Lower Extremity Diabetic Ulcers Research Articles

Comparative Effectiveness of Placental Allografts in the Treatment of Diabetic Lower Extremity Ulcers and Venous Leg Ulcers in U.S. Medicare Beneficiaries: A Retrospective Observational Cohort Study Using Real-World Evidence.

Objective: To compare the effectiveness of cellular tissue products (CTP) versus standard care in U.S. Medicare beneficiaries with diabetic lower extremity ulcers (DLEUs) or venous leg ulcers (VLUs). Approach: We performed a retrospective cohort study using real-world evidence from U.S. Medicare claims for DLEUs or VLUs between 2016 and 2020. There were three cohorts evaluated: viable cryopreserved placental membrane (vCPM) or viable lyopreserved placental membrane (vLPM); other CTP; and standard care. Claims were collapsed into episodes of care. Univariate and bivariate statistics were used to examine the frequency distribution of demographics and clinical variables. Multivariable zero-inflated binomial regressions were used to evaluate mortality and recurrence trends. Logistic regression compared three adverse outcomes (AOs): amputation; 1-year mortality; and wound recurrence. Results: There were 333,362 DLEU episodes among 261,101 beneficiaries, and 122,012 VLU episodes among 80,415 beneficiaries. DLEU treatment with vLPM was associated with reduced 1-year mortality (-26%), reduced recurrence (-91%), and reduced AOs (-71%). VLU treatment with vCPM or vLPM was associated with reduced 1-year mortality (-23%), reduced recurrence (-80%), and 66.77% reduction in AOs. These allografts were also associated with a 49% and 73% reduced risk of recurrence in DLEU and VLU, respectively, compared with other CTPs. Finally, vCPM or vLPM were associated with noninferior prevention of AOs related to amputation, mortality, and recurrence (95% CI: 0.69-1.14). Conclusions: DLEUs and VLUs treated with vCPM and vLPM allografts are associated with lowered 1-year mortality, wound recurrence, and AOs in DLEUs and VLUs compared with standard care. Decision makers weighing coverage of placental allografts should consider these added short- and long-term clinical benefits relative to costly management and high mortality of Medicare's most frequent wounds.

Use of Homologous Platelet Gel to Manage Refractory Diabetic Lower Extremity Ulcers: Additional Experience at a Tertiary Hospital

Background. DLEUs are a major cause of morbidity. Appropriate treatment is essential, and newer methods to achieve ulcer healing have been described, including application of PG. Objective. This study evaluated the effectiveness and safety of homologous PG in patients with chronic noninfected DLEU refractory to standard treatment as well as possible correlations between patient comorbidities and response to treatment. Materials and Methods. Data from patients with chronic refractory DLEU managed with homologous PG between January 2014 and October 2022 were evaluated (comorbidities, wound characteristics, number and time of treatment, outcome). Outcome was classified as complete response (complete ulcer healing with reepithelialization), partial response (≥50% reduction in area and/or improvement of pain), or absence of response. The chi-square test was used to compare groups, with alpha level set at less than .05. Results. A total of 81 patients (63 male, 18 female; median age, 65 years; median HbA1c, 7.6%; median ulcer area, 2.9 cm2) were proposed for PG application. A total of 62 patients had 3 or more comorbidities. Outcome was evaluated in 69 patients, with response observed in 49% (complete, 32%; partial, 17%). Worse outcomes occurred in patients with polyneuropathy (chi-square statistic: 4.183; P = .041). Conclusion. Homologous PG is a safe and possibly effective therapeutic alternative for DLEU that is unresponsive to standard therapies.

Hypertonic saline solution 5% as an effective cost-beneficial alternative to normal saline for wound healing in patients with diabetic lower-extremity ulcers: a randomized controlled trial.

