Impaired Wound Research Articles

Single-Component Self-Healing Antibacterial Anti-Inflammatory Intracellular-Antioxidative Poly(itaconic acid-pluronic) Hydrogel for Rapid Repair of MRSA-Impaired Wound.

The rapid healing and repair of multidrug-resistant bacteria infected wound is still a challenge in the field of wound surgery. It is an effective strategy to develop multifunctional bioactive biomaterials with anti-infection therapy and promoting tissue regeneration. However, most of conventional multifunctional wound healing biomaterials possess the complicated composition and fabrication procedure, which may limit their clinical transformation. Herein, we report a single-component multifunctional bioactive self-healing scaffold (itaconic acid-pluronic-itaconic acid) (FIA) with robust antibacterial antioxidant anti-inflammatory bioactivity for treating methicillin-resistant Staphylococcus aureus (MRSA) impaired wound. FIA scaffolds exhibited the temperature-responsive sol-gel behavior, good injectability, and broad-spectrum antibacterial activity (100% inhibition rate against S. aureus, E. coli, and MRSA). FIA possessed favorable hemocompatibility and cell compatibility and even stimulated the cellular proliferation. FIA could efficiently scavenge the intracellular reactive oxygen species (ROS), decrease the inflammation factors expression, promote endotheliocyte migration and blood tube formation, and reduce the M1 phenotype of macrophages in vitro. FIA could significantly clear the MRSA infection, speed up the MRSA-infected wound healing and rapid formation of the normal epithelial layer and skin appendages. This work may provide a simple and efficient multifunctional bioactive biomaterial strategy for overcoming the challenge of the MRSA-impaired wound.

Abstract OT2-11-02: Ameera-1 Arm 4: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with everolimus in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer

Abstract Background Amcenestrant (SAR439859) is an optimized oral SERD with potent dual activity that antagonizes and degrades the ER, resulting in inhibition of the ER signaling pathway. Amcenestrant, as monotherapy or in combination with palbociclib, has shown antitumor activity and a favorable safety profile in postmenopausal women with heavily pretreated ER+/HER2- advanced breast cancer. Published data support the addition of targeted therapy to endocrine therapy for patients with ER+/HER2- advanced breast cancer. The objective of Arm 4 of the AMEERA-1 study is to evaluate safety and antitumor activity of amcenestrant in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus for patients with ER+/HER2- advanced breast cancer. Methods AMEERA-1 (NCT03284957) is an open-label, non-comparative, dose escalation and dose expansion Phase 1/2 study of amcenestrant as monotherapy, then in combination with other anti-cancer targeted therapies. Arm 4 investigates dose escalation (Part H) and dose expansion (Part I), of amcenestrant in combination with everolimus. Postmenopausal women with ER+/HER2- advanced breast cancer, ECOG performance status 0-1, and ≥ 6 months prior endocrine therapy are eligible. In Arm 4 (Parts H and I), ≤ 1 prior line of a single endocrine therapy for advanced disease is allowed. Patients must have progressed on a non-steroidal aromatase inhibitor plus cyclin-dependent kinase 4/6 inhibitor as first-line therapy for advanced disease. Prior treatment with fulvestrant or any other SERD is not allowed. Part H allows ≤ 1 prior chemotherapy for advanced disease; no prior chemotherapy for advanced disease is allowed in Part I. Exclusion criteria in Arm 4 include prior drugs targeting the phosphoinositide 3-kinase axis; history of or concurrent pneumonitis; history of severe cutaneous reactions; type 1 diabetes; uncontrolled type 2 diabetes; uncontrolled hypercholesterolemia, hypertriglyceridemia, and hyperglycemia; any uncontrolled infection; uncontrolled stomatitis, angioedema due to angiotensin-converting enzyme inhibitors, and impaired wounds. Part H evaluates the selected amcenestrant dose for combination therapy plus everolimus 10 mg once daily (QD) (the approved standard dose) or everolimus 5 mg QD, taken in 28-day cycles. Additional amcenestrant doses may be explored based on safety and pharmacokinetics (PK). The objective of Part H is to determine the recommended dose (RD) of everolimus in combination with the selected amcenestrant dose for combination therapy, based on preliminary safety, PK, and antitumor activity data. The primary endpoint in Part H is the incidence of treatment-related dose-limiting toxicities (DLTs) at Cycle 1. Approximately up to 12 DLT-evaluable patients will be needed to establish the RD of everolimus in combination with amcenestrant in Part H. In Part I, approximately 12 patients will be treated at the RD of everolimus for combination therapy with amcenestrant, the primary endpoint being safety and tolerability. Secondary endpoints include PK and antitumor activity. Funding: Sanofi. Citation Format: Mario Campone, Patrick Neven, Katarina Petrakova, Sofia Braga, Marina Celanovic, Patrick Cohen, Alice Gosselin, Sylvaine Cartot-Cotton, Vasiliki Pelekanou, Valentina Boni. Ameera-1 Arm 4: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with everolimus in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-02.

