutaneous scars. Jean-Nicolas Marjolin was credited with describing this phenomenon in 1828. This entity is frequently overlooked and therefore inadequately treated leading to a poor prognosis. The malignant transformation of an ulcer is most commonly associated with burn scars, but has been reported in many other types of chronic, non healing wounds such as traumatic wounds, venous stasis and chronic pressure ulcers, fistulas, lacerations and leprosy ulcers. Development of malignancy tends to be slow with an average time of approximately 25 years. Various theories concerning pathogenesis of Marjolin ulcer have been proposed. Well-differentiated squamous cell carcinoma (SCC) is the most common histological type of Marjolin ulcer. Biopsy with histopathologic interpretation remains the gold standard for the diagnosis, with radical surgical excision being the treatment of choice. A high index of suspicion should be held by any health care provider when evaluating a chronic, non healing wound. This is a case report of a Marjolin ulcer arising on the left buttock of a patient with a long-standing history of a traumatic wound.     

Platelet‐rich plasma for resistant oral erosions of pemphigus vulgaris: A pilot study

Oral erosions and ulcers of pemphigus vulgaris (PV) are a debilitating condition that is usually difficult to treat. The wound healing properties of platelet‐rich plasma (PRP) encouraged us to evaluate its usefulness in treatment of non‐healing oral PV lesions. Seven patients with chronic oral PV, resistant to conventional therapy, were treated with weekly to monthly injections of PRP of affected mucosal membranes. All recruits reported improvement in pain and mastication and 6 of 7 patients had an improvement in pemphigus disease area index scores with PRP treatment. PRP injections seems to accelerate the healing process and decrease the pain and eating discomfort associated with the oral erosions and ulcers induced by PV.     

Skin grafting for the treatment of chronic leg ulcers – a systematic review in evidence‐based medicine

Skin grafting is one of the most common surgical procedures in the area of non‐healing wounds by which skin or a skin substitute is placed over a wound to replace and regenerate the damaged skin. Chronic leg ulcers are an important problem and a major source of expense for Western countries and for which many different forms of treatment have been used. Skin grafting is a method of treatment that decreases the area of chronic leg ulcers or heals them completely, thus improving a patient's quality of life. Skin grafting is an old technique, rediscovered during the first and second world wars as the main treatment for wound closure. Nowadays, skin grafting has a pivotal role in the context of modern wound healing and tissue regeneration. The aim of this review was to track and to analyse the specific outcomes this technique achieved, especially in the last decade, in relation to venous, arterial, diabetic, rheumatoid and traumatic leg ulcers. Our main findings indicate that autologous split‐thickness skin grafting still remains the gold standard in terms of safety and efficacy for chronic leg ulcers; skin grafting procedures have greater success rates in chronic venous leg ulcers compared to other types of chronic leg ulcers; skin tissue engineering, also supported by genetic manipulation, is quickly expanding and, in the near future, may provide even better outcomes in the area of treatments for long‐lasting chronic wounds.     

Application of standardized platelet‐rich plasma in elderly patients with complex wounds

In recent years, autologous platelet‐rich plasma (PRP) derivatives have been used widely in the regeneration and repair of tissue, but a standard definition and preparation method for PRP are lacking. We developed a standardized method using platelet indices as quality‐control indicators for PRP preparation. Twenty‐one elderly patients (9 males, 12 females) with complex wounds were treated with standardized platelet‐rich plasma (S‐PRP). The platelet count in PRP after the second centrifugation was 1,069–1,436 × 10⁹/L. We adjusted the platelet concentration in PRP after a second centrifugation to 1,000 × 10⁹/L according to a formula using platelet‐poor plasma (PPP). The standardized preparation method that we developed gave S‐PRP with a relatively uniform platelet concentration. The wounds of 21 patients showed accelerated healing after S‐PRP treatment, and there were no obvious side effects during treatment. These data suggest that our preparation method of S‐PRP, using platelet indices as quality‐control indicators with platelet count of 1,000 × 10⁹/L could be used for the treatment of complex wounds in the elderly. The preparation method of S‐PRP proposed in the present study may be a simple and effective method of PRP quality control.     

Estimating the costs associated with the management of patients with chronic wounds using linked routine data

Chronic wounds are known to represent a significant burden to patients and National Health Service (NHS) alike. However, previous attempts to estimate the costs associated with the management of chronic wounds have been based on literature studies or broad estimates derived from incidence rates and extrapolations from relatively small‐scale studies. The aim of this study is therefore to determine the extent of resource utilisation by patients classed as having chronic wounds within Wales using linked routine data – available through the Secure Anonymised Information Linkage (SAIL) database – to estimate the costs associated with the management of these patients by the NHS in Wales. The SAIL database brings together, and anonymously links, a wide range of person‐based data from general practitioner (GP) practices within Wales, which includes primary and secondary care consultations to create an encrypted anonymised linking field for each individual. This linkage allows the patient pathway to be tracked through the NHS system both retrospectively and prospectively from a specific reference date. The estimated costs were derived by extrapolating to an all‐Wales level from the results gleaned from the SAIL database using the respective READ codes to capture relevant patients with chronic wounds. The number of patients identified as having chronic wounds within the SAIL database was 78 090, which equates to 190 463 across Wales as a whole and a prevalence of 6% of the Welsh population. The total cost of managing patients with chronic wounds in Wales amounted to £328·8 million – an average cost of £1727 per patient and 5·5% of total expenditure on the health service in Wales. A relatively few READ codes represented a significant proportion of expenditure, with diabetic foot ulcers, leg ulcers, foot ulcers, varicose eczema, bed sores and postoperative wound care constituting 93% of total expenditure. When a more conservative perspective was used in relation to classification of chronic wounds, the total cost amounted to £303 million. However, these are likely to be underestimates because of the lack of information for patients with treatments lasting over 6 months and not including patients who might have entered the health care system of wound management elsewhere – such as patients contracting pressure ulcers in hospitals and having surgical wound infections.     