Diabetic foot ulcer is among the most common complications and causes of mortality and morbidity in patients with diabetes. Herein, we propose using 5% Hypertonic Solution as an alternative to Normal Saline in treating patients with diabetic foot ulcers as an effective cost-benefit therapeutic approach. In this clinical trial, 100 patients with diabetic foot ulcers were divided into two groups. Foot ulcer was washed and treated three times a day with the 5% hypertonic saline solution in the first group, while the second group was treated with normal saline 0.9% and normal washing. Patients were examined for the size and depth of the wound weekly, and the results were recorded after six weeks. The mean length and width of the wound in the experimental group significantly decreased six weeks after the start of treatment with hypertonic saline (p < 0.05). The wound healing rate was lower after treatment in both groups of patients who had a longer disease duration and higher HbA1c. Treating diabetic foot ulcers with hypertonic saline solution may help improve wound healing. Therefore, rinsing with hypertonic saline is a cheap, safe, simple, and non-invasive treatment protocol for these patients.

Specialty specific quality measures needed to improve outcomes in wound care.

Despite the health care community's best efforts, 20% of diabetic patients who develop a diabetic foot ulcer will require some form of amputation. Those undergoing a major lower extremity amputation risk an increase in their five-year mortality rate to 56.6%, which is comparable to or higher than many forms of cancer. Given this perspective, quality measures need to be considered at each patient inflection point to drive increased compliance with best practices in order to redirect patients whose therapies fail. Medicare limited datasets (October 2015 through October 2019) retrospectively analyzed patients with diabetes receiving care for chronic lower extremity diabetic ulcers (LEDUs). The analysis demonstrated that only 21% of Medicare patients with hard-to-heal LEDUs received sharp debridement at intervals of every 7 days and less, while only 40% received sharp debridement at intervals of every 8 to 14 days. This is despite landmark prospective randomized controlled trials showing the benefits of frequent sharp debridement to patients with LEDUs. According to the Medicare data, when patients received debridement at intervals of 7 days or less with concurrently applied skin substitutes, observed amputation rates dropped by 65% to the lowest levels identified among Medicare LEDU episodes (2.1%). Optimal use of debridement and adjunctive use of skin substitutes significantly improves outcomes and lowers the use of healthcare resources. Another unexpected finding highlighted in the Medicare data analysis was that wound care providers have not been applying skin substitutes early enough. Clinical guidelines related to LEDUs have long relied on the seminal Sheehan marker study, which identified that diabetic ulcers that have not progressed to at least 53% healing after four weeks of conservative care have only a 9% chance of proceeding to closure by 12 weeks. It is therefore vital that patients move to advanced therapies within 30 to 45 days after initiation of failed conservative care; however, the Medicare claims data shows this is not happening regularly enough (average time to first skin substitute application >69 days) to benefit both the patient and the healthcare system. There is a demonstrable need for quality measures that encourage (1) frequent and adequate debridement throughout wound treatment, (2) earlier adoption of advanced treatments, such as skin substitutes, for LEDUs to align with clinical guidelines, (3) the application of skin substitutes to better align with medical evidence, which is associated with improved patient outcomes, as well as (4) expansion of best practices across all demographic and socioeconomic populations.

Deriving International Classification of Diseases, 9th and 10th revision, codes for identifying and following up patients with diabetic lower extremity ulcers.

Administrative claims data offer a rich data source for clinical research. However, its application to the study of diabetic lower extremity ulceration is lacking. Our objective was to create a widely applicable framework by which investigators might derive and refine the International Classification of Diseases, 9th and 10th revision (ICD-9 and ICD-10, respectively) codes for use in identifying diabetic, lower extremity ulceration. We created a seven-step process to derive and refine the ICD-9 and ICD-10 coding lists to identify diabetic lower extremity ulcers. This process begins by defining the research question and the initial identification of a list of ICD-9 and ICD-10 codes to define the exposures or outcomes of interest. These codes are then applied to claims data, and the rates of clinical events are examined for consistency with prior research and changes across the ICD-9 to ICD-10 transition. The ICD-9 and ICD-10 codes are then cross referenced with each other to further refine the lists. Using this method, we started with 8 ICD-9 and 43 ICD-10 codes used to identify lower extremity ulcers in patients with known diabetes and peripheral arterial disease and examined the association of ulceration with lower extremity amputation. After refinement, we had 45 ICD-9 codes and 304 ICD-10 codes. We then grouped the codes into eight clinical exposure groups and examined the rates of amputation as a rudimentary test of validity. We found that the rate of lower extremity amputation correlated with the severity of lower extremity ulceration. We identified 45 ICD-9 and 304 ICD-10 ulcer codes, which identified patients at risk of amputation from diabetes and peripheral artery disease. Although further validation at the medical record level is required, these codes can be used for claims-based risk stratification for long-term outcomes assessment in the treatment of patients at risk of limb loss.

