Beta-Glucans: A Biomimetic Approach for Reducing Chronicity in Delayed Wound Healing

Arthe Rajarajaran, Arivuoli Dakshanamoorthy*

Crystal Growth Centre, Anna University, Chennai


The challenge which grows over time in the chronic wound healing is a self-care wound dressing. These wounds have unfavourable impact on patients wellbeing and also challenging to the health economy. The wound healing requires a complex series of physiological and immunological processes with adequate nutrition. Any derangement of immune signals at any stage can lead to impaired wound healing which alters the key transition point that lies between the inflammatory and proliferation phase that destroys the components of Extracellular matrix. The Extracellular matrix is responsible for regulating the growth factors and its receptors that are important for wound healing. To boost up the growth factor signalling and accelerating the chronic wound healing, a new biomimetic approach of mimicking the role of extracellular matrix helps in the development of instructive wound dressing. Thus this review deals in discussing the tremendous activity of the Natural polysaccharide called β-glucan on wound healing signalling which may help in mimicking the role of extracellular matrix.


The thriving ubiquity of diabetes, obesity, aging population and change in life style continues to increase the frequency of the chronic wounds. Chronic skin wounds are one of the serious issue that is reaching epidemic proportions which are estimated to affect 20-60 million people worldwide by 20261. Unlike acute wounds, which heal after a certain period of time, chronic skin wounds heal slowly or not at all heal. These wounds can lead to long term hospitalization which is highest burden to the healthcare sector as there is a mortality of the patients as they have shown to cause loss of mobility and ability to perform daily tasks, limb amputation and poor quality of life. The effect of non-healing wounds on mortality has even been comparable to or worse than that of few common cancers like prostate, breast and colon cancer2.

The healing process starts from the hemostasis stage that is connected with forming a temporary matrix, secreting cytokines and other growth factors, and interaction of the latter ones with Extracellular Matrix(ECM), which initiates the repairing process, preparing the wound bed to the next stage of the healing process. In a healthy person with no underlying inhibitory factors an acute wound should heal within 3 weeks with the remodeling occurs over the next year or so. If a wound does not follow the normal path of healing, one of the phase of healing may be hindered and lengthened which makes the wound to becomes chronic3. Chronic wounds are thus defined as wounds, which have “failed to proceed through an orderly and timely process to produce anatomic and functional integrity, or proceeded through the repair process without establishing a sustained anatomic and functional result”4. Conventionally, a period of 6-8 weeks has been accepted by various authorities as the cut off time, beyond which the wound is labeled as chronic/non-healing3.

There are number of causes of delayed healing such as ischemia, wound infection, persistence of foreign body or bacterial proteins, chronic irritation, trauma and so on5. Ischemia is one of the key factor that makes the chronic wound to develop and makes it severe in the old age patients when it occurs repetitively. Ischemia decreases the blood supply to tissues leading to decreased oxygen and nutrients in the affected area causing inflammation in the tissues that triggers the cells to release factors such as chemokines, interleukins, leukotriences and complement system that attract neutrophils6. During the response against pathogens, neutrophils tend to release inflammatory cytokines and various other enzymes. Myeloperoxidase is one of the essential enzyme produced by neutrophils which inturn kills the bacteria by developing the reactive oxygen species (ROS)7. The increase in these enzymes and ROS production of neutrophils and other leukocytes damage cells that are essential for the proliferation phase by preventing proliferation and wound closure thereby causing damages in DNA, lipids, proteins, ECM and cytokines that normally aid the healing process8. Neutrophils remain extended in chronic wounds than that of acute wounds contributing to the elevated level of inflammatory cytokines and ROS. Also the wound fluid from chronic wounds has high amount of proteases and ROS which inhibit healing by inhibiting cell growth and breaking down growth factors and proteins in the ECM9.

