Polymeric Biomaterials for Wound Healing Incorporating Plant Extracts and Extracellular Matrix Components

*Margaret O. Ilomuanya, Ibilola M. Cardoso-Daodu, Uloma N. Ubani-Ukoma and Adannaya C. Adebona*

## **Abstract**

Biomaterials are constructed to promote or stimulate the processes of wound healing. Polymeric biomaterials can be used to hydrate the wound and serve as barrier to pathogens with plant extracts, antimicrobial agents and extracellular components incorporated to stimulate the healing process. The biological and physical augmentation provided by extracellular matrix derived implants continues facilitate innovation in biomaterials utilized in management of nonhealing wounds. Tissue-processing methodologies can birth extracellular matrix-based devices with characteristic postimplantation responses ranging from the classic foreign body encapsulation of a permanent implant, to one where the implant is degraded and resorbed, to one where the processed extracellular matrix implant is populated by local fibroblasts and supporting vasculature to produce, a viable and metabolically active tissue. Extracellular matrix components and plant extracts have been shown to possesses pharmacological properties with potential for use in the treatment of skin diseases and wound healing. Antioxidant, anti-inflammatory assays, and wound healing assays have been shown to support the dermatological and wound healing usage of these medicinal plants extracts.

**Keywords:** Wound healing, Biomaterials, extracellular matrix, chronic wounds, plant extracts, Electrospun fibers

## **1. Introduction**

Biomaterials are polymers that are compatible with the body system introduced into the body to correct an anomaly or used for therapeutic purposes. These materials are broadly divided into three classes – synthetic polymers (usually hydrophobic), natural polymers and inorganic polymers [1]. These polymeric materials have found usefulness in various aspects of medicine such as tissue engineering [1], drug delivery [2], gene therapies [3], wound healing etc. Wounds occur when an intact body organ or tissue is compromised. The body immediately sets off several processes to ensure healing. The successful completion of this healing process is dependent on several factors such as immune cells, infection at the wound site, external factors such as drugs and underlying conditions like diabetes, and hypoxia. Wounds can either be classed as acute where the healing period is

between 8 to 12 weeks and chronic where healing is delayed beyond 12 weeks [4] as in vascular ulcers, diabetic foot ulcers and pressure ulcers [5].

Wound healing involves four sequential but partially overlapping processes of hemostasis, inflammation, proliferation, and remodeling [3, 5]. Ideally, with proper wound care such as regular cleaning, debridement and change of dressing, the healing process should proceed uninterrupted to completion. However, due to underlying conditions, poor nutrition, possible contamination of wound site and sometimes overactive immune responses, conventional therapy is introduced to control and ensure complete healing. Wound management also involve primary close by suturing, plastering or use of adhesives at first presentation to ensure proper healing [6]. The major objectives of wound care are to prevent infection, ensure proper wound closure and reduce scar formation [7].

#### **1.1 Biomaterials and wound healing**

Conventional treatment of wounds some of which have been alluded to above include drug therapies for pain, prevention or treatment of infections and wound cleaning. Bandages and closure systems are commonly used to create an enabling environment for healing. Polymeric biomaterials, synthetic or natural are an improvement on conventional wound therapy. These polymeric materials are constructed to ensure moisture and warmth is retained at the wound site while also sealing the wound from infectious agents [4]. Some of the materials are naturally occurring such as hyaluronan, chitosan, alginates. Others include hydrocolloids, polycaprolactone (PCL), polylactide-co-glycolide (PLGA), polyethylene glycol (PEG), polyurethane (PU) etc. A major advantage of biomaterials in wound care is their biocompatibility at the site of application [1]. These materials are also biodegradable; a quality that is particularly needed when the aim is to deliver medication to a wound site. This ensures that the biomaterial will degrade after drug delivery and so does not require surgical removal. Biomaterials are constructed to promote or stimulate the processes of wound healing. For instance, hydrogels can be used to hydrate the wound and serve as barrier to pathogens; curcumin, zinc nanoparticles and antibacterial can also be incorporated to stimulate the healing process [7, 8]. Polyethylene glycol when combined with polymyxin B or alginate has antibacterial activity and promotes wound regeneration respectively [9]. Biomaterials also act as scaffolds for incorporation of growth factors and as skin substitutes using hyaluronan and collagen to mimic the extracellular matrix (ECM) [9].

Injuries or wounds are currently treated via autografting or allografting. However, due to organ rejection by the immune system in some cases and lack of donors, the use of scaffolds has become increasingly popular. These scaffolds used in tissue repair are expected to be biocompatible, biodegradable, easily sterilizable and structurally desirable [10]. They can be cell or drug loaded to enhance healing; however, the constituent materials of the scaffolds can also have innate tissue repair properties. Depending on the desired properties, scaffolds are fabricated using synthetic or natural polymers which come with their unique characteristics.

Some synthetic polymers like polyurethane are used in the fabrication of semipermeable dressings because of its permeability to moisture and vapor while acting as barrier to bacteria [4]. Fibrous scaffolds made with Poly(lactide-co-glycolide) polymers have been employed in the regeneration of bone tissues, they are also formulated as injectable in situ scaffolds [10]. Polyethylene glycol (PEG) polymers are used as carriers for growth factors i.e., EGF for targeted delivery to the wound site [11] and electrospun scaffolds of polycaprolactone (PCL), a biocompatible and bioresorbable polymer mimics the extracellular matrix (ECM) and therefore suitable for the treatment of acute and chronic wounds [4]. Polyvinyl alcohol and eudragit polymers are also useful additions in tissue engineering.