Extracorporeal Pedicles for Free Flap Reconstruction in Diabetic Lower Extremity Wounds.

Diabetic foot ulcers are a severe complication of diabetes, and their management requires a multidisciplinary approach for optimal management. When treating these ulcers, limb salvage remains the ultimate goal. In this article, we present the "hanging" free flap for the reconstruction of chronic lower extremity diabetic ulcers. This two-staged approach involves standard free flap harvest and inset; however, following inset the "hanging" pedicle is covered within a skin graft instead of making extraneous incisions within the undisturbed soft tissues or tunnels that can compress the vessels. After incorporation, a second-stage surgery is performed in 4 to 6 weeks which entails pedicle division, flap inset revision, and end-to-end reconstruction of the recipient vessel. Besides decreasing the number of incisions on diabetic patients, our novel technique utilizing the "hanging" pedicle simplifies flap monitoring and inset and allows reconstruction of recipient vessels to reestablish distal blood flow.

Autologous wound margin point columnar full-thickness skin grafting combined with negative pressure wound therapy improves wound healing in refractory diabetic foot ulcers.

Diabetic lower extremity ulcers (DLEUs) are a severe complication of diabetes mellitus (DM) and are difficult to heal. This study aimed to explore the efficacy of autologous point columnar full-thickness skin graft taken from the ulcer wound margin combined with negative pressure wound therapy (NPWT) in refractory DLEUs. This is a prospective cohort study. A total of 40 inpatients with refractory DLEUs were recruited in the Diabetes Foot Center of Guangxi Zhuang Autonomous Region People's Hospital from October 2019 to November 2021. According to the doctors' professional suggestions and the patients' personal wishes, these enrolled patients were divided into two groups based on different topical wound management: the graft group (n=18) and the conventional wound therapeutic (CWT) group (n=22). The efficacy evaluations included the time to complete re-epithelialization of the wound and healing speed within 14 days of graft treatment or after 14 days of graft treatment in the two groups. Before the treatment, the graft group had a significantly larger ulcer area than the CWT group [27.22 (15.28, 46.59) versus 10.92 (7.00, 24.93) cm2 , P < .01]. However, the time to complete wound re-epithelialization in the graft group was shorter than in the CWT group [58.22 ± 30.60 versus 86.09 ± 49.54 d, P < .05]. Meanwhile, the healing speed in graft group was markedly faster than in CWT group, whether within 14 days [0.60 (0.40, 0.92) versus 0.16 (0.07, 0.34) cm2 /d, P < .01] or after 14 days of graft treatment [0.57 (0.45, 0.91) versus 0.13 (0.08, 0.27) cm2 /d, P < .01]. However, the total treatment cost in the graft group was lower than in the CWT group [419.59 ± 137.20 versus 663.97 ± 497.02 $, P < .05]. The novel treatment modality of autologous full-thickness skin graft taken from the ulcer wound margin combined with NPWT has hereby proposed for the first time, and is a safe, effective, and reliable method with a good performance-to-cost ratio to promote wound healing and shorten the healing time for DLEUs.

Cost-effectiveness of dehydrated human amnion/chorion membrane allografts in lower extremity diabetic ulcer treatment.

