There have been clinical observations indicating that wound healing could be affected in patients undergoing systemic isotretinoin treatment. However, the precise role of retinoids in wound healing is still unclear and controversial. It is generally assumed that systemic retinoids could be harmful to wound healing, but this requires further investigation.

Sprague-Dawley rats were gavaged with 2 mg/Kg/day of Isotretinoin and divided into three groups: Control, Isotretinoin/1month and Isotretinoin/2month. Photographic documentation and histomorphometric investigation were performed. The mRNA expressions of IL-6, MCP-1, VEGF, ICAM1, L-Selectin, TGF-1β, IL-10, IL-1α, and IL-8 were examined by qRT-PCR.

There was no significant impact on the rate of wound closure in Isotretinoin/1month group. However, a two-month regimen accelerated the wound-healing process. RT-PCR results revealed increased expression of IL-6, IL-8, IL-1α, TGF-β1, IL-10 MCP-1, ICAM1, L-Selectin, and VEGF rats that were administered Isotretinoin. Histological observations showed an increased number of mast cells in the wound areas of rats treated with Isotretinoin.

Our research indicated that taking Isotretinoin did not slow down wound healing and may even help the growth phase. Additionally, we did not observe any keloid formation during our histopathological analysis, suggesting that it may not be necessary to postpone invasive surgical procedures for six months after Isotretinoin therapy.

Chronic wounds present a substantial healthcare obstacle, marked by an extended healing period that can persist for weeks, months, or even years. Typically, they do not progress through the usual phases of healing, which include hemostasis, inflammation, proliferation, and remodeling, within the expected timeframe. Therefore, to address the socioeconomic burden in taking care of chronic wounds, hydrogel-based therapeutic materials have been proposed. Hydrogels are hydrophilic polymer networks with a 3D structure which allows them to become skin substitutes for chronic wounds. Knowing that peptides are abundant in the human body and possess distinct biological functionality, activity, and selectivity, their adaptability as peptide-based hydrogels to individual therapeutic requirements has made them a significant potential biomaterial for the treatment of chronic wounds. Peptide-based hydrogels possess excellent physicochemical and mechanical characteristics such as biodegradability and swelling, and suitable rheological properties as well great biocompatibility. Moreover, they interact with cells, promoting adhesion, migration, and proliferation. These characteristics and cellular interactions have driven peptide-based hydrogels to be applied in chronic wound healing.

Diabetic foot infections (DFIs) are a significant complication in diabetes mellitus, leading to increased morbidity, hospitalizations, and healthcare burdens. The growing prevalence of antibiotic-resistant pathogens has reduced the efficacy of conventional treatments, highlighting the need for alternative therapeutic strategies. Natural products, known for their antimicrobial, anti-inflammatory, and wound-healing properties, have garnered attention as potential treatments for DFIs. This review examines key natural compounds, including eugenol, thymol, carvacrol, curcumin, and Aloe vera, and their mechanisms of action in combating diabetic infections. We analyze the antimicrobial efficacy of these compounds, their ability to inhibit biofilm formation, and their role in wound healing. The review also explores challenges in integrating natural products into clinical practice and the potential for their use alongside or in place of traditional antibiotic therapies. Our findings suggest that natural products could play a crucial role in developing sustainable and effective treatment strategies for DFIs, especially in the face of rising antimicrobial resistance.

A diabetic wound exemplifies the challenge of chronic, nonhealing wounds. Elevated blood sugar levels in diabetes profoundly disrupt macrophage function, impairing crucial activities such as phagocytosis, immune response, cell migration, and blood vessel formation, all essential for effective wound healing. Moreover, the persistent presence of pro-inflammatory cytokines and reactive oxygen species, coupled with a decrease in anti-inflammatory factors, exacerbates the delay in wound healing associated with diabetes. This review emphasizes the dysfunctional inflammatory responses underlying diabetic wounds and explores preclinical studies of inflammation-modulating bioactives and biomaterials that show promise in expediting diabetic wound healing. Additionally, this review provides an overview of selected clinical studies employing biomaterials and bioactive molecules, shedding light on the gap between extensive preclinical research and limited clinical studies in this field.

