The use of fat grafting and platelet‐rich plasma for wound healing: A review of the current evidence

Fat grafting is becoming a common procedure in regenerative medicine because of its high content of growth factors and adipose derived stem cells (ADSCs) and the ease of harvest, safety, and low cost. The high concentration of ADSCs found in fat has the potential to differentiate into a wide range of wound‐healing cells including fibroblasts and keratinocytes as well as demonstrating proangiogenic qualities. This suggests that fat could play an important role in wound healing. However retention rates of fat grafts are highly variable due in part to inconsistent vascularisation of the transplanted fat. Furthermore, conditions such as diabetes, which have a high prevalence of chronic wounds, reduce the potency and regenerative potential of ADSCs. Platelet‐rich plasma (PRP) is an autologous blood product rich in growth factors, cell adhesion molecules, and cytokines. It has been hypothesised that PRP may have a positive effect on the survival and retention of fat grafts because of improved proliferation and differentiations of ADSCs, reduced inflammation, and improved vascularisation. There is also increasing interest in a possible synergistic effect that PRP may have on the healing potential of fat, although the evidence for this is very limited. In this review, we evaluate the evidence in both in vitro and animal studies on the mechanistic relationship between fat and PRP and how this translates to a benefit in wound healing. We also discuss future directions for both research and clinical practice on how to enhance the regenerative potential of the combination of PRP and fat.     

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.     

Systematic review and meta‐analysis of the efficacy of epidermal grafting for wound healing

Autologous skin grafting is an important method for wound coverage; however, it is an invasive procedure and can cause donor site morbidity. Epidermal grafting (EG) enables epidermal transfer to wounds with minimal donor site morbidity. However, data to date have been heterogeneous. This study aims to synthesise the current evidence on EG for wound healing to establish the efficacy of this surgical technique. A comprehensive search in the MEDLINE, EMBASE and CENTRAL databases was conducted. The endpoints assessed were proportion of wounds healed and mean wound‐healing time. This systematic review was conducted and reported according to the Meta‐Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. We identified 1568 articles, of which seven articles were included in this review – a total of 209 wounds in 190 patients. The mean wound duration was 17·06 weeks (95% CI 8·57–25·55). Of these, 71·5% (95% CI 56·7–84·2) of the wounds achieved complete healing. Mean time for complete wound healing was 5·53 weeks (95% CI 3·18–7·88). The mean donor site healing time was 7·48 days (95% CI 4·83–10·13), with no reported donor site morbidity. The current data are small and lack level 1 evidence.     

Healing modulation induced by freeze-dried platelet-rich plasma and micronized allogenic dermis in a diabetic wound model

The incidence and prevalence of chronic and diabetic wounds are increasing and clinical treatments to tackle these epidemics are still insufficient. In this study, we tested the ability of freeze‐dried platelet‐rich plasma (PRP) and an allogenic micronized acellular dermal matrix alone and in combination to modulate diabetic wound healing. Therapeutic materials were applied to 1.0 cm² excisional wounds on genetically diabetic (db/db) mice. Wound‐healing kinetics and new tissue formation were studied at 9 and 21 days posttreatment. Quantitative immunohistochemistry was used to study vascularity and cellular proliferation (days 9 and 21), and collagen deposition was evaluated 21 days postwounding. In vitro, micronized allogenic dermis, when combined with PRP, absorbed nearly 50% of original platelet‐derived growth factor, transforming growth factor‐β, vascular endothelial growth factor, and epidermal growth factor from platelets and stimulated fibroblast proliferation. In vivo, micronized dermis increased the formation of vascularized wound tissue by day 9. Freeze‐dried PRP alone or in combination with micronized dermis increased wound tissue revascularization and proliferation compared with spontaneous healing. The increase in cell proliferation persisted until day 21 only when freeze‐dried PRP was used in combination with micronized dermis. These results indicate that micronized allogenic dermis may be used to provide a dermal matrix to stimulate tissue formation and the combination with PRP may confer additional beneficial growth factors to chronic or diabetic wounds.     