Dual Drug Loaded pH-sensitive Micelles for Efficient Bacterial Infection Treatment.

Methicillin-resistant Staphylococcus aureus (MRSA) infection at impaired wound is associated with high risks of developing to persistent bacterial infections since bacterial biofilm is easy to form in MRSA infected wounds. An advanced therapeutic approach to effectively penetrate and eliminate bacterial biofilm and to accelerate cell proliferation and migration at the wound is crucial. The poly(ε-caprolactone)-monomethoxyl poly (ethylene glycol) (PCL-mPEG) micelles loaded with Quercetin and Rifampicin (QRMs) were prepared. Bacterial biofilm proliferation and elimination effect of QRMs were evaluated with confocal laser scanning microscopy. Antibacterial assay was further performed to detect antibacterial activity and mechanism. The cell scratch assay and cellular uptake were performed in HaCaT skin epithelial cells. Our results showed that the small sized QRMs could penetrate the interior of MRSA biofilm to disperse and eradicate biofilm. Then, antibiotics are released and accumulated in the acidic biofilm environment. QRMs could kill bacteria through increasing bacterial membrane permeability and altering membrane potential and membrane fluidity. Moreover, QRMs improved intracellular and cytoplasmic delivery efficiency of drugs to epithelial cells, and in the scratch test, presented a stronger ability to promote migration and proliferation of HaCaT cells compared with free drugs. Hemolysis test further proved good biocompatibility of QRMs. QRMs could potentially be used as a novel dual-functional nanotherapeutic for anti-bacterial infection by eradicating biofilm and accelerating cells proliferation at MRSA infected wound.

Linking hospital and residential aged care: a nurse-led vascular-geriatric model of care

The interplay of frailty, multimorbidity and polypharmacy in the older person results in complex care needs. Monitoring and proactive management of chronic diseases in this context can be challenging. Early identification of deterioration reduces the risk of hospitalisation in older people, particularly in residential care, where the person can be particularly vulnerable. Deterioration of a resident often results in an expectation of in-hospital care, which especially where there are life-limiting conditions, may not align to the wishes of the person and their family. However, links between tertiary hospital services with the expertise to upskill and mentor those providing the more complex care to residents of aged care facilities need to be developed. Current models of care need to be adapted to incorporate the provision of specialist nursing within residential facilities to support higher-level care delivered in the person’s familiar environment, improve the person and family experience, and reduce the costs and potential for iatrogenic problems associated with hospitalisation. Vascular dysfunction is common in aged care and results in impaired healing and complex wounds. We developed a Vascular and Geriatric (VaG) model of care to support specialist care for aged care residents with vascular dysfunction. The VaG model enhances existing links between hospital and residential care settings and builds workforce capacity in residential care facilities by the use of clinical consultation, peer learning and networking to increase the vascular skill set initially of the hospital outreach nurse and then modelled to residential care clinicians. This paper reports the development and implementation of the VaG model as part of the Aged Care Outreach Service.

Wound healing with topical BRAF inhibitor therapy in a diabetic model suggests tissue regenerative effects.