Wound management spans various techniques and materials tailored to address acute and chronic non-healing wounds, with the primary objective of achieving successful wound closure. Chronic wounds pose additional challenges, often necessitating dressings to prepare the wound bed for subsequent surgical procedures like skin grafting. Ideal dressing materials should not only expedite wound healing but also mitigate protein, electrolyte, and fluid loss while minimizing pain and infection risk. Nanotechnology has emerged as a transformative tool in wound care, revolutionizing the landscape of biomedical dressings. Its application offers remarkable efficacy in accelerating wound healing and combating bacterial infections, representing a significant advancement in wound care practices. Integration of nanotechnology into dressings has resulted in enhanced properties, including improved mechanical strength and controlled drug release, facilitating tailored therapeutic interventions. This review article comprehensively explores recent breakthroughs in wound healing therapies, with a focus on innovative medical dressings such as nano-enzymes. Additionally, the utilization of smart materials, like hydrogels and electroactive polymers, in wound dressings offers dynamic functionalities to promote tissue regeneration. Emerging concepts such as bio-fabrication, microfluidic systems, bio-responsive scaffolds, and personalized therapeutics show promise in expediting wound healing and minimizing scarring. Through an in-depth exploration of these advancements, this review aims to catalyze a paradigm shift in wound care strategies, promoting a patient-centric approach to therapeutic interventions.

Neutrophil/lymphocyte ratio (NLR) and platelet/ lymphocyte ratio (PLR) are readily available and inexpensive biomarkers that have received great attention for diagnosing type 2 diabetes(T2DM) complications. The objective of the present cross-sectional study was to compare diagnostic values of these biomarkers with C-reactive protein(CRP) in detecting diabetic foot ulcer (DFU) and osteomyelitis (OS) and discriminating between the degree of DFU according to Wagner's classification.

A total of 217 individuals (42 healthy controls, 40 T2DM patients without DFU, and 135 patients with DFU) were enrolled. The DFU patients were classified according to Wagner's classification into grade 1, grade 2, and grade 3. Blood samples were obtained and various biochemical and hematological parameters including creatine, CRP, HbA1c, NLR, and PLR were measured.

The levels of CRP, PLR, and NLR were significantly higher in the patients with DFU and OS compared to healthy controls and T2DM patients without DFU. The median values of CRP were correlated with the severity of DFU and increased with DFU grades. The highest values of CRP, NLR, and PLR were observed in the DFU patients with OS which were significantly higher than those of DFU patients with grades 1 and 2 as well as T2DM patients without DFU. The PLR and NLR had no significant performance in diagnosing DFU patients with grades 1 and 2 from the patients without DFU.

NLR and PLR could be useful for diagnosing OS but cannot be used for detecting lower grades of DFU. CRP showed higher performance in detecting OS compared to PLR and NLR.

The online version contains supplementary material available at 10.1007/s40200-023-01327-w.

The wound-healing process in diabetic foot is affected by pro and anti-inflammatory markers, and any disruption in the inflammatory reaction interferes with tissue homeostasis, leading to chronic non-wound healing.

This study aimed to determine the diagnostic value and effect of CRP, IL-6, TNF, and HbA1c on initiation the and progression of diabetic foot ulcers.

ELISA was used to quantify IL-6, TNF, CRP, and HbA1c in 205 patients with diabetes, and 105 were diabetic foot free. The prevalence and progression of diabetic foot were also evaluated. The area under the curve (AUC) was calculated using the receiver operating characteristic (ROC) curve to analyze the predictive values. Forward stepwise logistic regression analysis was used to compute the odds ratio (OR) and the corresponding 95% confidence intervals (CIs).

CRP, IL-6, and FBS were found to be significant predictors of diabetic foot (OR=1.717, 95% CI=1.250-2.358, P=0.001; OR=1.434, 95% CI=1.142-1.802, P=0.002; and OR=1.040, 95% CI=1.002-1.080, P=0.037), respectively. The AUCs for CRP, IL-6, and HbA1c in predicting diabetic foot were 0.839, 0.728, and 0.834, respectively, demonstrating a good predictive value for each diagnostic marker.

The current study demonstrated that IL-6, CRP, and HbA1c may be useful biomarkers to indicate diabetic foot progression. Furthermore, our findings showed a substantial relationship between CRP and HbA1c in individuals with diabetic foot conditions.

Growth factor (GF) mimicry involves recapitulating the signaling of larger molecules or cells. Although GF mimicry holds considerable promise in tissue engineering and drug design applications, difficulties in targeting the signaling molecule to the site of delivery and dissociation of mimicking peptides from their target receptors continue to limit its clinical application. To address these challenges, we utilized a self-assembling peptide (SAP) platform to generate synthetic insulin-like growth factor (IGF)-signaling, self-assembling GFs. Our peptide hydrogels are biocompatible and bind target IGF receptors in a dose-dependent fashion, activate proangiogenic signaling, and facilitate formation of angiogenic microtubules in vitro. Furthermore, infiltrated hydrogels are stable for weeks to months. We conclude that the enhanced targeting and long-term stability of our SAP/GF mimicry implants may improve the efficacy and safety of future GF mimic therapeutics.

