Collagen-Based Therapies for Accelerated Wound Healing

Abstract

Wound healing is a complex and dynamic process essential for maintaining tissue integrity and functionality. As a key component of the extracellular matrix (ECM), Collagen plays a crucial role in orchestrating this regenerative process. Acting as a vital fibrous protein, collagen serves as a dynamic conductor, coordinating tissue regeneration and repair. This chapter explores the application of collagen in accelerating the wound healing process, starting with the fundamental role of collagen in ECM remodeling. It discusses how collagen promotes wound healing through different types of scaffolds, micro/nanoparticles, synthetic peptides, and interactions with extracellular vesicles (EVs). The chapter also delves into the regulatory function of collagen in cellular processes and evaluates strategies to stimulate collagen synthesis. In conclusion, it provides an overview of upcoming advancements in the dynamic field of collagen-based therapies for wound treatment.

1. Introduction

The largest organ of the human body, having an average surface area of 1.85 m², is the skin [1]. Skin, apart from its critical function of homeostasis maintenance, serves as a barrier against the external environment, inhibiting the spread of infections and fluid losses [2]. Wounds are conditions characterized by skin defects or ruptures that result from physical or chemical traumas [3]. Bacterial maladies present a significant peril to human health, as stated by the World Health Organization [4]. Unhealed infected wounds represent a significant health concern, imposing substantial financial burdens on both patients and the healthcare system [5].

Wound healing involves critical stages including hemostasis, inflammation, proliferation, and remodeling, all influenced by extracellular matrix (ECM), collagen, and its derivatives [6, 7, 8, 9]. Collagen induces platelet activation and aggregation, leading to fibrin clot formation at the injury site. In the inflammatory phase, proinflammatory cytokines, triggered by immune cell activation, influence fibroblast, epithelial, and endothelial cell migration. Fibroblasts deposit collagen and its degradation releases fragments that promote fibroblast proliferation and growth factor synthesis, driving angiogenesis and re-epithelialization. The acquisition of tensile strength relies on ECM remodeling, balancing new matrix synthesis, and matrix metalloproteinase (MMP) degradation activities [10, 11, 12, 13].

The intricate interplay among cells, soluble factors, and ECM expedites inflammation resolution, fostering fibroblast and keratinocyte proliferation [14]. Platelet activation, secretion of inflammatory cytokines, migration of macrophages, fibroblasts, and keratinocytes, as well as the expression of matrix MMPs and growth factors, are all crucial for wound closure. These processes ultimately lead to the formation of mature ECM and new tissue. Collagen plays a pivotal role in ECM remodeling during wound healing, offering structural support and facilitating adhesion ligand binding to cell surface receptors. Tissue stiffness and matrix composition influence specific signaling pathways, profoundly impacting cell fate [15, 16].

This chapter explores the crucial role of collagen in wound healing and investigates diverse collagen-based therapeutic approaches, including scaffolds, drug delivery systems, synthetic peptides, and extracellular vesicle (EV) interactions. By analyzing collagen’s impact on cellular processes and its role in signaling pathways, the chapter provides valuable insights for enhancing therapeutic outcomes. It also examines factors influencing collagen synthesis, highlighting both chemical and physical inducers. Despite acknowledging constraints, the chapter concludes by outlining prospective developments, emphasizing the potential of collagen-based methods to advance wound care and regenerative medicine.

2. Collagen’s role in ECM remodeling during wound healing

The dermis relies on fibrillar collagens, mainly types I and III, with subsequent involvement of types XII, XIV, XVI, and VI [17]. Aging increases collagen types I and III concentration in the epidermis [18]. In healthy skin, ECM is 80% type I and 20% type III, crucial for skin elasticity. Imbalances in their ratio affect wound healing outcomes [19]. Fetal healing has higher type III collagen, promoting scar-free recovery [20].

During remodeling, myofibroblasts exit via apoptosis or clumping, leaving ECM proteins and collagen. Early repair favors type III collagen, shifting to type I as healing progresses [21]. Molecules precisely regulate collagen I and III synthesis, culminating in tissue closure. Remodeling, concluding in months, involves substituting healing collagen III with normal collagen I, enhancing wound strength [22, 23, 24].

Wound repair requires angiogenesis, driven by vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and type I collagen, mediated by integrin receptors [25, 26, 27]. Fibroblast migration forms granulation tissue, rich in connective tissue and blood vessels, driven by TGF-β synthesis during the proliferative phase [28, 29].