Histological analysis of fat grafting with platelet‐rich plasma for diabetic foot ulcers—A randomised controlled trial

Diabetic foot ulcers are often unresponsive to conventional therapy and are a leading cause of amputation. Animal studies have shown stem cells and growth factors can accelerate wound healing. Adipose‐derived stem cells are found in fat grafts and mixing them with platelet‐rich plasma (PRP) may improve graft survival. This study aimed to establish the histological changes when diabetic foot ulcers are treated with fat grafts and PRP. A three‐armed RCT was undertaken of 18 diabetic foot ulcer patients: fat grafting; fat grafting with PRP; and routine podiatry care. Biopsies were obtained at week 0, 1, and 4, and underwent quantitative histology/immunohistochemistry (H&E, CD31, and Ki67). Treatment with fat and PRP increased mean microvessel density at 1 week to 1645 (SD 96) microvessels/mm² (+32%‐45% to other arms, P = .035). PRP appeared to increase vascularity surrounding fat grafts, and histology suggested PRP may enhance fat graft survival. There was no clinical difference between arms. This study demonstrates PRP with fat grafts increased neovascularisation and graft survival in diabetic foot ulcers. The histology was not, however, correlated with wound healing time. Future studies should consider using apoptosis markers and fluorescent labelling to ascertain if enhanced fat graft survival is due to proliferation or reduced apoptosis. Trial registration {"type":"clinical-trial","attrs":{"text":"NCT03085550","term_id":"NCT03085550"}}NCT03085550.     

Effects of platelet‐rich plasma on the healing of sternal wounds: A meta‐analysis

Sternal wound infection (SWI) is a devastating complication after cardiac surgery. Platelet‐rich plasma (PRP) may have a positive impact on sternal wound healing. A systematic review with meta‐analyses was performed to evaluate the clinical effectiveness of topical application of autologous PRP for preventing SWI and promoting sternal wound healing compared to placebo or standard treatment without PRP. Relevant studies published in English or Chinese were retrieved from the Cochrane Central Register of Controlled Trials (The Cochrane Library), PubMed, Ovid EMBASE, Web of Science, Springer Link, and the WHO International Clinical Trials Registry Platform (ICTRP) using the search terms “platelet‐rich plasma” and “sternal wound” or “thoracic incision.” References identified through the electronic search were screened, the data were extracted, and the methodological quality of the included studies was assessed. The meta‐analysis was performed for the following outcomes: incidence of SWI, incidence of deep sternal wound infection (DSWI), postoperative blood loss (PBL), and other risk factors. In the systematic review, totally 10 comparable studies were identified, involving 7879 patients. The meta‐analysis for the subgroup of retrospective cohort studies (RSCs) showed that the incidence of SWI and DSWI in patients treated with PRP was significantly lower than that in patients without PRP treatment. However, for the subgroup of randomized controlled trials (RCTs), there was no significant difference in the incidence of SWI or DSWI after intervention between the PRP and control groups. There was no significant difference in PBL in both RCTs and RSCs subgroups. Neither adverse reactions nor in‐situ recurrences were reported. According to the results, PRP could be considered as a candidate treatment to prevent SWI and DSWI. However, the quality of the evidence is too weak, and high‐quality RCTs are needed to assess its efficacy on preventing SWI and DSWI.     

Comparison of Conventional and Platelet‐Rich Plasma-Assisted Fat Grafting: A Systematic Review and Meta-analysis

BackgroundAutologous fat grafting (FG) is a popular technique for soft-tissue augmentation, but the fat survival rate is unpredictable. Platelet-rich plasma (PRP) has emerged as an adjuvant to enhance fat graft survival.ObjectivesThis literature review and meta-analysis aimed to investigate the effect of PRP on the survival rate of fat grafting.MethodsA comprehensive systematic literature search was done to identify clinical studies on PRP and fat cotransplantation in PubMed, Cochrane Library, Web of Science, and EMBASE databases up to May 2020. The reference lists of selected articles were reviewed to identify any additional related articles. A meta-analysis was conducted to compare PRP + FG and conventional FG in terms of fat graft survival rate, patient satisfaction rate, and recovery time after surgery.ResultsEleven studies consisting of 1125 patients were analyzed. Patients were followed up from 3 to 24 months post-FG. The fat survival rate varied from 20.5% to 54.8% in FG alone and from 24.1% to 89.2% in the PRP + FG groups. The survival rate was significantly higher and recovery time was significantly lower in the PRP + FG group than in the FG alone group. However, there was no significant difference in the patient satisfaction rate between the groups.ConclusionsThis study demonstrates that PRP-enhanced fat transplantation has better efficacy than conventional fat grafting. Further studies are required to provide the optimum concentration of PRP and the long-term efficacy of the technique. There is not enough evidence to compare the rate of complications with PRP and fat cotransplantation and conventional fat grafting.     