*Polymeric Biomaterials for Wound Healing Incorporating Plant Extracts and Extracellular… DOI: http://dx.doi.org/10.5772/intechopen.98556*

Natural polymers employed in wound healing include collagen, gelatin, chitosan, and hyaluronic acid. Chitosan is used in burns and wound healing because of its biocompatibility, tissue repair ability and lack of side effects [12, 13]. It serves as a carrier for heavy molecules such as proteins, antigens, and peptides. Ahmad et al. [14] investigated the wound healing properties of mupirocin-loaded chitosan-based hydrogel membrane. The study showed promising reports of good wound healing potentials with controlled release and no skin irritation. Conventional treatment with topical mupirocin ointment requires multiple applications and is less acceptable because of complaints associated with soiling of patient wears. Similarly, an investigative study of high molecular weight chitosan in wound healing showed exceptionally good re-epithelialization and fast wound closure compared to fucidin-ointment treated wounds [13]. Collagen and gelatin nanofibrous scaffolds are fabricated for wound healing and cartilaginous tissue regeneration respectively [15, 16] and nanofibrous scaffolds of hyaluronic acid mimics the ECM essential in controlling cellular function [2, 17].

## **2. Extracellular matrix targeted for chronic wound**

Extracellular Matrix (ECM) is a structural scaffold that organizes cell adhesion and migration it also controls cellular growth, metabolism, and differentiation signals. It is composed of a wide variety of dynamic macromolecules and their regulatory factors which provide structural aid and physical protection [18]. Novel research has dynamically changed our understanding of the role of the extracellular matrix in tissue regeneration. The extracellular matrix is thought to provide passive structural support for cells however it has now been discovered that the individual or fragmented Extracellular matrix can send signals vital for cell processes during wound healing through integrin reactions coupled with growth factor activation [19]. Studies have shown that the Extracellular Matrix plays an active role in chronic wound healing. In a study by Baek et al. [20], the extracellular matrix was fabricated as a porous sheet matrix derived from human adipose tissue. Its aim was to act not just as a scaffold but a tool to enhance the overall process of wound healing through its components. Application of the extra cellular matrix sheet dressing showed enhanced wound healing rate compared to the control which was foam wound dressing [20]. The extracellular matrix is a broad molecule network made up of protein glycosaminoglycan and glycoconjugate, elastin and collagen. The extracellular matrix is a nonvascular structure that controls a vast number of cellular functions. The extracellular matrix is a complex structural network and undergoes constant restructuring of its network through matrix degrading enzymes [21]. The extra cellular matrix is composed of multiple matrix proteins that make up its main part. Proteins provide structural support to cells and tissues. The proteins that make up the extracellular matrix can be structural or non-structural depending on their roles and responsibilities [22]. In a study by Hui et al. [23], growth factor re-enforced extracellular matrix was prepared, and the wound healing properties were evaluated using a mouse model. It reflected that the extra cellular matrix promotes wound healing in the early stage of adipocyte recruitment. Rapid re-epithelization, enhanced granulation, tissue growth and supported angiogenesis were also observed. Growth factor re-enforced extracellular matrix was used to treat the wounds and total wound healing was observed on day seven of wound healing [23]. To accelerate healing processes and decrease the complication occurrence various agents, growth factors, natural and synthetic antioxidants (coenzyme Q10-CoQ10), are applied. Amajuoyi et al. incorporated natural ECM matrix co-enzyme Q10 and keratin in electrospun keratin/Co Enzyme Q10/Poly vinyl alcohol nanofibrous scaffold [24]. This potential dressing for infected wounds was effective in preventing the proliferation of microorganism. Encapsulation of

CoQ10 in nanoliposomes has also been shown to enhance CoQ10 activity by accelerating wound healing process after tooth extraction [24, 25]. A reduction in inflammatory reaction and increase in collagen deposition following surgical procedure, were previously obtained in animals when CoQ10 was applied in a form of ointment resulting. The expression of IL-1β, TNF-α, NF-κB and HO-1, cytokines involved in inflammation and oxidative tissue damage, were significantly suppressed by CoQ10 application for 3 days following surgical procedure [25]. The ECM was shown to be more stimulated to facilitate wound healing when formulated with biomaterials. **Table 1** show in details the Drug delivery technologies incorporating Extracellular matrix and Plant extract targeted for management of chronic wounds.



*Polymeric Biomaterials for Wound Healing Incorporating Plant Extracts and Extracellular… DOI: http://dx.doi.org/10.5772/intechopen.98556*

#### **Table 1.**

*Drug delivery technologies incorporating extracellular matrix and plant extract targeted for management of chronic wounds.*

## **2.1 GAG (Glycosaminoglycans)**

GAG is a lengthy linear polysaccharide chain. It is a sulphated di-saccharide formed by uronic acid and N-acetyl- glucosamine or N-acetyl -galactosamine. GAG in partnership with proteoglycans control the wound healing process, GAG is involved in the remodeling phase as it supports capillary growth, fibronectin, and collagen formation at the site of the injury so that vascular density of the wound can be restored. GAG also participates in cell to cell and cell to matrix interactions cell proliferation migration and cytokine and growth factor signaling associated with wound healing. GAG chain reflects an impressive structural diversity because of the dynamic biosynthesis that is tightly controlled in biological systems allowing modified GAG to particularly interact with various ligands in a controlled and timely manner [35]. In a study by Amaral et al. [35], Collagen-GAG scaffolds were fabricated with platelet rich protein infused in the pores of its scaffold. The composite scaffold containing collagen, GAG and platelet rich protein was observed to release key growth factors such as, TGFβ, FGF, VEGF and PDGF for vascular regeneration for 14 days. Growth factors released were enough to enhance the proliferation of major cells involved in wound healing. It also increased the angiogenic and vascularization abilities which are key indices for progress in wound healing, conclusively indicating promising results as therapy for wound healing [36].