The therapeutic approaches observed based on the accurate knowledge about the pathophysiology of a chronic wound have broadly focused on developing methods to decrease the ECM degradation, restoration of a healthy ECM and production of artificial ECM to activate chronic wound healing process10. Thus development of biomimetic material is a favourable approach for chronic wound healing11. Every tissue inside the body has a unique set of cells and ECM proteins arranged into a distinctive architecture, thus requiring the properties of bioengineering materials to be designed in an organ-specific way12. The lengthed inflammation and higher level of Matrix Metalloproteniases (MMPs) at the wound site causes significant degradation of ECM that delays wound healing process leading to chronicity (Fig.1&2). Thus the development of therapeutic dressing to control and positively regulate MMPs balance helps in achieving faster healing. The design of biomaterial matrices has the challenge to mimic the function of ECM that helps in fibroblast migration at wound site13. Recently, natural polymers have highly attracted the scientific community interest. By knowing the biocompatibility and biodegradable, nature of the naturally occurring polymers helps in highest level of biomimicry, replicating the biological and physicochemical features of the native ECM. By looking into our natural surroundings and by re-using some of the discarded natural resources, several functional biomaterials can be easily identified and implemented for promising wound healing applications, with a reduced impact on the environment. Nature itself can be better inspiration to develop economical, reduced energy consumption and fully biodegradable materials, providing great environmental sustainability. The increase interest in the use of either protein-based or polysaccharide-derived dressings provides striking and reflects the growing approach of giving back what we borrowed from Nature14. Naturally derived polymers provide a versatile, multitasking and tunable platform to design appropriate extracellular environments that actively contrast the onset of infection and inflammations, while promoting tissue regeneration and scar remodeling.

JDSS-20-1122-Fig1-Fig1

Figure 1: Acute and Chronic Wound Healing Process

JDSS-20-1122-Fig2-Fig2

Figure 2: Inflammation cycle that contribute to the chronicity

Natural polysaccharides are abundant in nature which are useful in many applications due to their unique properties. One of the most predominant class of polysaccharides is the β-glucans which are carbohydrate polymers that are found in the cell walls of many organisms such as bacteria, fungi, yeasts and some cereals like barley and oat15. All β-glucans comprises of glucose polymer linked by 1-3 linear glycosidic chain core of varing length and branching structures16. These branches that are derived from the glycosidic chain core are highly different with two main group of branching such as 1-4 or 1-6 glycosidic chains17. Also, different types of β-glucans exhibit distinct molecular weight, solubility and viscosity causing diverse physiological functions18. It is also most known for its powerful immune stimulant, antagonist of both benign and malignant tumors, anti-biotic properties and lower blood pressure or cholesterol levels19. Since beta-glucan enhances the production of growth factor that are essential for skin, promotes collagen biosynthesis and maintains skins moisture and elasticity20, we discussed the activity of various β-glucans on wound healing to make it evident for boosting the wound healing process of chronic wounds.

β-glucans also exhibited in vitro antimicrobial activity directly against a broad range of bacterial species, including E.coli, P.aeruginosa and S.aureus or indirectly by enhancing phagocytic activity and resistance towards the microbes21. In another study it was confirmed that the oat β-glucan showed antimicrobial activity against E.coli and B.subtilis22. β-glucan have a broad spectrum of effects on different cell types that can evident their proficiency on wound healing20. The ability of β-glucan to stimulate wound healing was first described by Leibovich and Danon in 198023, who observed faster re-epithilisation and increased macrophage activity and fewer polymorphonuclear neutrophils in the wound bed during inflammatory stage of repair. Various clinical trials reported that the topical application of fungal beta glucan accelerated healing in chronic ulcers24-28. β-glucan also activates macrophages that can remove cellular debris resulting from oxidative stress, thereby speeding up the recovery of damages tissue29. Fuste30 also confirmed that the barley β-glucan induced an early response in Human dermal fibroblast (HDF) cells favouring movement versus proliferation, and accelerated wound closure in vivo. According to Van den Berg31 et al., β-glucan have immuno-stimulatory capacity in temporary wound and show enhanced wound healing in burns. Curdlan enhanced migration, proliferation and wound closure of human kerotinocytes in a dectin-1 dependent manner both in vitro and in ex vivo. Numerous studies that are evident for the wound healing property of different type of β-glucan (Table 1).