An evaluation of the bacteriostatic effect of platelet‐rich plasma

Chronic wounds are a considerable health burden with high morbidity and poor rates of healing. Colonisation of chronic wounds by bacteria can be a significant factor in their poor healing rate. These bacteria can develop antibiotic resistance over time and can lead to wound infections, systemic illness, and occasionally amputation. When a large number of micro‐organisms colonise wounds, they can lead to biofilm formation, which are self‐perpetuating colonies of bacteria closed within an extracellular matrix, which are poorly penetrated by antibiotics. Platelet‐rich plasma (PRP) is an autologous blood product rich in growth factors and cytokines that are involved in an inflammatory response. PRP can be injected or applied to a wound as a topical gel, and there is some interest regarding its antimicrobial properties and whether this can improve wound healing. This study aimed to evaluate the in vitro bacteriostatic effect of PRP. PRP was collected from healthy volunteers and processed into two preparations: activated PRP—activated with calcium chloride and ethanol; inactivated PRP. The activity of each preparation against Staphylococcus aureus and Staphylococcus epidermis was evaluated against a control by three experiments: bacterial kill assay to assess planktonic bacterial growth; plate colony assay to assess bacterial colony growth; and colony biofilm assay to assess biofilm growth. Compared with control, both preparations of PRP significantly inhibited growth of planktonic S aureus and S epidermis. Activated PRP reduced planktonic bacterial concentration more than inactivated PRP in both bacteria. Both PRP preparations significantly reduced bacterial colony counts for both bacteria when compared with control; however, there was no difference between the two. There was no difference found between biofilm growth in either PRP against control or against the other preparation. This study demonstrates that PRP does have an inhibitory effect on the growth of common wound pathogens. Activation may be an important factor in increasing the antimicrobial effect of PRP. However, we did not find evidence of an effect against more complex bacterial colonies.     

Platelet-rich plasma combined with skin substitute for chronic wound healing: a case report

Contemporary management of chronic wounds focuses on improving natural healing and individualization of treatment. Incorporating multiple therapies has become increasingly common. Of interest are autologous growth factors, which are especially important in chronic wound healing and may contribute to tissue formation and epithelialization. Autologous platelet concentrate or platelet-rich plasma (PRP) is a concentration of at least five autologous growth factors and has been shown to accelerate wound healing and may have infection-fighting properties. Chronic wound healing is complicated by both decreased growth factor availability and infection, making PRP use valuable in these types of wounds. In this report, the use of PRP therapy alone and in combination with a bioengineered skin substitute as a platelet-rich tissue graft in a chronic, non-healing wound is detailed. Over 27 weeks, the patient received multiple therapies in attempts to heal a severe decubitus ulcer of the sacrum. The introduction of PRP therapy at Week 14 led to a 26% reduction in wound depth over 4 weeks. At Week 19, PRP therapy was combined with a powdered skin substitute to create a platelet-rich tissue graft. The combination brought dramatic results, eliminating wound tunneling and reducing the wound dimensions from 6.2 cm long x 6.7 cm wide x 2.7 cm deep to 5.0 cm long x 6.0 cm wide x 1.4 cm deep. The promising observations from this case report indicate that further study on the combining of PRP therapy and skin substitutes is necessary.     

Defining complete wound closure: Closing the gap in clinical trials and practice

We investigate how wound closure is determined in recent randomized controlled wound trials and real‐world studies, identify solutions to the current limitations of wound assessment, and propose a standard methodology to define and assess wound healing in research. We searched PubMed for randomized clinical trials using the terms “complete wound closure” and “wound healing rate” and for real‐world studies using the terms “real‐world wound healing,” “real‐world wound data,” and “wound registries” dating from March 2010 through March 2018. We selected studies that had “complete wound closure” or “healed wound” as an endpoint. Sixty‐five trial articles and 10 real‐world articles met our criteria, from which we extracted the wound type studied, definition of healed wound used, wound assessment method, the number of weeks assessed, the number of wounds, and the percent of healed wounds in the study group(s) and control group. There were 7,194 trial wounds included. The most common definition of healing used by 26 studies (40.6%) was complete/full/100% (re)epithelialization or closure without discharge, drainage/scab, and/or dressing. Fifty‐two studies (81.2%) used blinded wound assessment, and at least 10 studies (15.6%) used blinded adjudication. The real‐world studies analyzed more than 901,396 wounds. Only three studies (33.3%) defined a healed/closed wound, two of which used “complete epithelialization.” Eight studies (88.9%) did not define the wound assessment method; none indicated a blinded assessment. We support the Food and Drug Administration definition: 100% reepithelialization of the wound surface with no discernable exudate and without drainage or dressing, confirmed at two visits 2 weeks apart, and we recommend blinded adjudication for wound assessment. The widespread adoption of a standard wound healing definition and assessment method in wound care research would allow for stronger comparisons of treatment effects across studies to improve the evidence base and strengthen the treatment decision‐making process in clinical practice.     