To evaluate the cost-effectiveness and budget impact of using standard care (no advanced treatment, NAT) compared with an advanced treatment (AT), dehydrated human amnion/chorion membrane (DHACM), when following parameters for use (FPFU) in treating lower extremity diabetic ulcers (LEDUs). We analysed a retrospective cohort of Medicare patients (2015-2019) to generate four propensity-matched cohorts of LEDU episodes. Outcomes for DHACM and NAT, such as amputations, and healthcare utilisation were tracked from claims codes, analysed and used to build a hybrid economic model, combining a one-year decision tree and a four-year Markov model. The budget impact was evaluated in the difference in per member per month spending following completion of the decision tree. Likewise, the cost-effectiveness was analysed before and after the Markov model at a willingness to pay (WTP) threshold of $100,000 per quality adjusted life year (QALY). The analysis was conducted from the healthcare sector perspective. There were 10,900,127 patients with a diagnosis of diabetes, of whom 1,213,614 had an LEDU. Propensity-matched Group 1 was generated from the 19,910 episodes that received AT. Only 9.2% of episodes were FPFU and DHACM was identified as the most widely used AT product among Medicare episodes. Propensity-matched Group 4 was limited by the 590 episodes that used DHACM FPFU. Episodes treated with DHACM FPFU had statistically fewer amputations and healthcare utilisation. In year one, DHACM FPFU provided an additional 0.013 QALYs, while saving $3,670 per patient. At a WTP of $100,000 per QALY, the five-year net monetary benefit was $5003. The findings of this study showed that DHACM FPFU reduced costs and improved clinical benefits compared with NAT for LEDU Medicare patients. DHACM FPFU provided better clinical outcomes than NAT by reducing major amputations, ED visits, inpatient admissions and readmissions. These clinical gains were achieved at a lower cost, in years 1-5, and were likely to be cost-effective at any WTP threshold. Adoption of best practices identified in this retrospective analysis is expected to generate clinically significant decreases in amputations and hospital utilisation while saving money.

A prospective, randomized, controlled clinical study on the effectiveness of a single‐use negative pressure wound therapy system, compared to traditional negative pressure wound therapy in the treatment of diabetic ulcers of the lower extremities

AbstractA multicenter, phase 4, randomized, comparative‐efficacy study in subjects with lower extremity wounds was carried out to compare wound closure rates, for a single‐use negative pressure wound therapy (s‐NPWT) versus traditional NPWT (t‐NPWT) systems over a 12‐week treatment period. From the initial population of patients with diabetic foot ulcers (DFU) and venous leg ulcers (VLU), we analyzed a subgroup of patients with diabetes mellitus and leg and foot ulcers (either DFUs or VLUs in diabetics), termed, the diabetic lower extremity ulcers (DLEU). In the DLEU group, there were 95 patients in intention‐to‐treat (ITT) and 61 patients in per protocol (PP) populations, respectively. We found a significant difference in favor of s‐NPWT over t‐NPWT in the confirmed wound closures at 12 weeks both in ITT (p &lt; 0.001) and PP populations (p = 0.017). Significantly higher wound closure rates in s‐NPWT group suggest that s‐NPWT should be preferred NPWT option for DLEU.

The Effectiveness and Safety of Platelet-Rich Plasma for Chronic Wounds: A Systematic Review and Meta-analysis

ObjectiveTo evaluate the effectiveness and adverse events of autologous platelet-rich plasma (PRP) in individuals with lower-extremity diabetic ulcers, lower-extremity venous ulcers, and pressure ulcers. Patients and MethodsWe searched multiple databases from database inception to June 11, 2020, for randomized controlled trials and observational studies that compared PRP to any other wound care without PRP in adults with lower-extremity diabetic ulcers, lower-extremity venous ulcers, and pressure ulcers. ResultsWe included 20 randomized controlled trials and five observational studies. Compared with management without PRP, PRP therapy significantly increased complete wound closure in lower-extremity diabetic ulcers (relative risk, 1.20; 95% CI, 1.09 to 1.32, moderate strength of evidence [SOE]), shortened time to complete wound closure, and reduced wound area and depth (low SOE). No significant changes were found in terms of wound infection, amputation, wound recurrence, or hospitalization. In patients with lower-extremity venous ulcers or pressure ulcers, the SOE was insufficient to estimate an effect on critical outcomes, such as complete wound closure or time to complete wound closure. There was no statistically significant difference in adverse events. ConclusionAutologous PRP may increase complete wound closure, shorten healing time, and reduce wound size in individuals with lower-extremity diabetic ulcers. The evidence is insufficient to estimate an effect on wound healing in individuals with lower-extremity venous ulcers or pressure ulcers. Trial RegistrationPROSPERO Identifier: CRD42020172817

Observed impact of skin substitutes in lower extremity diabetic ulcers: lessons from the Medicare Database (2015-2018).