Wound healing is a multi-step process to rapidly restore the barrier function. This process is often impaired in diabetic patients resulting in chronic wounds and amputation. We previously found that paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway via topical administration of the BRAF inhibitor vemurafenib accelerates wound healing by activating keratinocyte proliferation and reepithelialization pathways in healthy mice. Herein, we investigated whether this wound healing acceleration also occurs in impaired diabetic wounds and found that topical vemurafenib not only improves wound healing in a murine diabetic wound model but unexpectedly promotes hair follicle regeneration. Hair follicles expressing Sox-9 and K15 surrounded by CD34+ stroma were found in wounds of diabetic and non-diabetic mice, and their formation can be prevented by blocking downstream MEK signaling. Thus, topically applied BRAF inhibitors may accelerate wound healing, and promote the restoration of improved skin architecture in both normal and impaired wounds.

Antifibrotic drugs in lung transplantation and chronic lung allograft dysfunction: a review.

This review aims to provide an overview of pre-transplant antifibrotic therapy on peri-transplant outcomes and to address the possible role of antifibrotics in lung transplant recipients with chronic lung allograft dysfunction.Lung transplantation is an established treatment modality for patients with various end-stage lung diseases, of which idiopathic pulmonary fibrosis and other progressive fibrosing interstitial lung diseases are growing indications. Theoretically, widespread use of antifibrotics prior to lung transplantation may increase the risk of bronchial anastomotic complications and impaired wound healing.Long-term graft and patient survival are still hampered by development of chronic lung allograft dysfunction, on which antifibrotics may have a beneficial impact.Antifibrotics until the moment of lung transplantation proved to be safe, without increasing peri-transplant complications. Currently, best practice is to continue antifibrotics until time of transplantation. In a large multicentre randomised trial, pirfenidone did not appear to have a beneficial effect on lung function decline in established bronchiolitis obliterans syndrome. The results of antifibrotic therapy in restrictive allograft syndrome are eagerly awaited, but nonrandomised data from small case reports/series are promising.

23 Nutritional Intake and Weight Change in Severely Burned Patients

Abstract Introduction Nutrition is crucial for recovery from burn injuries, as severe weight (wt.) loss can lead to impaired immunity and wound healing, infections, skin graft failure, and mortality. Previous studies recommended avoiding more than 10% wt. loss, as this level resulted in increased infection rates. However, wt. loss is often not quantifiable during the critical illness phase, with severe edema masking non-fluid related body wt. changes. Energy (kcal) deficits can be used to estimate wt. loss until the edema has resolved, but previous studies in non-burn patients indicate that actual wt. loss is less than the commonly used 3500 kcal per pound of fat (7700 kcal per kg of fat). The objective of this performance improvement project was to evaluate nutritional intake and the resulting dry wt. change in severely burned patients. Methods This performance improvement project was approved by our regulatory compliance division. We performed a retrospective evaluation on patients with at least 20% total body surface area (TBSA) burns admitted for initial burn care to our intensive care unit over a 7-year period. Patients who died or who had major fascial excisions or limb amputations were excluded. Patients who did not achieve a recorded dry wt. after wound healing were not included in this analysis. Retrospective data were collected, including sex, age, burn size, kcal intake, kcal goal per the Milner equation using activity factor of 1.4, admission dry wt., dry wt. after wound healing (defined as less than 10% TBSA open wound), and days to dry wt. after wound healing. Descriptive statistics and linear regression were performed using JMP. Significance was set at p< 0.05. Results The 30 included patients had the following characteristics: 90% male, 30 ± 11 years old, 45% ± 15% TBSA burn. They received 2720 ± 1092 kcal/day, meeting 68% ± 24% kcal goal, and took approximately 53 ± 30 days from injury to achieve dry wt. after wound healing. These patients had wt. loss of 8 ± 8 kg from the kcal deficit of 69,819 ± 51,704 during this time period. The kcal deficit was significantly associated with wt. change [p < 0.001, R2 = 0.49, wt. change in kg = (-0.000103 x kcal deficit) – 1]. This translates to one kg of body wt. loss resulting from 9709 kcal deficit. Conclusions This performance improvement project found that an energy deficit of approximately 9700 kcal in our patients equates to 1 kg of body mass loss (4400 kcal deficit equates to 1 pound of body mass loss). These findings are similar to wt. loss studies in other patient populations and contrary to the commonly used 3500 kcal per pound of fat (7700 kcal per kg of fat).

