Innovations in drug delivery for chronic wound healing

: Wound healing is a varied and complex process designed to promptly restore standard skin structure, function, and appearance. To achieve this goal, different immune and biological systems participate in coordination through four separate steps, including homeostasis, inflammation, proliferation, and regeneration. Each step involves the function of other cells, cytokines, and growth factors. However, chronic ulcers, which are classified into three types of ulcers, namely vascular ulcers, diabetic ulcers, and pressure ulcers, cannot heal through the mentioned natural stages. It causes mental and physical problems for these people and, as a result, imposes high economic and social costs on society. In this regard, using a system that can accelerate the healing process of such chronic wounds, as an urgent need in the community, should be considered. Therefore, in this study, the innovations of drug delivery systems for the healing of chronic wounds using hydrogels, nanomaterial, and membranes are discussed and reviewed.

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Exploring Dendrimer Nanoparticles for Chronic Wound Healing

Frontiers in Medical Technology ◽

10.3389/fmedt.2021.661421 ◽

2021 ◽

Vol 3 ◽

Author(s):

Samuel Tetteh-Quarshie ◽

Eric R. Blough ◽

Cynthia B. Jones

Keyword(s):

Drug Delivery ◽

Wound Healing ◽

Drug Delivery Systems ◽

Chronic Wounds ◽

Chronic Wound ◽

Treatment Options ◽

The United States ◽

Delivery Systems ◽

Infection Age ◽

Nanoparticle Drug Delivery

The United States spends billions of dollars to treat chronic wounds each year. Wound healing is complex in nature which involves several intricate multiphase processes that can be delayed for a number of reasons leading to the development of chronic wounds. Wound healing therapies range from topical preparations to surgical repair with treatment options that vary based on other underlying factors like co-infection, age, or co-morbidities such as diabetes. Historically, micelles and liposomes are some of the nanoparticle drug delivery systems explored to treat chronic wounds; however, recent data suggests that dendrimers have shown potential to rival these systems in treating chronic wounds as well as other diseases. This mini review examines advances in dendrimer nanoparticle drug delivery systems to treat chronic wounds.

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Functional Mining of the Crotalus Spp. Venom Protease Repertoire Reveals Potential for Chronic Wound Therapeutics

Molecules ◽

10.3390/molecules25153401 ◽

2020 ◽

Vol 25 (15) ◽

pp. 3401

Author(s):

David Meléndez-Martínez ◽

Luis Fernando Plenge-Tellechea ◽

Ana Gatica-Colima ◽

Martha Sandra Cruz-Pérez ◽

José Manuel Aguilar-Yáñez ◽

...

Keyword(s):

Wound Healing ◽

Serine Proteases ◽

Chronic Wounds ◽

Chronic Wound ◽

Healing Process ◽

Wound Healing Process ◽

Major Health Problem ◽

Normal Wound Healing ◽

Alternative Sources ◽

Fibrin Clots

Chronic wounds are a major health problem that cause millions of dollars in expenses every year. Among all the treatments used, active wound treatments such as enzymatic treatments represent a cheaper and specific option with a fast growth category in the market. In particular, bacterial and plant proteases have been employed due to their homology to human proteases, which drive the normal wound healing process. However, the use of these proteases has demonstrated results with low reproducibility. Therefore, alternative sources of proteases such as snake venom have been proposed. Here, we performed a functional mining of proteases from rattlesnakes (Crotalus ornatus, C. molossus nigrescens, C. scutulatus, and C. atrox) due to their high protease predominance and similarity to native proteases. To characterize Crotalus spp. Proteases, we performed different protease assays to measure and confirm the presence of metalloproteases and serine proteases, such as the universal protease assay and zymography, using several substrates such as gelatin, casein, hemoglobin, L-TAME, fibrinogen, and fibrin. We found that all our venom extracts degraded casein, gelatin, L-TAME, fibrinogen, and fibrin, but not hemoglobin. Crotalus ornatus and C. m. nigrescens extracts were the most proteolytic venoms among the samples. Particularly, C. ornatus predominantly possessed low molecular weight proteases (P-I metalloproteases). Our results demonstrated the presence of metalloproteases capable of degrading gelatin (a collagen derivative) and fibrin clots, whereas serine proteases were capable of degrading fibrinogen-generating fibrin clots, mimicking thrombin activity. Moreover, we demonstrated that Crotalus spp. are a valuable source of proteases that can aid chronic wound-healing treatments.