Over the past years, the development of innovative smart wound dressings is revolutionizing wound care management and research. Specifically, in the treatment of diabetic foot wounds, three-dimensional (3D) bioprinted patches may enable personalized medicine therapies. In the present work, a methacrylated hyaluronic acid (MeHA) bioink is employed to manufacture 3D printed patches to deliver small extracellular vesicles (sEVs) obtained from human mesenchymal stem cells (MSC-sEVs). The production of sEVs is maximized culturing MSCs in bioreactor. A series of in vitro analyses are carried out to demonstrate the influence of MSC-sEVs on functions of dermal fibroblasts and endothelial cells, which are the primary functional cells in skin repair process. Results demonstrate that both cell populations are able to internalize MSC-sEVs and that the exposure to sEVs stimulates proliferation and migration. In vivo experiments in a well-established diabetic mouse model of pressure ulcer confirm the regenerative properties of MSC-sEVs. The MeHA patch enhances the effectiveness of sEVs by enabling controlled release of MSC-sEVs over 7 days, which improve wound epithelialization, angiogenesis and innervation. The overall findings highlight that MSC-sEVs loading in 3D printed biomaterials represents a powerful technique, which can improve the translational potential of parental stem cell in terms of regulatory and economic impact.

Impaired wound healing is a common complication for diabetic patients and effective diabetic wound management remains a clinical challenge. Furthermore, a significant problem that contributes to patient morbidity is the suboptimal quality of healed skin, which often leads to reoccurring chronic skin wounds. Herein, a novel compound and biomaterial building block, panthenol citrate (PC), is developed. It has interesting fluorescence and absorbance properties, and it is shown that PC can be used in soluble form as a wash solution and as a hydrogel dressing to address impaired wound healing in diabetes. PC exhibits antioxidant, antibacterial, anti-inflammatory, and pro-angiogenic properties, and promotes keratinocyte and dermal fibroblast migration and proliferation. When applied in a splinted excisional wound diabetic rodent model, PC improves re-epithelialization, granulation tissue formation, and neovascularization. It also reduces inflammation and oxidative stress in the wound environment. Most importantly, it improves the regenerated tissue quality with enhanced mechanical strength and electrical properties. Therefore, PC could potentially improve wound care management for diabetic patients and play a beneficial role in other tissue regeneration applications.

Delay in wound healing remains one of diabetes's worse side effects, which increases mortality. The proposed study sought to scrutinize the implications of bee gomogenat (BG) on diabetic's wound closure in a streptozotocin-(STZ)-enhanced type-1 diabetes model's rodents. We used 3 different mice groups: group 1 non-diabetic rodents "serving as control", group 2 diabetic rodents, and group3 BG-treated diabetic rodents. We noticed that diabetic rodents experience a delayed wound closure, which emerged as a significant (*P < 0.05) decline in the deposition of collagen as compared to control non-diabetic animals. We noticed that diabetic rodents have a delayed wound closure characterized by a significant (*P < 0.05) decrease in the CD31 expression (indicator for wound angiogenesis and neovascularization) and an apparent elevation in the expression of such markers of inflammation as MCP-1 and HSP-70 as compared to control animals. Moreover, diabetic animals displayed a significant (*P < 0.05) increase in the expression of gap junction proteins Cx43 and a significant decrease in the expression of Panx3 in the wounded skin tissues when compared to the controls. Intriguingly, topical application with BG on the diabetic wounded skin tissues contributes to a significant (#P < 0.05) enhancing in the collagen deposition, up-regulating the level of CD31 expression and a significant (#P < 0.05) down-regulation in the MCP-1 and HSP-70 expressions as compared to diabetic non-treated animals. The expression's levels of Cx43 and Panx3 were significantly (#P < 0.05) retrieved in diabetic rodents after BG treatment. Taken together, our findings showed for the first time that BG promotes the recovering process and accelerated the closure of diabetic related wounds.