Effect of NIR Laser Therapy by MLS-MiS Source on Fibroblast Activation by Inflammatory Cytokines in Relation to Wound Healing.

The fine control of inflammation following injury avoids fibrotic scars or impaired wounds. Due to side effects by anti-inflammatory drugs, the research is continuously active to define alternative therapies. Among them, physical countermeasures such as photobiomodulation therapy (PBMT) are considered effective and safe. To study the cellular and molecular events associated with the anti-inflammatory activity of PBMT by a dual-wavelength NIR laser source, human dermal fibroblasts were exposed to a mix of inflammatory cytokines (IL-1β and TNF-α) followed by laser treatment once a day for three days. Inducible inflammatory key enzymatic pathways, as iNOS and COX-2/mPGES-1/PGE2, were upregulated by the cytokine mix while PBMT reverted their levels and activities. The same behavior was observed with the proangiogenic factor vascular endothelial growth factor (VEGF), involved in neovascularization of granulation tissue. From a molecular point of view, PBMT retained NF-kB cytoplasmatic localization. According to a change in cell morphology, differences in expression and distribution of fundamental cytoskeletal proteins were observed following treatments. Tubulin, F-actin, and α-SMA changed their organization upon cytokine stimulation, while PBMT reestablished the basal localization. Cytoskeletal rearrangements occurring after inflammatory stimuli were correlated with reorganization of membrane α5β1 and fibronectin network as well as with their upregulation, while PBMT induced significant downregulation. Similar changes were observed for collagen I and the gelatinolytic enzyme MMP-1. In conclusion, the present study demonstrates that the proposed NIR laser therapy is effective in controlling fibroblast activation induced by IL-1β and TNF-α, likely responsible for a deleterious effect of persistent inflammation.

Vitamina E e Nanopartículas Lipídicas Sólidas (NLSs): parceiras na cicatrização da ferida diabética.

O pé diabético acomete de 4 a 10% dos pacientes diabéticos por ano, e apresenta um alto índice de amputação e mortalidade (39-80%). O diabetes mellius (DM) está dentre as doenças crônicas que aumentam a geração das espécies moleculares reativas de oxigênio (EROs) pela oxidação da glicose. O uso de antioxidantes associados a nanocarreadores lipídicos é uma ferramenta promissora no tratamento da cicatrização diabética deficiente. O objetivo dessa mini-review é apresentar o mecanismo fisiopatológico e como a vitamina E atua na prevenção e tratamento da ferida diabética, assim como os nanocarreadores lipídicos sólidos (NLS) associados a vitamina E podem auxiliar acelerando o processo de cicatrização deficiente da ferida diabética.

Menopause and the Skin: Old Favorites and New Innovations in Cosmeceuticals for Estrogen-Deficient Skin.

Estrogen is a pivotal signaling molecule; its production is regulated by the expression of the aromatase (CYP19A1) gene from ovarian and peripheral tissue sites, and it is transmitted via estrogen receptors to influence many important biological functions. However, the narrative for this overview focuses on the decline of 17β-estradiol levels from ovarian sites after menopause. This estrogen-deficient condition is associated with a dramatic reduction in skin health and wellness by negatively impacting dermal cellular and homeostatic mechanisms, as well as other important biological functions. The changes include loss of collagen, elastin, fibroblast function, vascularity, and increased matrix metalloproteinase(s) enzymatic activities, resulting in cellular and extracellular degradation that leads to dryness, wrinkles, atrophy, impaired wound healing/barrier function, decreased antioxidant capacity [i.e., defense against reactive oxygen species (ROS) and oxidative stress], decreased attractiveness and psychological health, and increased perception of aging. While topical estrogen may reverse these changes, the effects of today’s low-dose systemic hormone treatments are not well established, raising the need for more concentrated local administration of hormones or newer cosmeceutical agents such as selective estrogen receptor modulators (SERMs), including phytoestrogens that have become major active ingredients for skin care products, especially when addressing estrogen-deficient skin. Two example compounds are presented, an analog of resveratrol (i.e., 4′-acetoxy resveratrol) and the isoflavonoid equol, both of which are involved in a variety of biochemical/molecular actions and mechanisms, as demonstrated via in vitro and clinical studies that enhance human dermal health, especially in estrogen-deficient skin.