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Biological Mechanisms of Chronic Wound and Diabetic Foot Healing: The Role of Collagen

Serbian Journal of Experimental and Clinical Research ◽

10.2478/sjecr-2018-0077 ◽

2018 ◽

Vol 19 (4) ◽

pp. 373-382 ◽

Cited By ~ 5

Author(s):

Victor Alexandrovich Stupin ◽

Ruslan Borisovich Gabitov ◽

Tatiana Georgievna Sinelnikova ◽

Ekaterina Vladimirovna Silina

Keyword(s):

Wound Healing ◽

Diabetic Foot ◽

World Literature ◽

Chronic Wounds ◽

Chronic Wound ◽

Treatment Algorithm ◽

Diabetic Foot Syndrome ◽

Results Of Treatment ◽

Native Collagen ◽

Chronic Ulcers

Abstract The treatment of chronic wounds is a continuously developing research focus. The problems of excessive mechanical forces, infection, inflammation, reduced production of growth factors, and lack of collagen will affect the results of treatment. The purpose of this study was to analysse the elements that lead to long-term non-healing of chronic wounds and trophic ulcers, including diabetic foot syndrome, by determining the optimal treatment algorithm. The paper presents an analysis of the world literature on the etiopathogenesis and principles of chronic wound treatment in diabetic foot syndrome. The epidemiology of chronic wounds of different genesis is presented. The issues of physiological and metabolic disorders in chronic ulcers affecting the process of wound healing are discussed. Particular attention is paid to collagen, which is a protein that forms the basis of connective tissue; collagen ensures the strength and elasticity of the skin, which confirms the importance of its role not only in aesthetics but also in the process of wound healing. Different types of collagen and their roles in the mechanisms of chronic wound healing in diabetic foot syndrome are described. The results of clinical studies evaluating the effectiveness of medical products and preparations, consisting of collagen with preserved (native collagen) and fractionated structures, in treating chronic wounds of diabetic foot syndrome are analysed. It has been shown that the use of native collagen preparations is a promising treatment for chronic ulcers and wounds, including diabetic foot syndrome, which makes it possible to increase the effectiveness of treatment and reduce the economic costs of managing these patients.

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Bionanomaterials: Advancements in Wound Healing and Tissue Regeneration

10.5772/intechopen.97298 ◽

2021 ◽

Author(s):

Priyanka Chhabra ◽

Kajol Bhati

Keyword(s):

Wound Healing ◽

Chronic Wounds ◽

Wound Care ◽

Health Care Organization ◽

Healing Process ◽

Volume Ratio ◽

Wound Healing Process ◽

Care Organization ◽

Complex Process ◽

High Degree

Abnormal wound healing represents a major healthcare issue owing to upsurge number of trauma and morbid physiology which ultimately posed a healthcare burden on patient, society and health care organization. A wound healing is a complex process so effective management of chronic wounds is often hard. Recently in addition to many conventional wound treatment’s advances in bionanomaterial are attaining much attention in wound care and skin tissue engineering. Bionanomaterials are biomolecule-based nanocomposite synthesized by plants, microbes and animals which possess high degree of biocompatibility, biodegradability, non-toxicity and bioactive assets. Bioactive assets like antimicrobial, immune modulatory, cell proliferation and angiogenesis of biomolecules forms fortunate microenvironment for the wound healing process. Nature has provided us with a significant set of biomolecules like chitosan, hyaluronic acid, collagen, cellulose, silk fucoidan etc. have been exploited to construct engineered bionanomaterials. These biopolymeric nanomaterials are currently researched comprehensively as they have higher surface to volume ratio and high chemical affinity showing a promising augmentation of deadly wounds. In this chapter we aimed to highlight the biological sources and bioengineering approaches adapted for biopolymers so they facilitate wound healing process.