Guided bone regeneration (GBR) is a widely used technique in preclinical and clinical studies due to its predictability. Its main purpose is to prevent the migration of soft tissue into the osseous wound space, while allowing osseous cells to migrate to the site. GBR is classified into two main categories: resorbable and non-resorbable membranes. Resorbable membranes do not require a second surgery but tend to have a short resorption period. Conversely, non-resorbable membranes maintain their mechanical strength and prevent collapse. However, they require removal and are susceptible to membrane exposure. GBR is often used with bone substitute graft materials to fill the defect space and protect the bone graft. The membrane can also undergo various modifications, such as surface modification and biological factor loading, to improve barrier functions and bone regeneration. In addition, bone regeneration is largely related to osteoimmunology, a new field that focuses on the interactions between bone and the immune system. Understanding these interactions can help in developing new treatments for bone diseases and injuries. Overall, GBR has the potential to be a powerful tool in promoting bone regeneration. Further research in this area could lead to advancements in the field of bone healing. This review will highlight resorbable and non-resorbable membranes with cellular responses during bone regeneration, provide insights into immunological response during bone remodeling, and discuss antibacterial features.

Chronic wounds, depending on the bacteria that caused the infection, can be associated with an extreme acidic or basic pH. Therefore, the application of pH-responsive hydrogels has been instigated for the delivery of therapeutics to chronic wounds. Herein, with the aim of developing a flexible pH-responsive hydrogel, we functionalized hydrophilic polyurethanes with either cationic (polyethylene imine) or anionic (succinic anhydride) moieties. A comprehensive physicochemical characterization of corresponding polymers was carried out. Particularly, when tested in aqueous buffers, the surface charge of hydrogel films was closely correlated with the pH of the buffers. The loading of the cationic and anionic hydrogel films with various compound models (bromophenol blue; negatively charged or Pyronin Y; positively charged) showed that the electrostatic forces between the polymeric backbone and the compound model will determine the ultimate release rate at any given pH. The potential application of these films for chronic wound drug delivery was assessed by loading them with an antibiotic (ciprofloxacin). In vitro bacterial culturing was performed using Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Results showed that at the same drug dosage, different release profiles achievable from cationic and anionic polyurethanes can yield different degrees of an antibacterial effect. Overall, our results suggest the potential application of cationic and anionic hydrophilic polyurethanes as flexible pH-responsive materials for the delivery of therapeutics to chronic wounds.

Nanofiber scaffolds have emerged as a revolutionary drug delivery platform for promoting wound healing, due to their unique properties, including high surface area, interconnected porosity, excellent breathability, and moisture absorption, as well as their spatial structure which mimics the extracellular matrix. However, the use of nanofibers to achieve controlled drug loading and release still presents many challenges, with ongoing research still exploring how to load drugs onto nanofiber scaffolds without loss of activity and how to control their release in a specific spatiotemporal manner. This comprehensive study systematically reviews the applications and recent advances related to drug-laden nanofiber scaffolds for skin-wound management. First, we introduce commonly used methods for nanofiber preparation, including electrostatic spinning, sol-gel, molecular self-assembly, thermally induced phase separation, and 3D-printing techniques. Next, we summarize the polymers used in the preparation of nanofibers and drug delivery methods utilizing nanofiber scaffolds. We then review the application of drug-loaded nanofiber scaffolds for wound healing, considering the different stages of wound healing in which the drug acts. Finally, we briefly describe stimulus-responsive drug delivery schemes for nanofiber scaffolds, as well as other exciting drug delivery systems.

Diabetic foot ulcer is a chronic health issue leading to lower leg amputations in approximately 15% of patients with diabetics. There are many factors directly or indirectly involved in the physiology of wound healing but being a multisystem disorder, wound healing in diabetic patients retard or worsen with heavy exudates and severe microbial infections. Wound management is of prime importance and is an emerging area to incorporate wound regenerative materials in natural or synthetic dressing materials along with proper microbial control. The article aim to identify suitable dressing materials which exhibit inherent wound healing properties at the same time flexible to be used as drug carriers for slow, consistent and effective delivery of 'functional drugs' to the wound environment. The authors selected nine materials from the popular and well accepted dressings of patient choice, analyzed them using graph theoretic approach and ranked them on the basis of graph index values obtained. A critical review has also been done on the basis of their ranking, providing insights to the advantages, disadvantage and potential of top 5 ranked candidate materials. Alginate, Honey, Medifoam, Saline, and Hydrogel dressings were the top five candidate materials ranked respectively, even then, the authors suggests that 'modified hydrogels' can have the potential to be used as a future candidate in DFU treatment as it is the only material (among the top ranked ones) which can effectively used as regenerative drug carrier, while providing all other wound healing properties in relative proportions. The proposed framework can be modified and applied in the selection and ranking of materials for any kind of applications both in industry and medical fields by identifying factors influencing the final outcome of study and by listing the characteristics of the materials selected.