Three dimensional spongy fibroin scaffolds containing keratin/vanillin particles as an antibacterial skin tissue engineering scaffold

Despite major progress in the field of skin tissue engineering and wound care products, reconstruction of skin defects still represents a significant challenge associated with impaired healing and wound infection. In the present study, a novel antibacterial 3 D spongy fibroin-based skin tissue engineering scaffold incorporated with vanillin-loaded keratin particles was fabricated through a freeze-drying process. The obtained scaffolds offered a well-connected porous structure with a pore size of higher than 100 nm, a high water uptake capacity (>700%) and slow in vitro degradation over 60 days, and drug release profile indicated a prolonged vanillin release up to 14 days from the scaffolds. Furthermore, anti-bacterial and in vitro cell experiments demonstrated a bactericidal activity by incorporating vanillin into the scaffolds, besides excellent cell attachment and cytocompatibility at lower vanillin concentrations (1, 5 and 10 mM, FKV1, FKV5 and FKV10, respectively); however, a significant cytotoxicity was observed at elevated vanillin concentration (20 mM, FKV20). Hence, these findings indicate that local delivery of incorporated vanillin within fibroin-based scaffolds presents promising potential for improving anti-bacterial biomaterials for skin tissue engineering.

Experimental models and methods for cutaneous wound healing assessment.

Wound healing studies are intricate, mainly because of the multifaceted nature of the wound environment and the complexity of the healing process, which integrates a variety of cells and repair phases, including inflammation, proliferation, reepithelialization and remodelling. There are a variety of possible preclinical models, such as in mice, rabbits and pigs, which can be used to mimic acute or impaired for example, diabetic and nutrition-related wounds. These can be induced by many different techniques, with excision or incision being the most common. After determining a suitable model for a study, investigators need to select appropriate and reproducible methods that will allow the monitoring of the wound progression over time. The assessment can be performed by non-invasive protocols such as wound tracing, photographic documentation (including image analysis), biophysical techniques and/or by invasive protocols that will require wound biopsies. In this article, we provide an overview of some of the most often needed and used: (a) preclinical/animal models including incisional, excisional, burn and impaired wounds; (b) methods to evaluate the healing progression such as wound healing rate, wound analysis by image, biophysical assessment, histopathological, immunological and biochemical assays. The aim is to help researchers during the design and execution of their wound healing studies.

P141 GREEN TEA POLYPHENOL EPIGALLOCATECHIN-3-GALLATE DIFFERENTIALLY MODULATES ENDOPLASMIC RETICULUM STRESS-MEDIATED WOUND HEALING PROCESS IN SUBEPITHELIAL MYOFIBROBLASTS

Abstract Epigallocatechin-3-gallate (EGCG) has multifaceted roles in the preclinical treatment of diseases including liver and lung fibrosis. EGCG has also been tested with fewer reported side effects than therapeutic drugs. Previously we showed that increase in endoplasmic reticulum (ER) stress response in subepithelial myofibroblasts (SEMF) contributes to activation of TGF-β1 and resultant intestinal fibrosis in patients with fibrostenotic Crohn’s disease. Moreover, different migratory potential of myofibroblasts isolated from inflamed, fibrostenotic, or fistulized Crohn’s disease mucosa could be an explanation for impaired or excess wound healing and subsequently for fistula or fibrosis in patients with Crohn’s disease. To investigate the effect of EGCG on ER stress-mediated wound healing process, SEMF were isolated from normal ileum and affected ileum in the same patient with Crohn’s disease. Cells were cultured and treated with EGCG (10 μg/ml), AG1024 (a tyrosine kinase inhibitor, 6 μM), U1026 (an ERK inhibitor, 6 μM), LY294002 (a PI3K inhibitor, 10 μM), SB202190 (a p38 inhibitor, 50 nM), 4-PBA (a chemical chaperone, 10 μg/ml), and MG132 (a NF-KB inhibitor, 3 μM) for 2 hours in serum free medium. Cell lysates were obtained for Western blot analysis. An ER stress agonist tunicamycin (5 μg/ml) was incubated with SEMF for different time points. Wound healing assay was used in a cell monolayer, capturing the images at the beginning and at regular intervals during cell migration to close the wound, and comparing the images to quantify the migratory potential of the cells. In vivo effect of EGCG was tested in a murine TNBS colitis model and observed by Storz Coloview standard operating procedures. Here we showed that EGCG further decreased endogenous GRP78 protein expression by 18∼29±1.5% in SEMF compared to that treated with different inhibitors targeting other non-ER stress signals. EGCG prevented tunicamycin-induced migratory potential of SEMF isolated from normal ileum by 40±2.5%, 65±3.3% after 48 and 72 hours, as well as cell proliferation by 85±3.3%, 120±6.1% after 48 and 72 hours, respectively. Moreover, EGCG also further decreased cell migratory potential of SEMF isolated from affected ileum by 15±1.2% and 50±1.8% compared to the control group after 48 and 72 hours, respectively. Coloview showed that EGCG decreased inflammatory activity in the mice colon compared to TNBS colitis group after 8-week treatment. Ongoing study includes methylene blue staining of the colonic mucosa during endoscopy, endoscopic scoring of inflammation activity, and trichrome staining of collagen production in a colonic biopsy. Taken together, EGCG alleviates ER Stress response, leads to greater inhibition of migratory potential of SEMF, and decreases TGF-β1 and collagen productions, which is the major molecular feature of fibrosis.