Antimicrobial photodynamic therapy in skin wound healing: A systematic review of animal studies

Bacterial infection is a common wound complication that can significantly delay healing. Classical local therapies for infected wounds are expensive and are frequently ineffective. One alternative therapy is photodynamic therapy (PDT). We conducted a systematic review to clarify whether PDT is useful for bacteria‐infected wounds in animal models. PubMed and Medline were searched for articles on PDT in infected skin wounds in animals. The language was limited to English. Nineteen articles met the inclusion criteria. The overall study methodological quality was moderate, with a low‐moderate risk of bias. The animal models were mice and rats. The wounds were excisional, burn, and abrasion wounds. Wound size ranged from 6 mm in diameter to 1.5 × 1.5 cm². Most studies inoculated the wounds with Pseudomonas aeruginosa or methicillin‐resistant Staphylococcus aureus. Eleven and 17 studies showed that the PDT of infected wounds significantly decreased wound size and bacterial counts, respectively. Six, four, and two studies examined the effect of PDT on infected wound‐cytokine levels, wound‐healing time, and body weight, respectively. Most indicated that PDT had beneficial effects on these variables. PDT accelerated bacteria‐infected wound healing in animals by promoting wound closure and killing bacteria.     

自体富血小板血浆治疗供皮区创面延迟不愈的疗效观察

目的 探讨自体富血小板血浆(platelet-rich plasma,PRP)治疗供皮区延迟不愈创面的疗效.方法 回顾性分析自2016年10月至2019年10月三峡大学人民医院烧伤整形外科收治的7例取皮后延迟不愈创面患者的临床资料.应用PRP凝胶进行治疗后随访6～24个月,观察创面愈合时间及愈后瘢痕增生情况.结果 本组...     

The smart negative pressure (SNaP) wound care system: A case series from Singapore

The Smart Negative Pressure (SNaP) wound care system is a novel device that is single‐patient use, ultra‐portable, and light weight and does not rely on battery or need recharging. A systematic search was performed on major databases to identify relevant articles including case reports, retrospective case series, and randomised controlled trials. Ten studies were identified, showing that the SNaP wound care system is an effective tool in treating small‐sized wounds and may serve as an alternative to current electrically powered modalities. Furthermore, the system's small size and convenience leads to greater patient satisfaction and improves quality of life. Finally, we report our initial positive experiences with two cases in our institution. Although the evidence thus far has been encouraging, and patient satisfaction is higher than other wound care systems, further evidence is required to determine its superiority over current systems in terms of wound‐healing outcomes.     

Noncontact,low‐frequency ultrasound as an effective therapy against Pseudomonas aeruginosa–infected biofilm wounds

Bacterial biofilms, a critical chronic wound mediator, remain difficult to treat. Energy‐based devices may potentially improve healing, but with no evidence of efficacy against biofilms. This study evaluates noncontact, low‐frequency ultrasound (NLFU) in the treatment of biofilm‐infected wounds. Six‐millimeter dermal punch wounds in rabbit ears were inoculated with 10⁷ colony‐forming units of Pseudomonas aeruginosa or left as sterile controls. A biofilm was established in vivo using our published model. NLFU treatment was carried out every other day or every day, with contralateral ear wounds acting as internal, untreated controls. Wounds were harvested for several quantitative endpoints and scanning electron microscopy to evaluate the biofilm structure. The P. aeruginosa biofilm consistently impaired wound epithelialization and granulation. NLFU, both every other day and every day, improved healing and reduced bacterial counts relative to untreated controls (p < 0.05). Scanning electron microscopy confirmed a qualitative decrease in bacteria after both treatments. NLFU also reduced inflammatory cytokine expression (p < 0.05). Our study suggests that NLFU is an effective therapy against P. aeruginosa wound biofilm. This represents the first in vivo evidence of energy‐based modalities' impact on wound biofilm, setting the foundation for future mechanistic studies. Continued wound care technology research is essential to improving our understanding, and treatment, of biofilm‐infected chronic wounds.     

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.     