### **2.2 Collagen**

Collagen is the most common protein in the body. It is highly populated in the extracellular matrix of the connective tissue like the tendon, cartilage, and skin. It is the most abundant structured protein found in the extra cellular matrix. It gives tensile strength and takes part in adhesion and migration. In the extra cellular matrix collagen is aligned as fibrils to allow for support of the structural framework of the tissues. Collagen type I is in all tissues, tendon, and skin. Collagen type II is found in the cartilage and cornea. Collagen type III is found in the walls of blood vessels [18, 19]. In a study by Lei et al. [37], Collagen hydrogel was fabricated for wound dressing. It was shown to enhance the rate and quality of wound healing. It also improved the tensile strength of regenerated tissue and skin at the wound site. In the study the effect of collagen hydrogel dressing on chronic wound healing and capillary regeneration was explored in diabetic Sprague Dawley rat models. Rats treated at the wound site with collagen hydrogel showed faster healing with smaller wound areas by days seven and fourteen compared to the untreated rats [37]. In another study by Morteza et al. [38] bacterial cellulose/collagen hydrogel as wound dressing was compared to collagenase ointment and the control was an untreated wound. Bacterial Cellulose Collagen hydrogel showed better regeneration and tissue repair when applied at the wound site than the collagenase ointment or control. The study concluded that Bacterial Cellulose/Collagen hydrogel serves as a promising biologically active hydrogel dressing for skin regeneration [38, 39].

## **2.3 Elastin and fibronectin**

It is found in the extra cellular matrix spaces of tissues and is responsible for the flexibility and distensibility of tissues. Elastin is responsible for the dermis stretching ability along with fibrillin and fibulin. The study by Kawabata et al. [40], highlighted cutaneous ulcers treated with silk elastin-based hydrogels. It was shown that silks elastin enhanced rapid wound healing in chronic ulcers of diabetic mice. Silk elastin hydrogels showed enhanced epithelialization rate compared to

#### *Polymeric Biomaterials for Wound Healing Incorporating Plant Extracts and Extracellular… DOI: http://dx.doi.org/10.5772/intechopen.98556*

conventional hydrogels in chronic ulcer models. Indicating that elastin hydrogel is a promising material for accelerating the healing of chronic ulcers [40].

Fibronectins exist in two different forms, firstly as plasma that migrates the blood, secondly as cellular protein created by fibroblast. Fibronectin is aligned into a network of fibrils. It is created in the form of a disulphide-bonded dimer that can be broken down. Fibronectin is involved in the development and response to injury. It plays an important role in enhancing and modulating cell functions in the extracellular matrix [18, 19, 40]. In a study by Norris et al. [41] an Acoustic fabrication of Collagen -Fibronectin composite gels were carried out to accelerate microtissue regeneration. The ultrasound-based fabrication altered the collagen fiber structure and arrangement this led to improvement in its bioactivity. The study investigated how the synergistic effect of collagen and fibronectin coupled with the ultrasound effect altered the protein alignment and bioactivity of composite hydrogels. Results from the investigation showed that the fibronectin can be redistributed within three-dimensional hydrogels under the influence of ultrasound to produce composite hydrogels which lead to the improvement of microtissue regeneration. Conclusively ultrasound waves can lead to protein realignment and fibronectin rearrangement which can enhance wound healing. This is a promising and novel tool and provides a less invasive treatment for chronic wounds [12].

Extra cellular matrix also plays an indirect role in the modulation of extra cellular protease production and activation it also modifies growth factor availability and activity for wound healing [42]. In a study by Riis et al. 2020, adipose derived stem cells which have the ability to deposit extracellular matrix are being investigated for novel treatment of chronic wound and enhancement of wound healing. The extracellular matrix eventually forms a scaffold which is composed of collagen I and III and fibronectin, all of which are essential for progress in wound healing processes [13]. PLA-based electrospun fibers loaded with hyaluronic acid-valsartan hydrogels have been shown to be stable and possess proven diabetic wound healing property. This was as a result of the known biomimetic effect of the fibers and increased reepithelization facilitated by the hydrogels containing angiotensin inhibitors which is facilitated by the presence of hyaluronic acid as the ECM components [43].

## **3. Biomaterials and drug delivery incorporating plant extracts targeted for management of chronic wounds**

Biomaterials such as biomimetic polymers have been utilized as carrier systems for plant extracts utilized in management of chronic wounds. The problems of resistance and environmental degradation associated with irrational use of orthodox medicines have increased interests in natural and safer alternatives when managing chronic of wounds. Chah et al. [44] evaluated the antibacterial and wound healing activities of methanolic extracts of *Ageratum conyzoides* L (Asteraceae), *Anthocleista djalonen*, A. Chev (Loganiaceae), *Napoleonaea imperialis*, P. *Beauv(Lecythidaceae)*, *Ocimum gratissimum*, *Briq (Lamiaceae*) and *Psidium guajava*. The antibacterial and wound healing properties of *Napoleona imperialis*, *Ocimum gratissimum* and *Ageratum conyzoides* were established however utilization of these extracts as crude portends a setback for quality control and wide utilization of these herbal products. Incorporation of herbal extracts into biomaterials have been shown to increase the stability of the herbal extracts within the biomaterial whilst ensuring that plant extract elicits its desired effect. The polyherbal antioxidant preparation containing extracts of *T. conophorum* and *O. gratissimum* was shown to exhibit excellent antioxidant and wound healing properties. The formulation served to protect the skin from reactive oxygen species created by UV

radiation and environmental toxin, thus protecting the skin from photo aging. This hence showed a migration from the work of Shah et al., where the extracts elicit wound healing activities to the instance where extracts incorporated into biomaterials could effectively be utilized as a dosage form in management of chronic wounds [44, 45]. Elegbede et al. [26] studied the therapeutic properties of green and fermented *Aspalanthus linearis* extract loaded hydrogels in surgical wound healing. The best wound healing indices shown by the hydrogels containing fermented rooibos extract due to shortening the inflammatory phase which resulted in quicker wound closure and reduced fibrosis (**Table 1**). Biomaterials have also incorporated both plant extracts and conventional medicine in management of chronic wounds.