Silk fibroin nanofibrous mats for visible sensing of oxidative stress in cutaneous wounds.

Wound healing is of major clinical concern and is constantly being explored for early restoration and enhanced recovery. While the etiology of the wound healing is multifactorial, high inflammation and increased oxidative stress which results in chronic inflammation, endothelial dysfunction and collagen degradation, delay the overall healing process. Thus, visual sensing of the oxidative stress would be highly informative in the successful implementation of wound healing therapies based on specific requirements. In this study, electrospinning was used to fabricate silk fibroin nanofibrous mats infused with Amplex red capable of detecting hydrogen peroxide, a reactive oxygen molecule. These mats produced a visible change in color with the limit of detection at 1 μM H2O2 concentration. In vivo studies carried out in diabetic mice with impaired wounds also displayed a visible change in color of the mats infused with Amplex red within 24 hours. These electrospun silk fibroin nanofibrous Amplex infused mats has the potential to enable a futuristic platform where decisions can be made for enhanced wound healing therapy.

RISK FACTORS FOR DIABETIC FOOT AND LOWER LIMB AMPUTATION

Introduction: Diabetic foot syndrome (DFS) is the major cause of hospitalization for diabetes-related complications. Protective sensation loss and impaired vision increase the susceptibility for minor feet trauma, which results in diabetic foot ulceration with or without subsequent infection. Peripheral arterial disease is a major cause of impaired ulcer, wound healing and gangrenous diabetic foot. The most important intervention to prevent diabetic foot ulceration and its consequences is early recognition of high-risk patients and their risk factors and referral to appropriate medical departments. There are various risk factors for major lower extremity amputations related to diabetic foot, which includes microvascular diseases, infections, long duration of diabetes, poor glycemic control, peripheral arterial disease, old age and associated cardiovascular comorbidities.
 Material and Methods: This study was done on the review of medical records of consecutive type 2 diabetic patients. Admitted patients were treated and managed according to the standard protocol of the hospital. History, clinical and physical examination were carried out on each patient. Ulcer characteristics like infection and depth of the ulcer, site of ulcer were assessed. Associated diabetic neuropathy and peripheral arterial disease was assessed by a clinical method. Age, sex, body mass index (BMI), smoking, duration of diabetes, diabetic control therapy, associated hypertension, cardiac diseases were recorded. The glycated haemoglobin level (HbA1c) were recorded.
 Results: A total of 128 patients with diabetic foot were included in the study of which 76(59.4%) were male and 52(40.6%) were female. Of the 76 male 6 (4.7%) had major amputation and out of 52 female 4(3.1%) had major amputation, thus total number of major amputations were 10(7.8%). Statistically significant difference was observed in HbA1C and duration of diabetes group in amputation. High HbA1C and more duration of diabetes was associated with the higher number of amputation. The rate of amputation was much higher among patients hypertension, smoking, cardiac diseases and stroke. Conclusion: Poor glycemic controls and duration of diabetes are the important independent risk factors for diabetes-related major lower extremity amputations.
 Keywords: DFS, BMI, smkoing, DM