Epidemiological characteristics and clinical analyses of chronic cutaneous wounds of inpatients in China: Prevention and control

The increased incidence of chronic cutaneous wounds is likely to lead to increased mortality, and therefore, deserves greater attention. More insight is needed into the magnitude of the problem of chronic cutaneous wounds and methods for their prevention and treatment in China. A retrospective analysis of data retrieved from an electronic health‐records database on 3300 patients with chronic skin wounds was conducted from 1 January 2018 to 31 December 2018. The patients had been admitted to the medical and surgical wards of 17 third‐grade class‐A hospitals in China. The study's aim was to compare the characteristics (eg, demographic and clinical) associated with different causes and distributions of patients' chronic wounds. Among the 3300 patients, 66.03% were males and 33.97% were females. The mean age was 57 years and the increasing prevalence of chronic skin wounds with aging was quite high. The primary causes of chronic wounds were diabetes or infection, followed by pressure ulcers, trauma, and iatrogenic wounds. The distribution of skin wounds was mainly in the lower extremities (56.1%), followed by the trunk (18.6%). The mean duration of hospital stay was 29 days and the mean recurrence was 3 months. Chronic skin wounds were related to occupation, educational level, lifestyle habits, and income. The main cause of chronic skin wounds has shifted from trauma to chronic disease. Normalization checks, bacterial cultures, and antibiotic use in China need to be standardized and the training of wound specialists should be further strengthened. The association of aging and wound infection was significant. Preventive management and efficient treatment should correspond to the needs of the different regions of China. These results may serve as a reference for other developing countries in their transitional development.     

Treatment of chronic diabetic lower leg ulcers with activated protein C: a randomised placebo‐controlled,double‐blind pilot clinical trial

Lower leg ulcers are a serious and long‐term complication in patients with diabetes and pose a major health concern because of the increasing number of patients diagnosed with diabetes each year. This study sought to evaluate the clinical benefit of topical activated protein C (APC) on chronic lower leg ulcers in patients with diabetes. Twelve patients were randomly assigned to receive either APC (N = 6) or physiological saline (placebo; N = 6) in a randomised, placebo‐controlled, double‐blind pilot clinical trial. Treatment was administered topically, twice weekly for 6 weeks with final follow‐up at 20 weeks. Wound area was significantly reduced to 34·8 ± 16·4% of week 0 levels at 20 weeks in APC‐treated wounds (p = 0·01). At 20 weeks, three APC‐treated wounds had completely healed, compared to one saline‐treated wound. Full‐thickness wound edge skin biopsies showed reduced inflammatory cell infiltration and increased vascular proliferation following APC treatment. Patient stress scores were also significantly reduced following APC treatment (p < 0·05), demonstrating improved patient quality of life as assessed by the Cardiff Wound Impact Questionnaire. This pilot trial suggests that APC is a safe topical agent for healing chronic lower leg ulcers in patients with diabetes and provides supporting evidence for a larger clinical trial.     

A change in the prevalence and the etiological factors of chronic wounds in Helsinki metropolitan area during 2008‐2016

The prevalence of chronic wounds in the Helsinki metropolitan area in 2008 was investigated. Thereafter, a specialised wound care team was founded as part of the City of Helsinki Health Services, aiming for early diagnoses of chronic wounds. In the current study, we have repeated the prevalence study to analyse the changes in the prevalence of chronic wounds. A questionnaire on wound patients was sent to all units of social and health care in the Helsinki metropolitan area. We asked about the number of patients with wounds treated during a 24‐hour period, as well the aetiology and location of the wounds. A total of 911 patients had, altogether, 1021 wounds. Thus, prevalence was 0.08%. Pressure and multifactorial ulcers were the most common aetiological groups, whereas wound without defined aetiology had diminished greatly (61%) The prevalence of chronic wound decreased when compared with 2008 (0.08% vs 0.1%). The number of elderly people aged over 65 years had increased 35%, and the age‐adjusted prevalence had decreased. Wounds are treated mostly in primary care units and as outpatients. Therefore, the following conclusion may be reached: diagnostic process and implementation of treatment paths are strengthened within primary care units, yet prevalence of wounds has decreased.     

A pilot study investigating lactic acid bacterial symbionts from the honeybee in inhibiting human chronic wound pathogens

Treatment and management of chronic wounds is a large burden on the health sector and causes substantial suffering for the patients. We believe that 13 lactic acid bacteria (LAB) symbionts isolated from the honey crop of the honeybee are important players in the antimicrobial action of honey, by producing antimicrobial substances and can be used in combination with heather honey as an effective treatment in wound management. A total of 22 patients with chronic ulcers were included; culture‐dependent and molecular‐based (MALDI‐MS and 16S rRNA gene sequencing) techniques were used to identify bacteria from chronic wounds. These clinical isolates were used for in vitro antimicrobial testing with standardised viable LAB and sterilised heather honey mixture. Twenty of the patients' wounds were polymicrobial and 42 different species were isolated. Patient isolates that were tested in vitro were inhibited by the LAB and honey combination with inhibitory zones comparable with different antibiotics. LAB and heather honey in combination presents a new topical option in chronic wound management because of the healing properties of honey, antimicrobial metabolite production from the LAB and their bactericidal effect on common chronic wound pathogens. This new treatment may be a stepping stone towards an alternative solution to antibiotics.