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An EGF- and Curcumin-Co-Encapsulated Nanostructured Lipid Carrier Accelerates Chronic-Wound Healing in Diabetic Rats

Molecules ◽

10.3390/molecules25204610 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4610

Author(s):

Hye-Jin Lee ◽

Moses Jeong ◽

Young-Guk Na ◽

Sung-Jin Kim ◽

Hong-Ki Lee ◽

...

Keyword(s):

Wound Healing ◽

Chronic Wounds ◽

Chronic Wound ◽

Healing Process ◽

Double Emulsion ◽

Average Diameter ◽

Diabetic Rats ◽

Wound Healing Process ◽

Nanostructured Lipid Carrier

Nanostructured lipid carriers (NLC) are capable of encapsulating hydrophilic and lipophilic drugs. The present study developed an NLC containing epidermal growth factor (EGF) and curcumin (EGF–Cur-NLC). EGF–Cur-NLC was prepared by a modified water-in-oil-in-water (w/o/w) double-emulsion method. The EGF–Cur-NLC particles showed an average diameter of 331.8 nm and a high encapsulation efficiency (81.1% and 99.4% for EGF and curcumin, respectively). In vitro cell studies were performed using two cell types, NIH 3T3 fibroblasts and HaCaT keratinocytes. The results showed no loss of bioactivity of EGF in the NLC formulation. In addition, EGF–Cur-NLC improved in vitro cell migration, which mimics the wound healing process. Finally, EGF–Cur-NLC was evaluated in a chronic wound model in diabetic rats. We found that EGF–Cur-NLC accelerated wound closure and increased the activity of antioxidant enzymes. Overall, these results reveal the potential of the NLC formulation containing EGF and curcumin to promote healing of chronic wounds.

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Immunology of Acute and Chronic Wound Healing

Biomolecules ◽

10.3390/biom11050700 ◽

2021 ◽

Vol 11 (5) ◽

pp. 700

Author(s):

Kamila Raziyeva ◽

Yevgeniy Kim ◽

Zharylkasyn Zharkinbekov ◽

Kuat Kassymbek ◽

Shiro Jimi ◽

...

Keyword(s):

Wound Healing ◽

Chronic Wounds ◽

Chronic Wound ◽

Healing Process ◽

Inflammatory Factors ◽

Wound Healing Process ◽

Macrophage Phenotype ◽

Microbial Biofilms ◽

Inflammatory Phase ◽

Persistent Inflammation

Skin wounds greatly affect the global healthcare system, creating a substantial burden on the economy and society. Moreover, the situation is exacerbated by low healing rates, which in fact are overestimated in reports. Cutaneous wounds are generally classified into acute and chronic. The immune response plays an important role during acute wound healing. The activation of immune cells and factors initiate the inflammatory process, facilitate wound cleansing and promote subsequent tissue healing. However, dysregulation of the immune system during the wound healing process leads to persistent inflammation and delayed healing, which ultimately result in chronic wounds. The microenvironment of a chronic wound is characterized by high quantities of pro-inflammatory macrophages, overexpression of inflammatory mediators such as TNF-α and IL-1β, increased activity of matrix metalloproteinases and abundance of reactive oxygen species. Moreover, chronic wounds are frequently complicated by bacterial biofilms, which perpetuate the inflammatory phase. Continuous inflammation and microbial biofilms make it very difficult for the chronic wounds to heal. In this review, we discuss the role of innate and adaptive immunity in the pathogenesis of acute and chronic wounds. Furthermore, we review the latest immunomodulatory therapeutic strategies, including modifying macrophage phenotype, regulating miRNA expression and targeting pro- and anti-inflammatory factors to improve wound healing.