To evaluate large propensity-matched cohorts to assess outcomes in patients receiving advanced treatment (AT) with skin substitutes for lower extremity diabetic ulcers (LEDUs) versus no AT (NAT) for the management of LEDUs. The Medicare Limited Dataset (1 October 2015 through 2 October 2018) were used to retrospectively analyse people receiving care for a LEDU treated with AT or NAT (propensity-matched Group 1). Analysis included major and minor amputations, emergency department (ED) visits and hospital readmissions. In addition, AT following parameters for use (FPFU) was compared with AT not FPFU (propensity-matched Group 2). A paired t-test was used for comparisons of the two groups. For comparisons of three groups, the Kruskal-Wallis test was used. A Bonferroni correction was performed when multiple comparisons were calculated. There were 9,738,760 patients with a diagnosis of diabetes, of whom 909,813 had a LEDU. In propensity-matched Group 1 (12,676 episodes per cohort), AT patients had statistically fewer minor amputations (p=0.0367), major amputations (p<0.0001), ED visits (p<0.0001), and readmissions (p<0.0001) compared with NAT patients. In propensity-matched Group 2 (1131 episodes per cohort), AT FPFU patients had fewer minor amputations (p=0.002) than those in the AT not FPFU group. AT for the management of LEDUs was associated with significant reductions in major and minor amputation, ED use, and hospital readmission compared with LEDUs managed with NAT. Clinics should implement AT in accordance with the highlighted parameters for use to improve outcomes and reduce costs.

Potential cost-effectiveness of using adjunctive dehydrated human amnion/chorion membrane allograft in the management of non-healing diabetic foot ulcers in the United Kingdom.

The aim of this study was to estimate the cost‐effectiveness of using dehydrated human amnion/chorion membrane (dHACM) allografts (Epifix) as an adjunct to standard care, compared with standard care alone, to manage non‐healing diabetic foot ulcers (DFUs) in secondary care in the United Kingdom, from the perspective of the National Health Service (NHS). A Markov model was constructed to simulate the management of diabetic lower extremity ulcers over a period of 1 year. The model was used to estimate the cost‐effectiveness of using adjunctive dHACM, compared with standard care alone, to treat non‐healing DFUs in the United Kingdom, in terms of the incremental cost per quality‐adjusted life year (QALY) gained at 2019/2020 prices. The study estimated that at 12 months after the start of treatment, use of adjunctive dHACM instead of standard care alone is expected to lead to a 90% increase in the probability of healing, a 34% reduction in the probability of wound infection, a 57% reduction in the probability of wound recurrence, a 6% increase in the probability of avoiding an amputation, and 8% improvement in the number of QALYs. Additionally, if £4062 is spent on dHACM allografts per ulcer, then adjunctive use of dHACM instead of standard care alone is expected to lead to an incremental cost per QALY gain of £20 000. However, if the amount spent on dHACM allografts was ≤£3250 per ulcer, the 12‐month cost of managing an ulcer treated with adjunctive dHACM would break‐even with that of DFUs treated with standard care, and it would have a 0.95 probability of being cost‐effective at the £20 000 per QALY threshold. In conclusion, within the study's limitations, and within a certain price range, adjunctive dHACM allografts afford the NHS a cost‐effective intervention for the treatment of non‐healing DFUs within secondary care among adult patients with type 1 or 2 diabetes mellitus in the United Kingdom.