*Panax ginseng*, extracted by soxhlation from the clean and dried root and incorporated into PCL (polycaprolactone nanofibers) by electrospinning for bone tissue regeneration was demonstrated to induce the expression of osteogenic genes like osteocalcin and collagen type 1 [46]. The mineralization and phosphatase activity of the ginseng extract was shown to be significantly higher due to the presence of *Panax ginseng* hence its usefulness in bone engineered scaffold development in management of surgical wounds [3, 45, 46]. Nanoscaffolds of polycaprolactone have been incorporated and electrospun with the medicinal extracts of *Tecomella undulata*, *Asparagus racemosus*, *Glycyrrhiza glabra*, and *Linum usitatissimum* to impart their wound healing properties and antimicrobial activity. Morphological examination shows that the supplement of these plant extracts did not alter the final morphology of the nanofibers, but the average diameter was increased in all the extract loaded nanofibers. The release studies using acetate buffer with a pH of 5.5 shows that the nanoscaffolds released the antibacterial extracts in a sustained manner up to a 24-hour period and also shows zones of inhibition when cultured on agar plates with growth of *S. aureus* and *K. pneumoniae* [9, 47]. The fabricated wound dressings exhibited significant moisture vapor transmission rate, which is a suitable criterion for gases permeability in facilitating wound healing. When correlated and compared with commercially accessible dressing materials, it was established that nanofiber incorporated with herbal drug was 50% more efficient [46, 47]. The plant extract from *Garcinia manostana* have been found to have usefulness as wound dressing material. Charernsriwilaiwat et al. [46–48], *in vitro* analysis using Franz's diffusion cells method and an *in vivo* analysis using Male Wistar rats shows that the plant extract fabricated with chitosan-ethylenediaminetetraacetic acid/polyvinyl alcohol composite reduces inflammation and also leads to increase in antioxidant activity. It also demonstrated antimicrobial activity against *Staphylococcus aureus* and *Escherichia coli* [48].

Curcumin is a known natural polyphenolic compound which is gotten from the rhizome of the natural plant *Curcuma longa*. It is a novel, proven treatment that facilitates faster wound healing due to its possessing antioxidant and antiinflammatory properties. It helps in accelerating healing of wounds by contributing to the three phases of wound healing such as the inflammatory, proliferatory and the remodeling phases [49]. Curcumin has been reported to have a wide range of pharmacologic actions ranging from anti-inflammatory, anti-HIV, an antibacterial, anti-oxidant activity, anti-parasitic, anti-mutagenic and anti-cancer, with very low or no intrinsic toxicity [49, 50]. Curcumin has significant effect on the inflammatory phase during wound healing. The Inflammatory phase is one of the most important phases during wound healing, and it is often counted as the first step in optimal wound healing. Since tissue damage causes early acute inflammation, the control of inflammation can help optimize the wound healing process [49–52].

*Polymeric Biomaterials for Wound Healing Incorporating Plant Extracts and Extracellular… DOI: http://dx.doi.org/10.5772/intechopen.98556*

The *in vitro* analysis using myoblast cells and an *in vivo* analysis using Female mice when curcumin was electrospun with polylactic acid demonstrated greater cell mobility, early remodeling and inhibition of nitric oxide which usually impede wound healing [49, 53].

*Momordica charantia* is a traditional herbal commonly used for its antidiabetic, antioxidant, contraceptive, and antibacterial properties [54]. When formulated as a powder ointment, *Momordica charantia* showed a stastically significant response (P < 0.01), in terms of wound-contracting ability, wound closure time and period of epithelization, with increased tissue regeneration at wound bed when compared with povidone iodine which served as control [54, 55]. Hussan et al. developed biomaterial based *Momordica charantia* ointment which was evaluated as an alternative topical medication for diabetic wounds. The ointment showed intense TGF-β expression and a high level of total protein content, showing that it accelerated wound healing in diabetic rats, via enhancing TGF-β expression [55].

Utilization of medicinal plants with known wound healing activities such as *Tetracarpidium conophorum* in collaboration with known conventional medicine have been shown to increase their activity as well as shorten wound healing times. Ezealisiji *et al.* [56] reported that the n-hexane and methanol extracts of the *Tetracarpidium conophorum* seed nut established accelerated dose-dependent wound healing activity of the extracts. This was attributed to the presence of some secondary metabolites like flavonoids with repeated antioxidant and immune stimulating activities. However, Ilomuanya et al. [45, 57] utilized response surface methodology coupled with statistically designed experiments to optimize the multivariable processes in developing *Tetracarpidium conophorum* hydrogel containing gentamicin. The extract synergistically facilitated a potential wound healing activity that either active ingredient wound not have been able to achieve.

### **4. Conclusion and future trends**

Wound healing is a complex and dynamic process of restoring cellular structures and tissue layers in damaged tissues as closely as possible to its normal state. Plant extracts and human extra cellular matrices that have been seen to possess wound healing activities have the capability of facilitating re-epithelization and tissue regeneration which accelerates the wound healing process. Utilization of appropriate biomaterials as carrier systems can enhance the activity of the plant extracts in hastening the inflammatory, proliferative and the remodeling phases of chronic wounds without the inherent problem of antibiotic resistance and hypersensitivity to the very few medications available. Increased utilization of folkloric plant extracts with proven wound healing activities will ensure an increased option and platform for management of Chronic wounds. There still exits inherent challenges in the use of extracellular matrix loaded biomaterials, cellular and extra cellular treatments options which can enable delivery of multiple molecules at the wound site without degradation is required. The cost of these technologies should also be affordable to encourage scale up.

#### **Conflict of interest**

The authors have no conflict of interest.

*Recent Advances in Wound Healing*

## **Author details**

Margaret O. Ilomuanya1 \*, Ibilola M. Cardoso-Daodu1 , Uloma N. Ubani-Ukoma1 and Adannaya C. Adebona2

1 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, University of Lagos, Lagos, Nigeria

2 Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Federal University Oye Ekiti, Ekiti, Nigeria

\*Address all correspondence to: milomuanya@unilag.edu.ng

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Polymeric Biomaterials for Wound Healing Incorporating Plant Extracts and Extracellular… DOI: http://dx.doi.org/10.5772/intechopen.98556*

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## **Chapter 7**

## Bionanomaterials: Advancements in Wound Healing and Tissue Regeneration

*Priyanka Chhabra and Kajol Bhati*

## **Abstract**

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.