Table 1. β-glucan types from various source and their respective wound healing activity

Name of the β-glucan

Target cell type/ animal model

Inference

Baker’s yeast Glucan

HDF

increased the nuclear factor-1 binding capacity and enhanced collagen biosynthesis25

Porcine keratinocytes

enhanced the keratinocyte proliferation26

3T3 fibroblast

nanofibrous membranes enhanced the adhesion and proliferation of fibroblasts and kerotinocytes27

Venous ulcer biopsy

enhanced the healing in venous ulcer28

Barley Glucan

Adult Human dermal fibroblast (HDFa) / Mice

induces an early response in HDF cell favouring movement versus proliferation30.

Oat Glucan

 

Rats

increased anti microbial activity, reduction of cholesterol and blood pressure22

Xyloglucan

Wister rats

exerted good healing effect in rats with severe wound32

NHEK, HaCaT and NHDF

promoted skin regeneration33

Laminarin

Human corneal epithelial cells

enhanced the epithelial migration34

Paramylon

Mice

accompanied with a modest increase of inflammatory cytokines35

HEK 293 T cells

acts as a bioactive supplement by boosting the cell proliferation capacity36

Curdlan

Human Keratinocytes

stimulated the cell proliferation and migration in a Dectin-1 dependent manner31

Swiss 3T3 fibroblast & wister rats

Nanofibrous dressing of PVA/curdlan incorporated with Ag has fast healing of wound in rats37

β-(1,3–1,6)-D-Glucan from Aureobasidium pullulans

 

 

 

 

 

 

 

BALB / cnude mouse

Membrane containing 50% β-glucan and Poly-(lactic co glycolic acid), accelerated the wound interactions38

ddY mouse

Beta-glucan and chitosan complex enhanced the wound repair by activation macrophages and cytokine release39

Human dermal fibroblasts

enhanced the dermal fibroblast migration and proliferation that modulated the effect of transforming growth factors40

Human dermal fibroblasts, adipose tissue  derived stem cells

boosted up the cellular response, migration and proliferation of both the cells41

Schizophyllan (SPG)

 

 

L292 Fibroblast

SPG based nanofibrous scaffolds showed cell proliferation and cell migration42

 

PVA/SPG-AgNPs nanofibers showed anti-microbial activity thereby helping in reducing the infection in the wound43

Lichenan

 

NHEK and HaCaT keratinocytes

stimulated human keratinocytes by specific mechanism into the terminal differentiation44

Wound healing is a repair and restoration of tissues through the series of stages that involves different cells and signalling molecules to regulate the cellular response and the dynamic remodelling of the extracellular matrix. Chronic wounds contain elevated levels of inflammatory cells, giving rise to more amount of proteases that degrades the ECM components, growth factors and receptors which are essential for wound healing. To restore and regulate the chronic wound healing cascade, a new approach of mimicking the extracellular matrix was discussed with a help of immuno modulatory polysaccharide called β-glucans. Various in vivo and in vitro studies discussed are evident to confirm the wound healing activity of beta-glucans from various sources. Also the β-glucans induces the proliferation and migration of keratinocytes and fibroblasts through specific receptors such as Dectin-1, CR3 or TLRs. These data also confirmed that β-glucans directly or indirectly modulate the activity of diverse cells and growth factors that are central to the reparative process. Thus β-glucans may interact with the innate immune system by regulating the macrophages and release the cytokine to produce growth factors/receptors thereby providing a temporary ECM for chronic wound healing.

The authors declared that they have no conflicts of interest to this work.

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Article Info

  • Journal of Dermatology and Skin Science
  • Article Type : Mini Review Article
  • View/Download pdf

Article Notes

  • Published on: November 03, 2020

Keywords

  • Chronic wound

  • Wound healing
  • Extracellular matrix
  • β-glucan

*Correspondence:

*Dr. Arivuoli Dakshanamoorthy
Crystal Growth Centre, Anna University, Chennai
Email: arivuoli@annauniv.edu.

©2020 Dakshanamoorthy A. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.