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The Role of Calcium in Wound Healing

International Journal of Molecular Sciences ◽

10.3390/ijms22126486 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6486

Author(s):

Thayaalini Subramaniam ◽

Mh Busra Fauzi ◽

Yogeswaran Lokanathan ◽

Jia Xian Law

Keyword(s):

Wound Healing ◽

Chronic Wounds ◽

Healing Process ◽

Wound Healing Process ◽

Cutaneous Wound Healing ◽

Cutaneous Wound ◽

Cutaneous Wounds ◽

Venous Ulcers ◽

Complex Process ◽

New Ideas

Skin injury is quite common, and the wound healing is a complex process involving many types of cells, the extracellular matrix, and soluble mediators. Cell differentiation, migration, and proliferation are essential in restoring the integrity of the injured tissue. Despite the advances in science and technology, we have yet to find the ideal dressing that can support the healing of cutaneous wounds effectively, particularly for difficult-to-heal chronic wounds such as diabetic foot ulcers, bed sores, and venous ulcers. Hence, there is a need to identify and incorporate new ideas and methods to design a more effective dressing that not only can expedite wound healing but also can reduce scarring. Calcium has been identified to influence the wound healing process. This review explores the functions and roles of calcium in skin regeneration and reconstruction during would healing. Furthermore, this review also investigates the possibility of incorporating calcium into scaffolds and examines how it modulates cutaneous wound healing. In summary, the preliminary findings are promising. However, some challenges remain to be addressed before calcium can be used for cutaneous wound healing in clinical settings.

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Antioxidant dressing therapy versus standard wound care in chronic wounds (REOX study): Study protocol for a randomized controlled trial

10.21203/rs.3.rs-16762/v2 ◽

2020 ◽

Author(s):

Inés María Comino-Sanz ◽

María Dolores López-Franco ◽

Begoña Castro ◽

Pedro Luis Pancorbo-Hidalgo

Keyword(s):

Wound Healing ◽

Randomized Controlled Trial ◽

Wound Dressing ◽

Chronic Wounds ◽

Chronic Wound ◽

Controlled Trial ◽

Healing Process ◽

Intervention Group ◽

Control Group ◽

Randomized Controlled

Abstract Background: A wound that does not heal in the orderly stages of the healing process or does not heal within three months is considered a chronic wound. Wound healing is impaired when the wound remains in the inflammatory stage for too long. A range of factors can delay the healing process: imbalance between proteases and protease inhibitors in the wound bed; bacterial colonization and the presence of biofilm; and oxidative stress.Recently, wound management has improved significantly. A new antioxidant dressing has been developed, which combines an absorbent matrix obtained from Locust Bean Gum (LBG) galactomannan and a hydration solution with curcumin and N-acetylcysteine (NAC). This dressing combines the advantages of moist healing in exudate management and free radical neutralization, achieving wound reactivation.The primary aim of this study is to compare the effect of antioxidant dressing on chronic wound healing with the use of standard wound dressing in patients with hard-to-heal wounds.Methods: We will conduct a multicentre, single blinded, randomized, controlled trial with parallel groups. Participants will be selected from three primary public health-care centres, located in Andalucía (southern Spain). Patients will be randomized into an intervention group (antioxidant dressing) or control group (standard wound dressing). Assessment will be carried out in weeks 2, 4, 6 and 8. Follow-up will be of 8 weeks or complete healing, if it happens earlier.Discussion: The findings from this study should provide scientific evidence on the efficacy of the antioxidant dressing as an alternative for the treatment of chronic wounds. This study fills some of the gaps in the existing knowledge about patients with hard-to-heal wounds.Trial registration: ClinicalTrials.gov, NCT03934671. Registered on 2 May 2019.