Controlled Type -II Diabetes Mellitus - No More Contra-Indication for Delayed Loading of Two Piece Dental Implants - A Case Report

With changing lifestyle and increasing obesity, prevalence of type -II Diabetes Mellitus is increasing in geriatric individuals, who are generally prone to tooth loss. As a result the demand for implants in these patients is also increasing and planning implants has been a challenge to present day dentists. Diabetes Mellitus causes impaired metabolism in general, especially bone metabolism resulting in impaired Osseointegration and poor wound healing. Growing demand of implants in Type II DM patients has initiated research towards implants survival rates. Extensive research till now states - poorly controlled diabetic patients have higher implant failure rates, where as Diabetic patients with controlled blood glucose levels respond to implants in similar way as healthy patients. The present article is one such trail to confirm that type II Diabetes Mellitus is no more contra-indication for Implants till Blood glucose levels are controlled to normal levels. Key words: Type-II Diabetes Mellitus; Two-piece implant; Delayed loading;

Wound healing complications with lenvatinib identified in a pharmacovigilance database.

The U.S. Food and Drug Administration (FDA) has approved several vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, including lenvatinib, for thyroid and renal malignancies. Inhibition of the VEGFR signaling pathway impairs angiogenesis and can disrupt wound healing. The objective of this work was to evaluate wound healing complications as a potential safety risk for patients treated with lenvatinib. We searched the FDA Adverse Event Reporting System (FAERS) database for postmarketing reports of wound healing complications with lenvatinib between 13 February 2015 (FDA approval date) and 15 February 2017. The search identified nine FAERS cases of lenvatinib-associated wound healing complications that were not previously reported in the medical literature. Seven cases involved postoperative wound healing complications, such as impaired healing or wound dehiscence. In our case series, the reported time to identification of delayed wound healing from tissue injury or surgery varied over a wide range (4-58 days). The time of initial lenvatinib exposure relative to the tissue injury was also highly varied in our series, which may have influenced the development and detection of impaired healing. FAERS case-level evidence suggests that lenvatinib may have contributed to wound healing complications based on temporality and biologic plausibility. Healthcare professionals should be aware of this safety risk to facilitate prompt recognition and risk mitigation.

Clinical value of adipose tissue-derived stem cells application in healing of experimental diabetic and nondiabetic burn

Objectives: The mechanisms underlying delayed healing in diabetes are not completely understood and biomarkers to identify and to treat such pathways are needed. The aim of the present study is to assess the clinical effect of adipose tissue-derived stem cells in accelerating third-degree burns healing in diabetic and normal mouse model and to restore skin integrity. Assessment of healing by Serpin B3 and keratinocyte growth factor-1 (KGF-1) as novel biomarkers and possible molecular targets of impaired diabetic wound healing. Materials and methods: Forty male mice were set up as an experimental model for third-degree burn. They were randomly divided into four groups as follows: the control group, the diabetic (received high-fat diet) burnt group, the diabetic burnt group treated with adipose tissue-derived stem cells, and the nondiabetic burnt group treated with adipose tissue-derived stem cells. The rate of burn healing, the degree of angiogenesis, and collagen formation were evaluated by histological examination, Serpin B3 (enzyme-linked immunosorbent assay), and KGF-1 measured by real-time polymerase chain reaction. They were sacrificed after the 3rd week for tissue sampling. Results: Adipose tissue-derived stem cells accelerate the healing of experimental burns. Serpin B3 was upregulated in adipose tissue-derived stem cells treated burns associated with denser collagen deposition, angiogenesis, and increased expression of KGF-1. Hair growth occurred in adipose tissue-derived stem cells-treated groups but not in the untreated groups. Conclusion: Adipose tissue-derived stem cells represent an effective treatment for burn healing especially in resistant diabetic burns. High Serpin B3 and KGF-1 were found to be valuable biomarkers of successful healing in diabetic burns.