Chronic levels of inflammation lead to autoimmune diseases such as rheumatoid arthritis and atherosclerosis. A key molecular mediator responsible for the progression of these diseases is Chemokine C-C motif ligand 2 (CCL2), a homodimerized cytokine that dissociates into monomeric form and binds to the CCR2 receptor. CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), attracts monocytes to migrate to areas of injury and mature into macrophages, leading to positive feedback inflammation with further release of proinflammatory molecules such as IL-1β and TNF-α. Sequestering CCL2 to prevent its binding to CCR2 may prevent this inflammatory activity. Prior work adapted an α-helical CCL2-binding peptide (WKNFQTI) from murine CCR2 through extracellular loop analysis. Here, higher-affinity peptide binders were computationally designed through homology modeling and energy calculations, yielding an 11-amino acid peptide with high binding affinity. In addition, Rosetta mutations improved binding affinity in silico with blockage of the CCL2 dimerization site. Future work in analyzing binding kinetics and in vivo inflammation abrogation will confirm the accuracy of computational modeling techniques in de novo rational design of CCL2 cytokine binders.

Chronic inflammation is a typical feature and a major impediment in refractory diabetic foot ulcer (DFU). High levels of extracellular cell-free nucleic acid (cfDNA) have recently been known to play a critical role in the cause of inflammation. Herein, we fabricated polyacrylamide-based cationic hydrogels and topically applied them to the ulcer of a diabetic rat model. The cfDNA level in the wound area was significantly reduced after hydrogel adsorption, and the level of inflammation was eliminated. In turn, the wound closure was significantly promoted without introducing systemic toxicity. Cationic hydrogels represent an effective material to combat uncontrolled inflammation in DFU.

The metabolic disorder diabetes mellitus affects an increasing proportion of the population, a number projected to double by 2060. Non-life-threatening comorbidities contribute to an interrupted healing process which is first delayed, then prolonged, and associated with increased susceptibility to infection and sustained and unresolved inflammation. This leads to chronic non-healing wounds and eventually potential amputation of extremities. Here we examine the use of a bioactive angiogenic peptide-based hydrogel, SLan, to improve early wound healing in diabetic rats, and compare its performance to clinically utilized biosynthetic peptide-based materials such as Puramatrix. Streptozotocin-treated diabetic rats underwent 8 mm biopsy wounding in their dorsum to remove the epithelium, adipose tissues and muscle layer of the skin, and served as a model for diabetic wound healing. Wounds were treated with either Low (1w%) SLan, High (4w%) SLan, PBS, Puramatrix or K2 (an unfunctionalized non-bioactive control sequentially similar to SLan), covered with Tegaderm and monitored on days 0, 3, 7, 10, 14, 17, 21, 28; animals were sacrificed for histomorphic analyses and immunostaining. An LC/MS method developed to detect SLan in plasma allows pharmacokinetic analysis showing no trafficking of peptides from the wound site into the circulation. Low and High SLan groups show similar final outcomes of wound contraction as control groups (Puramatrix, PBS and K2). SLan-treated rats, however, show marked improvement in healing in earlier time points, including increased deposition of new mature blood vessels. Additionally, rats in the Low SLan treatment groups showed significantly improved wound contraction over other groups and significantly improved healing in early time points. Altogether our results suggest this material can be used to "jumpstart" the diabetic wound healing process. This article is protected by copyright. All rights reserved.

A wound can be surgical, cuts from an operation or due to accident and trauma. The infected wound, as a result of bacteria growth within the damaged skin, interrupts the natural wound healing process and significantly impacts the quality of life. Wound dressing is an important segment of the skincare industry with its economic burden estimated at $ 20.4 billion (in 2021) in the global market. The results of recent clinical trials suggest that the use of modern dressings can be the easiest, most accessible, and most cost-effective way to treat chronic wounds and, hence, holds significant promise. With the sheer number of dressings in the market, the selection of correct dressing is confusing for clinicians and healthcare workers. The aim of this research was to review widely used types of antibacterial wound dressings, as well as emerging products, for their efficiency and mode of action. In this review, we focus on introducing antibiotics and antibacterial nanoparticles as two important and clinically widely used categories of antibacterial agents. The perspectives and challenges for paving the way for future research in this field are also discussed. This article is protected by copyright. All rights reserved.