**Keywords:** Biopolymers, Bionanomaterials, wound healing, nanocomposites, tissue engineering

## **1. Introduction**

Wound healing process involves a series of intricate cellular events involving organized and regulated events such as hemostasis, inflammation, cell migration, proliferation, and remodeling [1]. Upon the onset of the inflammatory response, fibroblasts begin to proliferate and migrate into the wound area which involve the interaction and participation of different types of growth factors, cells and supporting cell-ECM interaction and ultimately reconstitute the wounded skin after injury [2]. Sometimes the normal wound healing process gets altered due to morbid physiology for example, in case of burns, accidents, diabetic foot ulcers, wound healing is delayed. This leads to the compromised mobility, amputation of limbs, even death, which cause the foremost social, and financial burden for decades [3]. Nowaday's nanotechnology and nanomedicine has created a new way to treat acute and chronic wound which ultimately encourage tissue regeneration and remolding. Indeed, many research studies and clinical trials data have already been published [4]. This chapter

summarized the systematic evaluation of different types of bionanomaterials which promote wound healing process and introduce their future scope [5].

## **2. Physiology of normal wound healing**

The normal wound healing cascade involves a complex series of cellular and biochemical events which begin with hemostasis and inflammation, proliferation, maturation, remodeling, and wound contraction. These phases are not exactly distinguishable from each other, because occasionally they overlap or proceed concurrently [6].

#### **2.1 Hemostasis**

It is the first stage of wound healing which start immediately after the injury and cause the stoppage of bleeding. In hemostasis various platelets factors are released by the degranulation thrombocytes cells like insulin-like growth factor (IGF-I), Platelet-derived growth factor (PDGF), Transforming growth factor beta (TGF-β) and Epidermal growth factor (EGF) followed by coagulation cascade. Coagulation cascade is the multifaceted chain reaction which begin at the site of injury in which the conversion of prothrombin to enzyme thrombin takes place. Thrombin converts the fibrinogen in to fibrin monomers at the site of the wound surface. Fibrinogen polymerizes the fibrin monomers to form a fibrin chain which are interlinked by coagulation factor XIII and form a stable fibrin network.

#### **2.2 Inflammatory phase**

After the hemostasis is achieved inflammation is initiated at the site of injury. Immediately after the rupturing of blood vessel mast cells releases various inflammatory factors like thromboxanes, histamins and prostaglandins which causes the vasoconstriction to prevent blood loss.

Initially, Polymorphonuclear neutrophils (PMNs) are arrived at the wounded area within an hour of injury. PMNs cells are the predominant cells for the first two days at the site of injury, which are attracted to the site by growth factors and fibronectins. Neutrophils release free radicals which phagocyte the debris and kill bacteria at the site of injury. This process is known as respiratory burst. Other leukocytes like helper T cells also present in the wounded area helps in the secretion of cytokine which divide T cells and increases inflammation, vasodilatation, vessel permeability and activity of macrophage. Macrophages are essential for the tissue regeneration and wound healing. Macrophages are stimulated by the low oxygen content to produce various factors which enhance the angiogenesis, stimulate the cells to re-epithelialise the wound, form granulation tissue, built a new ECM ultimately pushing the wound healing process into next phase. Macrophages become prominent by replacing the PAMs cells at the wound site. As inflammation decreases, few inflammatory factors are secreted and numbers of neutrophils and macrophages are decreased at the wound site create a clean wound bed which indicate that inflammatory phase is ending and enters in to the proliferative phase [7].

#### **2.3 Migration and proliferation phase**

After few days of injury migration and proliferation phase starts and last up to 21 days from the day of the wound takes place. This phase is characterized by angiogenesis, epithelisation and fibroplasias. In proliferation phase wound start *Bionanomaterials: Advancements in Wound Healing and Tissue Regeneration DOI: http://dx.doi.org/10.5772/intechopen.97298*

to rebuilt with healthy granulation tissue. To form the granulation tissue sufficient supply of oxygen and nutrient is required by the blood vessels. A new network of blood vessels is replaced by the damaged one by the process of angiogenesis, formation of extra cellular matrix (ECM) and collagen takes place. With the formation of the granulation tissue damaged mesenchymal cells are converted into the fibroblast cells which act as a bridge for the movement of the cells around the affected area. In healthy wound these fibroblasts start to appear within three days of the injury and liberate liquids and collagen which help to strengthen the wound site. The wound continues to grow stronger in the proliferation phase with the reorganization of the fibroblast cells and help in the formation of new tissue and speed up the wound healing process [7].

#### **2.4 Remodeling phase**

Remodeling or maturation phase is the last phase of healing process which finalizes the wound healing process. Remodeling phase start approximately 21 days after the injury and can go up to 2 years with the change in the matrix composition over the time. During this phase, the collagen formation and organization takes place with the help of collagenases and matrix metalloproteinases. The tensile strength of the dermal tissue increases and nonfunctional fibroblasts are recouped by the functional ones. With the passage of the time cellular activity decreases and the blood vessels in the affected area reduced. Wound contraction takes place and type III collagen is remodeled in type I collagen which increase the tensile strength of the wound and wound is fully closed [8, 9].