Relationship Between Hemoglobin A1c Value and Bone Healing in Diabetic Ankle Fractures Treated Operatively versus Non-operatively

Category: Ankle Introduction/Purpose: Diabetic ankle fractures create unique challenges to fracture management, such as impaired wound / bone healing and increased infection rate. There is inconclusive evidence regarding a specific hemoglobin A1c (A1c) value or glucose level at which the risk of adverse outcomes increases. The aim of this study was to evaluate the A1c level at which the rate of nonunion and other major complications significantly increased in diabetic ankle fractures treated operatively (Op) and non-operatively (Nonop). Methods: This is a retrospective cohort study of diabetic ankle fractures treated Op or NonOp with at least 3 months follow up and a hemoglobin A1c value within 90 days of injury. A query of electronic medical records was performed to identify all patients 18 years of age or older with a diagnosis of diabetes and who underwent Op or NonOp management as the initial treatment of an ankle fracture between January 1, 2004 and December 31, 2014 within a single health system. Union was defined as callus formation at 3 of 4 cortices on radiographs, while nonunion was defined as lack of fracture healing at 6 months based on radiographs of the injured ankle. Multivariable logistic regression analysis was performed to explore demographic, injury-related, and management-related risk factors that influence nonunion and major complications. Results: A total of 243 ankle fractures (130 Op, 113 NonOp) were identified. Nine patients in the NonOp group failed nonoperative management and required surgical fixation. There were 51 patients that developed nonunion/malunions (19 Op, 32 NonOp). Patients with diabetic neuropathy or nephropathy had significantly higher risk of nonunion. In both groups, length of immobilization greater than 12 weeks was a significant predictor of nonunion. There was no A1c level nor preinjury glucose level at which there was significantly increased rate of nonunion or deep infections in either treatment group. However, A1c was a predictor of wound complications at 3 months postoperative in the Op group with an odds ratio of 1.26. There was no significant difference in wound complications at 3 months between treatment groups. Conclusion: While no specific A1c value or glucose level demonstrated a significant rise in fracture nonunion, this study found that diabetic neuropathy and diabetic nephropathy play a significant role in fracture healing. However, hemoglobin A1c was found to be a predictor of wound complications at 3 months postoperative. Additionally, the data suggested a longer duration of immobilization may negatively impact fracture union. These results highlight the complexity of treating diabetic ankle fractures and suggest prolonged immobilization may not be beneficial for this subpopulation.

Abstract 265: Oral Nitrite Supplementation Improves Rates of Wound Healing in Diabetic Mice

Introduction: Nitric oxide (NO) is required for cutaneous wound healing. Impaired diabetic wound healing has been linked to a deficiency in local NO production and can be enhanced with NO delivery. NO is a short-lived, highly reactive molecule and local delivery is complicated by these properties. An alternate source of NO can be achieved through the ability of nitrite reductases to convert the stable NO end-product, nitrite, back to NO. We have previously demonstrated that skin and wound edge express high levels of xanthine oxidoreductase (XOR). XOR is a strong nitrite reductase. We hypothesize that dietary nitrite supplementation will improve wound healing in diabetic mice. Methods: Db/db mice (N>8/group) were pretreated for 1 week with sodium nitrite supplemented drinking water (50 mg/L), nitrite-free chow, or standard chow. Additionally, nitrite supplemented mice were gavaged with nitrite supplemented water (0.2 ml) every other day for the duration of the experiment. A 1 cm 2 excisional wound was created on the back of each mouse. Wounds were photographed every other day until closure and wound areas calculated with ImageJ and compared with ANOVA and Kaplan Meier. Results: Time to complete healing was significantly different between nitrite supplemented (NS), nitrite depleted (ND), and control mice (18.9±0.7, 21.6±3.3, and 23±3.5 days, respectively, P = 0.035). NS mice reached 75% and 100% healed faster than ND or control mice (P = .009 and P = .042, respectively) [Figure]. Initial wound expansion on day 2 was decreased in NS mice compared to ND mice. XOR activity was increased in wounds compared to skin but similar between all treatment groups. Conclusion: Nitric oxide is a critical component of wound healing. Oral systemic nitrite supplementation improves diabetic wound healing in mice. Dietary nitrite may be an inexpensive and safe method of augmenting NO production through wound XOR expression to improve wound repair.