Application of decellularized human reticular allograft dermal matrix promotes rapid re-epithelialization in a diabetic murine excisional wound model

Background aimsThe treatment and care of human wounds represent an enormous burden on the medical system and patients alike. Chronic or delayed healing wounds are characterized by the inability to form proper granulation tissue, followed by deficiencies in keratinocyte migration and wound re-epithelialization, leading to increased likelihood of infection and poor wound outcomes. Human reticular acellular dermal matrix (HR-ADM) is one type of tissue graft developed to enhance closure of delayed healing wounds that has demonstrated clinical utility through accelerating closure of lower extremity diabetic ulcers, but the mechanisms underlying this clinical success are not well understood. MethodsThe authors utilized a diabetic murine splinted excisional wound model to investigate the effects of HR-ADM application on wound closure. ResultsThe authors demonstrate that application of HR-ADM served as a dermal scaffold and promoted rapid re-epithelialization and keratinocyte proliferation, resulting in accelerated wound closure while minimizing granulation tissue formation. HR-ADM-applied wounds also demonstrated evidence of cellular infiltration, neovascularization and collagen remodeling by the host organism. ConclusionsThese data suggest that HR-ADM supports epidermal closure in delayed healing wounds and remodeling of the matrix into host tissue, lending further support to the clinical success of HR-ADM described in clinical reports.

Free-Flap Reconstruction for Diabetic Lower Extremity Limb Salvage

BackgroundMicrosurgical free tissue transfer is an important treatment option for nonhealing lower extremity diabetic wounds. The purpose of this study was to identify factors that affect flap survival and wound complications. MethodsA retrospective review was conducted of 806 lower extremity free-flap reconstructions performed from 1979 to 2016. A total of 33 free flaps were used for coverage of nonhealing lower-extremity diabetic ulcers. Primary outcome measures were perioperative complications and long-term wound breakdown. ResultsThe average age was 54 ± 12.3 y. 15.2% of patients were smokers, 12.1% had coronary artery disease and 12.1% had end-stage renal disease. Muscle flaps predominated (75.8%) compared to fasciocutaneous flaps (24.2%). There were 7 patients (21.2%) that underwent a revascularization procedure before (71.4%) or at the same time (28.6%) as the free flap. Immediate complications occurred in 7 flaps (21.2%) with 4 partial losses (12.1%) and 3 total flap failures (9.1%). Major wound complications occurred in 18.2% of patients. An end-to-side (E-S) anastomosis for the artery was used in 63.6% (n = 22) of flaps compared with an end-to-end (E-E) anastomosis. E-S anastomosis was associated with a significantly lower risk of wound complications compared with an arterial E-E anastomosis (0% versus 45.5%, P = 0.001). ConclusionsThe use of microvascular free flaps can be used successfully to cover lower-extremity diabetic wounds. E-E arterial anastomosis should be avoided if possible as it is associated with higher rates of wound breakdown, likely by impairing perfusion to a distal limb with an already compromised vasculature. Level of evidenceLevel III.

Comparison of Allogeneic Platelet-rich Plasma With Autologous Platelet-rich Plasma for the Treatment of Diabetic Lower Extremity Ulcers