## **3. Pathophysiology of chronic wounds**

A chronic wound is defined as one in which the normal process of healing is disrupted at one or more points in the phases of hemostasis, inflammation, proliferation and remodeling and do not heal completely within 90 days after the onset of any injury [10]. Chronic wounds, unlike acute wounds, do not undergo the ordered molecular and cellular processes of physiological tissue repair previously discussed. However, the healing process of chronic wounds is thought to be stuck in inflammation [11]. Chronic wounds can also be considered to be an imbalance between tissue deposition stimulated by growth factors, and tissue destruction mediated by proteases. Hereby, the imbalance favors the destructive process [10]. Thus, the molecular and cellular processes are disrupted leading to significant differences in the microenvironment of the wound, both in terms of the constituents of the exudates and the cellular components of the wound area. In addition, oxidative damage by free radicals, condition specific factors of underlying diseases, and accumulated necrotic tissue as well contributes to the chronic state. The further healing of those wounds results in skin defects of excessive fibrous appearance, for instance keloids and scar contractures, or alternatively in insufficient tissue replacement, i.e., a nonhealing wound [12].

### **4. Challenges in tissue regeneration**

The role of ECM in wound healing has been traditionally thought of as a passive structural support for cells. It is now clear that cell-ECM interactions, in concert with growth factors, are necessary for rapid wound healing. Hence, the main challenge in wound therapeutics is to provide an ideal microenvironment for optimal

cell migration and proliferation [13]. Many strategies have been adopted for accelerating tissue repair. Exogenous growth factors, ECM molecules, and short peptide sequences targeting specific integrin receptors have been shown to accelerate wound healing both *in vitro* and *in vivo*. However, native ECM molecules or growth factors lack structural properties, and are expensive to produce in large quantities [14]. On the other hand, polymeric materials offer excellent physical support, and enhance biological activity. To circumvent these disadvantages, polymeric materials have also been functionalized with bioactive peptide sequences, nanoparticles and growth factors in to bionanomaterial [4].

## **5. Biomaterials for wound healing**

Recent years have witnessed extraordinary growth of research and applications in the field of nanoscience and nanotechnology. The field of nanoscience is one of the most dynamic research areas in modern material science and combination of physics, chemistry, biology, material science & medicine has materialized as nanotechnology. Nanoparticles and nanostructure are rapidly increasing for new application in the field of biomedicine and wound healing.

Nanomaterials are the materials which are having a maximum diameter of 100 nm and nanoproducts which lies in nanoscale are known as nanomaterial. Nanomaterial possesses large surface to volume ration due to which they offer wide-ranging application in the field of science and technology. There are variety of biomaterials which acquire excellent candidature for numerous biomedical applications. When these biomaterials are used in nanoforms like nanotubes, nanocomposite, nano pockets and nanoparticles they are known as bionanomaterial [15, 16].

The size of the bionanomaterial hold an important parameter in terms of biological application because of its similarity in size as compared to genetic material i.e., around 2.5 nm in width and to building block of cell i.e., protein which is around 1-20 nm. So, for biological application the size and surface properties of the bionanomaterial can be personalized as per the prerequisite.

The nature has provided us with a significant set of biomaterials like chitosan, cellulose, silk, hyaluronic acid, alginate, fucoidan, pectin, gelatin, keratin, carboxymethyl cellulose, Bovine serum albumin. These proteins and polysaccharides-based biomaterials possess a physiochemical property like biocompatibility, biodegradability and non-toxicity which makes them apposite for inclusion in living systems thereby accelerate or replace the function of bodily tissues, organs or damaged tissue & augment wound healing process. Polymeric biomaterials can be fabricated in to variety of nanostructures like nanotubes, nanoparticles, nano- capsules, nanopockets, nanocrystals, nanowhiskers which ultimately possess the potential to encourage self-healing mechanisms that can mimic tissue regeneration [17, 18]. The summery of all the biomaterials in provided in the **Table 1**.

#### **5.1 Nano-biomaterials in wound healing**

As we know wound healing is well orchestrated process involving a significant number of physiochemical events in different phases of healing process involving hemostasis, inflammation, proliferation and remolding. There are variety of factors which significantly influence the wound healing course and slow down their activities, completely disturb the wound healing process. It is difficult to visualize the necessity of altered tissue and ample the requirements for tissue regeneration. Nature has provided with us a significant set of biomaterials which possess fundamental properties like non-toxicity, biocompatibility, biodegradability and


## *Bionanomaterials: Advancements in Wound Healing and Tissue Regeneration DOI: http://dx.doi.org/10.5772/intechopen.97298*


*Biomaterials and their wound healing properties.*

**142**

#### *Bionanomaterials: Advancements in Wound Healing and Tissue Regeneration DOI: http://dx.doi.org/10.5772/intechopen.97298*

also mimic with the host extra cellular environment. Moreover, several of them are non-immunogenic and fulfill the demands of suitable wound healing dressing material. Biomaterials and their composites are comprehensively investigated by the researchers which can be tailored in nanostructure like nanoparticles, nanofilms, nanoflakes, nanocomposites, nano capsules, nanotubes, nanogels, nanofibrils, nanospikes and nanowhikers. These nanostructures encourage the potential to endorse self-healing mechanism that can mimic tissue regeneration. With the extended knowledge of nanotechnology and nanomedicine they represent a great prospect to improve currently available medical treatments and prognosis impaired wound healing [33].

## *5.1.1 Nanoparticles*

As a functioning field of nano-research, the molecular designing of different self-assembling biocompatible nanoparticles has been created in recent years. Nanoparticle, exhibit unique physiochemical properties and maximized its use for biomedical and therapeutic application, including for wound healing. Using the nanoparticles, delayed wound healing and burn care has been enhanced. Polymeric nanoparticles are manufactured from biodegradable polymers or copolymers to remove, capture, encapsulate or bind the drug. They can be made up of natural ones, Synthetic and semi-synthetic polymers and their copolymers, such as alginate, chitosan, gelatin, poly (glycolic acid), albumin, poly-alkyl cyanoacrylate, PLGA, etc. They have the benefits of controlled and sustained discharge, enhanced bioavailability, elevate level of exemplification, and biocompatibility with tissues and cells. Chitosan nanoparticles have traditionally been among the most commonly researched groups of natural biopolymer products for biomaterials. Using either "bottom-up" or "top-down" methods or a mixture of both techniques, Chitosan nanoparticles can be synthesized. Chitosan can be used as a wound-healing agent due to its antimicrobial, haemostatic, film-forming, anti-inflammatory, and anticoagulant activities. Curcumin loaded chitosan nanoparticles accelerate the wound healing by regulating inflammation and neovascularisations. As chitosan is remarkable antimicrobial agent which modulate the production of reactive oxygen species, IL-6 secretion and augment proinflammatory activation and ultimately augment healing in chronic wound [34].