Enhanced healing of mitomycin C‐treated healing‐impaired wounds in rats with hydrosheets composed of chitin/chitosan,fucoidan, and alginate as wound dressings

To create a moist environment for rapid wound healing, a hydrosheet composed of alginate, chitin/chitosan, and fucoidan (ACF‐HS) has been developed as a functional wound dressing. The aim of this study was to evaluate the accelerating effect of ACF‐HS on wound healing for rat mitomycin C‐treated healing‐impaired wounds. Full‐thickness skin defects were made on the back of rats and mitomycin C was applied onto the wound for 10 minutes to prepare a healing‐impaired wound. After thoroughly washing out the mitomycin C, ACF‐HS was applied to the healing‐impaired wounds. The rats were later euthanized and histological sections of the wounds were prepared. The histological examinations showed significantly advanced granulation tissue and capillary formations in the healing‐impaired wounds treated with ACF‐HS on days 7 and 14, in comparison with that in alginate fiber (Kaltostat^®), hydrogel wound dressing (DuoACTIVE^®), and nontreatment (negative control). Furthermore, in cell culture studies, ACF‐HS‐absorbed serum and fibroblast growth factor‐2 was found to be proliferative for fibroblasts and endothelial cells, respectively, and ACF‐HS‐absorbed serum was found to be chemoattractive for fibroblasts. However, our results may not be strictly comparable with general healing‐impaired wound models in humans because of the cell damage by mitomycin C. In addition, more biocompatibility studies of fucoidan are essential due to the possibility of renal toxicity.     

Conservative surgical debridement as a burn treatment: Supporting evidence from a porcine burn model

In thermal deep‐dermal burns, surgical debridement is normally used in conjunction with skin grafting or skin substitutes and debridement alone as a burn treatment is not usually practiced. The current study addresses whether or not debridement alone would enhance burn wound healing on small deep‐dermal‐partial thickness burns. This was a prospective and blinded experimental trial using a porcine deep‐dermal‐partial thickness burn model. Four burns, approximately 50 cm² in size, were created on each of eight pigs. Two burns from each pig were immediately surgically debrided and the other two were not debrided as the internal control. Hydrate gel together with paraffin gauze were used to cover the burns for four pigs and silver dressings for the other four. Clinical assessment of wound healing was conducted over a 6‐week period. Skin samples were collected at the end of the experiment and histopathological evaluation was performed. The results show thinner scar formation and lower scar height in the debrided compared with nondebrided wounds in the hydrate gel/paraffin gauze groups. There were no statistically significant differences in wound healing assessment between the debrided and nondebrided wounds dressed with silver dressings. This study provides supporting evidence that immediate debridement with an appropriate dressing and without skin grafting may promote wound healing, suggesting its potential benefit for clinical patients.     

Clinical recommendations and practical guide for negative pressure wound therapy with instillation

Effective wound management involves a comprehensive assessment of the patient and the wound to determine an optimal wound treatment plan. It is critical to identify and address factors that may impair wound healing, prior to selecting the most appropriate therapy for each patient. Negative pressure wound therapy (NPWT) is a well‐established advanced therapy that has been successful in adjunctive management of acute and chronic wounds. In recent years, the introduction of topical wound solution delivery in combination with NPWT has provided further benefits to wound healing. A commercially available system now offers automated, volumetric control of instilled topical wound solutions with a dwell time in combination with NPWT (NPWTi‐d; V.A.C. VeraFlo? Therapy, KCI, an Acelity company, San Antonio, TX). This NPWTi‐d system differs from other instillation systems in that a timed, predetermined volume of topical wound solution is intermittently delivered (versus continuously fed) and allowed to dwell in the wound bed (without NPWT), for a user‐selected period of time before NPWT is resumed. This added accuracy and process simplification of solution delivery in tandem with NPWT have prompted use of NPWTi‐d as first‐line therapy in a wider subset of complex wounds. However, considerably more research is required to validate efficacy of NPWTi‐d in various wound types. The purpose of this review is to provide a relevant overview of wound healing, describe current literature supporting the adjunctive use of NPWTi‐d, propose a clinical approach for appropriate application of NPWTi‐d and conclude with case studies demonstrating successful use of NPWTi‐d. Based on this review, we conclude that either a large case series examining effects of NPWTi‐d on different wound types or possibly a large prospective registry evaluating NPWTi‐d with real‐world topical wound solutions versus immediate debridement and closure would be valuable to the medical community in evaluating the efficacy of this promising therapy.