Autologous platelet-rich plasma (au-PRP) has been widely used for the management of refractory chronic wounds. However, patients with diabetic lower extremity ulcers (DLEUs) usually have complicated clinical conditions, and the utility of au-PRP is limited. In this study, the feasibility, effectiveness, and safety of allogeneic platelet-rich plasma (al-PRP) and au-PRP were investigated and compared in the treatment of DLEUs. A total of 75 in-patients with type 2 diabetes were assigned to the al-PRP group (n = 20), au-PRP group (n = 25), and conventional wound therapeutic (CWT) group (n = 30) matched by the ankle brachial index and ulcer size from December 2015 to August 2018. Based on metabolic and nutritional regulation, infective control, and topical wound management, al-PRP, au-PRP, and CWT were administered to each group, respectively. Evaluation of treatment outcomes was determined by the parameters of wound healing and adverse reactions. The therapeutic times and average concentration of platelets were not significantly different between the au-PRP and al-PRP groups. The wound healing times of the al-PRP group (56.9 ± 29.22 d) and au-PRP group (55.6 ± 33.8 d) were significantly shorter than those of the CWT group (88.0 ± 43.4 d) (P < 0.01), but there was no significant difference between the groups with PRP treatment. Although there was no significant difference in the daily healing area among all groups (P > 0.05), the trend of the healing rate in the al-PRP group (16.77 ± 12.85 mm2), au-PRP group (14.31 ± 18.28 mm2), and CWT group (9.90 ± 8.51 mm2) gradually decreased. No obvious adverse reactions (fever, edema, pain, skin itching, rash, or other sensory abnormalities) were observed in either the au-PRP or the al-PRP groups. Both al-PRP and au-PRP could effectively and safely promote wound healing in patients with DLEUs. Alternatively, al-PRP could be used for DLEUs as an off-the-shelf solution when au-PRP is limited. Registration number of clinical trials: ChiCTR1900021317

Epidermal Growth Factor in Healing Diabetic Foot Ulcers: From Gene Expression to Tissue Healing and Systemic Biomarker Circulation.

Lower-extremity diabetic ulcers are responsible for 80% of annual worldwide nontraumatic amputations. Epidermal growth factor (EGF) reduction is one of the molecular pillars of diabetic ulcer chronicity, thus EGF administration may be considered a type of replacement therapy. Topical EGF ad-ministration to improve and speed wound healing began in 1989 on burn patients as part of an acute-healing therapy. Further clinical studies based on topically administering EGF to different chronic wounds resulted in disappointing out-comes. An analysis of the literature on unsuccessful clinical trials identifi ed a lack of knowledge concerning: (I) molecular and cellular foundations of wound chronicity and (II) the phar-macodynamic requisites governing EGF interaction with its receptor to promote cell response. Yet, EGF intra- and perile-sional infi ltration were shown to circumvent the pharmacody-namic limitations of topical application. Since the fi rst studies, the following decades of basic and clinical research on EGF therapy for problem wounds have shed light on potential uses of growth factors in regenerative medicine. EGF's molecular and biochemical effects at both local and systemic levels are diverse: (1) downregulation of genes encoding infl ammation mediators and increased expression of genes involved in cell proliferation, angiogenesis and matrix secretion; (2) EGF in-tervention positively impacts both mesenchymal and epithelial cells, reducing infl ammation and stimulating the recruitment of precursor circulating cells that promote the formation of new blood vessels; (3) at the subcellular level, upregulation of the EGF receptor with subsequent intracellular traffi cking, includ-ing mitochondrial allocation along with restored morphology of multiple organelles; and (4) local EGF infi ltration resulting in a systemic, organismal repercussion, thus contributing to attenuation of circulating infl ammatory and catabolic reac-tants, restored reduction-oxidation balance, and decreased toxic glycation products and soluble apoptogenic effectors. It is likely that EGF treatment may rearrange critical epigenetic drivers of diabetic metabolic memory. KEYWORDS Epidermal Growth Factor, diabetes, diabetes complications, wound healing, diabetic foot, amputation, ulcer, Cuba.

627-P: Efficacy and Safety of Allogeneic Platelet Rich Plasma in Treatment of Diabetic Patients with Lower Limb Ulcers: A Pilot Study