Hyaluronic acid (HA-NPs) nanoparticles also showed good stability and had a potential to be applied as blood contact material. Studies showed that HA-NPs showed excellent comprehensive biocompatibility, strongly promoting adhesion and proliferation of extra cellular while still exerting inhibitory effects on platelets, and macrophages [35].

Gelatin is a naturally produced collagen-derived polymer utilized specifically in the manufacture of biodegradable materials, and biocompatible fabrics for wound dressing. Fibrin is also a natural polymer which, in the presence of the enzyme thrombin, is made from fibrinogen polymerized into fibrin. Fibrin has distinctive properties, including inflammation reduction and enhanced immunological response and cell permeability, and has been broadly included in wound healing and tissue engineering [36]. Under acidic conditions, pectin has the ideal consistency also at higher temperatures, making it the perfect choice for use in the drug delivery system. In the presence of divalent cations, pectin has a peculiar gel forming capacity that makes it an excellent carrier for supplying bioactive agents. At low pH, pectin forms an accumulation of macromolecules, but the pectin aggregates appear to dissociate at neutral pH and form an extended network. Thiolated pectinbased nanoparticles have recently been explored and their potential for delivery of ocular drugs has been studied. The thiolated pectin nanoparticles have been

prepared using magnesium chloride as an ionic crosslinker by ionotropic gelation and timolol maleate as the model drug. They indicated that the addition of crosslinker imparts a more pronounced effect on the nanoparticles' particle size, whereas the drug trap is influenced by polymer concentration. Mucoadhesive nanoparticles have been shown to extract the substance from the particles trapped in the cul-desac for a long period of time. Developed pectin nanoparticles through mechanical homogenization and showed enhanced drug dissolution [7].

Silk fibers are used by the textile industries and as suture material. Silk fibers are generated by the silkworm cocoons named *Bombyx mori*. Nowadays, silk is valuable in the biomedical sector because of its mechanical and biological properties like biodegradability, stiffness, biocompatibility, water vapor permeability, and antibacterial properties. Due to its different properties, silk can be used as a material for wound dressing. Hydrocolloid dressings loaded with silk fibroin nanoparticles showed enhanced effectiveness of medical dressing due to the hydrophobic nature of silk fibroin polymers, result in enhanced physical properties. It also maintains the environment of extra cellular matrix, furthermore cell viability is also increased in burn wound animals models [7].

#### *5.1.2 Nanofilms*

In current scenario of nanotechnology research, nanostructure of polymeric biomaterial has been attracted a great attention of researchers. Nanofilms are among them one type of nanomaterials which is widely used for wound healing applications. Nanofilms are the thin single or multilayer biomaterials structure which vary from few nanometers to several micrometers in thickness. They are flexible sheets and generally used in wound dressing. The nanofilms synthesized for wound healing applications are transparent in nature, also allow exchange of gases like oxygen and carbon dioxide and but impermeable to water, bacteria and other pathogens. The variety of biomaterials can easily be tailored in to nanofilms. Carboxymethylcellulose nano films own high absorption capacity of exude and also triggers the formation of new blood vessels and remove necrotic debris and devitalized tissues from a wound bed.

Chitosan and alginates based nanofilms augment the wound healing process in both excision and incision animal wound model studies and also facilitated cell viability, collagen deposition, tissue regeneration and remolding [37]. Nanofilms based on hyaluronic acid effectively accelerate wound healing process and cause less trauma while removing these nanofilms based wound dressing. Studies showed that low proportion of hyaluronic acid in chitosan-hyaluronic acid composite nanofilms will decrease the water vapor permeability and fibroblast adhesion which is beneficial to accelerate wound healing process. Collagen based nanofilms demonstrated in study enhance fibroblast migration which markedly improved wound healing process.

Fucoidan- is an emerging biomaterial from a family of sulfated polyfucose polysaccharides extracted from brown marine algae. Fucoidan comes under spotlight due to its significant properties like antioxidant, antivirus, anticoagulant and anti-inflammatory and non-toxicity. It was studied that fucoidan based nanofilms increase the potential wound healing in burns wounds by significantly induce wound contraction. It reacts with the basic fibroblast growth factor and transforming growth factor and mediate the wound healing process [38].

#### *5.1.3 Nanofibers*

Nanofibers display two main characteristics: a pore size and high surface/volume ratio which placed it under spot light in variety of biomedical application like drugs

#### *Bionanomaterials: Advancements in Wound Healing and Tissue Regeneration DOI: http://dx.doi.org/10.5772/intechopen.97298*

delivery and wound healing. High surface area and different fabrication process used for adjusting the composition of nanofibrils make it responsible to speed the wound healing process. It augments cell adhesion, proliferation and differentiation at the wound bed. The traditional method of processing these biomaterials is through the technique of electrospinning, which provides the possibility of operating with a high yield at a nano-scale. Low spinnability can be manage by adding synthetic polymers into the natural polymers. As we known natural polymers offers extensive variety of bioactive properties which makes then suitable for biomedical and wound healing applications. Many studies showed that nano porosity and large surface to volume ratio makes the nanofibers competent to smooth the wound healing process. Mesh like structure of nanofibers promote high absorption of wound exudate. It also promotes cell respiration and exchange of gases. Biopolymeric nanofibers boom the ability of fibrous mesh to react with biological components of wound healing process [39].