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Applications of Nanosized-Lipid-Based Drug Delivery Systems in Wound Care

Applied Sciences ◽

10.3390/app11114915 ◽

2021 ◽

Vol 11 (11) ◽

pp. 4915

Author(s):

Andreea-Mariana Matei ◽

Constantin Caruntu ◽

Mircea Tampa ◽

Simona Roxana Georgescu ◽

Clara Matei ◽

...

Keyword(s):

Drug Delivery ◽

Wound Healing ◽

Drug Delivery Systems ◽

Wound Care ◽

Drug Loading ◽

Healing Process ◽

Lipid Nanoparticles ◽

Delivery Systems ◽

Public Health Issue ◽

Impaired Wound Healing

Impaired wound healing is an encumbering public health issue that increases the demand for developing new therapies in order to minimize health costs and enhance treatment efficacy. Available conventional therapies are still unable to maximize their potential in penetrating the skin at the target site and accelerating the healing process. Nanotechnology exhibits an excellent opportunity to enrich currently available medical treatments, enhance standard care and manage wounds. It is a promising approach, able to address issues such as the permeability and bioavailability of drugs with reduced stability or low water solubility. This paper focuses on nanosized-lipid-based drug delivery systems, describing their numerous applications in managing skin wounds. We also highlight the relationship between the physicochemical characteristics of nanosized, lipid-based drug delivery systems and their impact on the wound-healing process. Different types of nanosized-lipid-based drug delivery systems, such as vesicular systems and lipid nanoparticles, demonstrated better applicability and enhanced skin penetration in wound healing therapy compared with conventional treatments. Moreover, an improved chemically and physically stable drug delivery system, with increased drug loading capacity and enhanced bioavailability, has been shown in drugs encapsulated in lipid nanoparticles. Their applications in wound care show potential for overcoming impediments, such as the inadequate bioavailability of active agents with low solubility. Future research in nanosized-lipid-based drug delivery systems will allow the achievement of increased bioavailability and better control of drug release, providing the clinician with more effective therapies for wound care.

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A Systematic Overview of Recent Methods for Non-Contact Chronic Wound Analysis

Applied Sciences ◽

10.3390/app10217613 ◽

2020 ◽

Vol 10 (21) ◽

pp. 7613

Author(s):

Domagoj Marijanović ◽

Damir Filko

Keyword(s):

Wound Healing ◽

Global Economy ◽

Chronic Wounds ◽

Chronic Wound ◽

Healing Process ◽

Significant Rise ◽

Wound Healing Process ◽

Obesity And Diabetes ◽

Wound Assessment ◽

Analysis System

Chronic wounds or wounds that are not healing properly are a worldwide health problem that affect the global economy and population. Alongside with aging of the population, increasing obesity and diabetes patients, we can assume that costs of chronic wound healing will be even higher. Wound assessment should be fast and accurate in order to reduce the possible complications, and therefore shorten the wound healing process. Contact methods often used by medical experts have drawbacks that are easily overcome by non-contact methods like image analysis, where wound analysis is fully or partially automated. Two major tasks in wound analysis on images are segmentation of the wound from the healthy skin and background, and classification of the most important wound tissues like granulation, fibrin, and necrosis. These tasks are necessary for further assessment like wound measurement or healing evaluation based on tissue representation. Researchers use various methods and algorithms for image wound analysis with the aim to outperform accuracy rates and show the robustness of the proposed methods. Recently, neural networks and deep learning algorithms have driven considerable performance improvement across various fields, which has a led to a significant rise of research papers in the field of wound analysis as well. The aim of this paper is to provide an overview of recent methods for non-contact wound analysis which could be used for developing an end-to-end solution for a fully automated wound analysis system which would incorporate all stages from data acquisition, to segmentation and classification, ending with measurement and healing evaluation.

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