Background and Objective: To observe the feasibility, efficacy and safety of al-PRP in the treatment of diabetic lower extremity ulcers. Furthermore, to explore the difference between au-PRP treatment, al-PRP treatment and only conventional treatment groups. Methods: A total of 75 inpatients with diabetic lower limbs ulcer (DLLU) were divided into au-PRP group (n=20), al-PRP group (n=25), conventional treatment group (n=30). All three groups were administered basic diabetic treatments. In addition, the above three different treatment methods were given. The feasibility, curative effect and safety of au-PRP in the treatment of DLLU were evaluated by observing wound healing time, the average daily healing area and adverse reactions. Results: No significant differences were observed in duration of diabetes, age, glycosylated hemoglobin, ankle brachial index, transcutaneous oxygen partial pressure, high-sensitivity C-reactive protein, IL-6, etc. among three groups (P&amp;gt;0.05). There was no significant difference in ulcer area and ulcer number between the three groups (8.43±6.93 cm2 vs. 5.64±3.91 cm2 vs. 9.73±9.72 cm2, P=0.19); The times and average of PRP treatment between two PRP groups have no significant difference (P&amp;gt;0.05). In the healing time, the al-PRP group and the au-PRP group were significantly shorter than the control group (56.9±29.22 days vs. 55.6±33.8 days vs. 88.0±43.4 days, P&amp;lt;0.01), while there was no significant difference between the al-PRP group and the au-PRP group (P&amp;gt;0.05). There was no significant difference in the average daily healing area (mm2) between the three groups (P&amp;gt;0.05). No significant adverse reactions (infection, itchy skin, redness, rash, etc.) were observed in two PRP groups. Conclusions: Al-PRP can effectively and safely promote the healing of diabetic lower extremity wounds. Al-PRP could be used as a beneficial cell therapy supplement when au-PRP is limited. Disclosure W. Deng: None. M. He: None. B. Chen: None. Y. Ma: None. D. Armstrong: None. J. Boey: None. Funding Natural Science Foundation of Chongqing (81500596)

Hyperbaric Oxygen Corrects the Peri-Wound Microvascular Flow

The efficacy of hyperbaric oxygen therapy (HBOT) to facilitate wound healing in diabetic lower extremity ulcers is well established. The impact of HBOT, however, on tissue perfusion and flow is not known. The purpose of this pilot study was to ascertain the effects of HBOT on the microvasculature of chronic wounds, as assessed by fluorescent angiography.

Remote ischaemic conditioning in the context of type 2 diabetes and neuropathy: the case for repeat application as a novel therapy for lower extremity ulceration.

An emerging treatment modality for reducing damage caused by ischaemia–reperfusion injury is ischaemic conditioning. This technique induces short periods of ischaemia that have been found to protect against a more significant ischaemic insult. Remote ischaemic conditioning (RIC) can be administered more conveniently and safely, by inflation of a pneumatic blood pressure cuff to a suprasystolic pressure on a limb. Protection is then transferred to a remote organ via humoral and neural pathways. The diabetic state is particularly vulnerable to ischaemia–reperfusion injury, and ischaemia is a significant cause of many diabetic complications, including the diabetic foot. Despite this, studies utilising ischaemic conditioning and RIC in type 2 diabetes have often been disappointing. A newer strategy, repeat RIC, involves the repeated application of short periods of limb ischaemia over days or weeks. It has been demonstrated that this improves endothelial function, skin microcirculation, and modulates the systemic inflammatory response. Repeat RIC was recently shown to be beneficial for healing in lower extremity diabetic ulcers. This article summarises the mechanisms of RIC, and the impact that type 2 diabetes may have upon these, with the role of neural mechanisms in the context of diabetic neuropathy a focus. Repeat RIC may show more promise than RIC in type 2 diabetes, and its potential mechanisms and applications will also be explored. Considering the high costs, rates of chronicity and serious complications resulting from diabetic lower extremity ulceration, repeat RIC has the potential to be an effective novel advanced therapy for this condition.

IP149. Hyperbaric Oxygen Acutely Increases Wound Circulation as Assessed by Fluorescent Angiography

The efficacy of hyperbaric oxygen therapy (HBOT) to facilitate wound healing in diabetic lower extremity ulcers is well established. The exact mechanism of HBOT-mediated wound healing is unclear but is thought to relate to increased reactive oxygen species and reactive nitrogen species (ROS and RNS). ROS and RNS lead to many downstream affects that impact wound healing, including increased growth factors, diminished inflammatory responses, and improved neovascularization. The impact of HBOT, however, on tissue perfusion and flow is not known. The purpose of this pilot study was to ascertain the immediate effects of HBOT on the microvasculature of chronic wounds as assessed by fluorescent angiography.