Gelatin is a natural polymer derived from collagen that is biocompatible and biodegradable. It enhanced the regeneration of tissue and helps in healing of wound. When used as a wound dressing material, gelatin nanofibers comply with all required specifications like haemostatic, low cytotoxicity, reduced antigenicity [40]. Their scarcity of antimicrobial properties, restricts the use of gelatin. The antimicrobial properties of gelatin have been enhanced by adding other substances into it like poly([2-(methacryloyloxy)ethyl] trimethylammonium chloride) (PMETAC) and showed good bacterial activity against *Staphylococcus aureus*, *Escherichia coli*, methicillin-resistant, and Acinetobacter baumannii. Further study on cell adhesion revealed that cells attached and proliferate on the nanofiber surface, resulted in the safe use of gelatin nanofibers as material for wound dressing [41].

Collagen type I nanofibers were also favored to enhance cell proliferation. 3D nanofibrous scaffolds as dressings of collagen accelerate the wound closure in 14 days [42].

Chitosan nanofibers are also emerging candidate in the area of biomaterials. Studies showed that many different types of drugs like chemotherapeutics agents, antibiotics and proteins can be successfully loaded in electrospun nanofibers. Chitosan nanofibers possess several bioactive properties and can be utilized for wound dressing, tissue engineering and drug delivery system [43].

Due the small pore size of chitosan nanofibers they reduce the bacterial infection at wound bed and also decrease dehydration during wound healing process [44].

As Ideal wound dressing should maintain the water loss at a range of 2000 and 2500 g−2 day−1 at the wound site indicates that the higher values dry the wound rapidly and cause hindrance in smooth wound healing progression. Studies showed that chitosan-based nanofibers has water vapor transmission rate of 1950 to 2050 g−2 day−1 makes it ideal candidate for wound healing dressing [45].

In addition to that nanofibers of hyaluronic acid [HA] also hold a potent position in the field of biomedical application due to their unique properties as an extracellular-matrix and accelerating wound healing. Hyaluronic acid nanofibers have very mechanical properties due to which they cannot be used alone as a wound healing dressing material. Thus, reinforcement agent is required to incorporate into nanofibers. Hyaluronic acid has carboxygroup, which is capable of forming hydrogen bond with the protonates amines. Chitosan possesses an amine group that helps in the formation of hydrogen bonds with hyaluronic acid. In turn, it increases the mechanical strength of hyaluronic acid nanofibers dressing [46].

#### *5.1.4 Nanocomposites*

Currently, due to the rapid development in the field of nanotechnology and nanomedicine formation of nanocomposites for biomedical and wound healing is more facile and development of biopolymer nanocomposites has bloomed due to its outstanding endorsements in structural, electrical, mechanical applications. They are enlightened materials to transport nanoparticles [47]. The distinct features of nanocomposite may reflect the mutual properties of their components; they can serve for different biomedical purpose. In wound dressing, nanocomposites aims to reinforce structural stability and increase antimicrobial activity [48].

Biopolymer nanocomposite loaded with nanoparticles of antimicrobial agent play a vital role in the tissue repair and regeneration. Due to high surface to volume ratio of nanoparticles, they significantly increase the efficacy of the wound dressing against different microorganisms by reducing the risk of developing bacterial resistance. Chitosan own functional amino group that can be further engineered for a wide range of applications. Studies showed that chitosan-based nanocomposites loaded with antimicrobial agent are attractive not only in food preservation but also in biomedical field. Antimicrobial nanoparticle loaded chitosan nanocomposites encourage controlled release of drug through the matrix at wound site which prevent the unwanted bacterial infection. Montmorillonite–chitosan–silver sulfadiazine nano composites were evaluated on skin lesions which showed increased efficacy of prepared nanocomposites and can be used as potent wound dressing material [49].

Silk nanocomposites also investigated for wound healing applications as silk own good permeability to oxygen and water vapors, also possess high thermal resistance, good tensile strength and antimicrobial properties [50].

Hyaluronic acid-based nanocomposite showed satisfied properties of an ideal wound dressing in terms of porosity, swelling, biocompatibility, biodegradation. They also showed haemostatic potential and antibacterial properties. Hyaluronic acid nanocomposite incorporated with silver nanoparticles own effective response against *S. aureus*, *E. coli*, *P. aeruginosa* and *K. pneumoniae* microbes. So they can be used as potential bio nanocomposite for wound dressing of chronic wound loaded with bacterial infections [51].

Guar gum loaded Carboxymethyl nanocomposites showed enhanced re- epithelial growth and very less inflammatory cells which confirm that they reduce microbial infections. Therefore, Guar gum loaded Carboxymethyl nanocomposites has the potential of effectively accelerate wound healing process and are a suitable candidate for wound dressing material [52].

## **6. Conclusions**

The nanotechnology and nanomedicine-based therapies are an emerging trend in the field of biomedical and wound healing application. Plentiful researchers have designed and innovate nanoplatforms to enhance wound healing process which demonstrate promising results in the field of wound healing. Recently biopolymeric nano systems have attracted much attention which showed a great response and benefits in treating acute and chronic wounds. The potential of bionanomaterials for biomedical and wound healing application is enormous due to their bioactive physiological properties like biocompatibility, biodegradability, non-toxicity, non-immunogenic which synthetic polymers do not possess. These nanomaterials play a significant role in cell attachment, differentiation and proliferation as well as delivery of target protein, drugs, stem cells and growth factors. Various types of nanomaterial can be engineered using these biomaterials like nanoparticles, nanofilms, nanocomposites, nanofibers which enhance the administration of different drugs and reduce the cytotoxicity. Topical application of bionanomaterials not only improve controlled drug delivery but also favors cell fibroblast proliferation,

and reduced tissue inflammation. Furthermore, the detailed insight of molecular mechanism in wound healing and the role of bionanomaterial in this process is needed attention to translate basic research into clinical application.

## **Conflict of interest**

There are no conflicts of interest.

## **Author details**

Priyanka Chhabra\* and Kajol Bhati Department of Forensic Science, School of Basic and Applied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India

\*Address all correspondence to: pchhabra188@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 8**