Several studies have investigated the effectiveness of collagen in cutaneous wound healing, emphasizing its biocompatibility. Research conducted by Wiegand et al. [30] demonstrated that native collagen promotes the migration of keratinocytes and fibroblasts, fostering a three-dimensional microenvironment that stimulates cell proliferation. Additionally, Jridi et al. [31] identified a positive interaction between collagen and human cells, leading to an increased hydroxyproline concentration at the injury site. In vivo experiments by Helary et al. [32] and Chen et al. [33], further supported collagen’s ability to enhance granulation tissue, collagenization, neovascularization, re-epithelization, and the expressions of epidermal growth factor (EGF), fibroblast growth factor (FGF), and a cluster of differentiation 31 (CD31), expediting the recovery process without eliciting an immune response.

However, abnormalities in ECM reconstitution during wound healing contribute to hypertrophic and keloid scars, characterized by elevated concentrations of collagen I and III, fibronectin, and laminin [34]. The collagen fiber orientation in these scars is perpendicular to the epithelial surface, contrasting with the three-dimensional network in normal skin [35]. Keloid scars exhibit abnormally thick, weakly organized collagen bundles with fewer cross-links in the deep dermis compared to the superficial dermis, while normotrophic and hypertrophic scars show variations in collagen bundle thickness [36, 37]. Keloids also have a higher proportion of collagen I to collagen III than normotrophic lesions, with heterogeneity in the collagen I/III ratio within keloid scars [11].

3. Collagen-based scaffolds

Collagen-based biomaterials can expedite the healing process of diverse tissue types by acting as a matrix [38]. These collagen scaffolds not only strengthen wounds but also facilitate vascularization and closure [39]. To enhance their therapeutic efficacy, bioengineered scaffolds can incorporate bioactive molecules, stem cells, and immunomodulation moieties. The effectiveness of these scaffolds depends on their architectures and material properties, emphasizing the importance of advances in biomaterial science and bioengineering [40]. Numerous collagen wound dressing formulations, designed to address challenging skin lesions, have been developed, showcasing the versatility of collagen in promoting wound healing [41, 42, 43, 44, 45]. Additionally, oral collagen-based supplements have been studied as a treatment to enhance the healing process of burn wounds. Miyab et al. [46] conducted a pilot clinical trial involving 31 men (aged 18–60) with 20–30% whole body burns. Their study revealed that an oral collagen supplement can effectively improve wound healing, elevate pre-albumin levels, and lead to reduced hospital stays. a pilot trial on 31 men (18–60 years) with 20–30% burns. Their study found that an oral collagen supplement significantly improved wound healing, increased pre-albumin levels, and clinically reduced hospital stays.

Even though collagen-based wound dressings have many benefits, there are inherent differences between the types, therefore a thorough evaluation of each kind is necessary to determine which is best for a specific case (Figure 1). This section aims to provide an insightful exploration of the distinct forms of collagen-based wound dressings.

Figure 1.

Collagen wound dressings: Pros and cons (created with Biorender.com).

3.1 Hydrogels

Hydrogels are highly sought-after substances for promoting the regenerative healing of injured tissues on account of their biomimetic porosity and effective water retention, which enable them to establish a moist environment locally [47]. Collagen hydrogels have the potential to serve as effective vehicles for functional nanoparticles and drug delivery, specifically as novel platform materials in the field of biomedical surgical dressings [47, 48]. A study by Ying et al. [49] has yielded a collagen-hyaluronic acid hydrogel that functions as a biomimetic dressing to facilitate uncomplicated wound recovery. According to the findings of the investigation, the hydrogel actively stimulated the development of vasculature. It has been demonstrated by Chen et al. [50] that a pullulan-collagen hydrogel wound dressing promotes dermal remodeling and wound healing more effectively than commercially available collagen dressings. This hydrogel dressing promoted the formation of healed tissue characterized by collagen fibers that were shorter, less dense, and more irregularly aligned. For cutaneous wound repair, a tough and tissue-adhesive polyacrylamide/collagen hydrogel incorporating dopamine-grafted oxidized sodium alginate as a crosslinker has been synthesized by Bai et al. [51]. The hydrogel exhibited favorable mechanical characteristics, adhesion to cutaneous tissue, water absorption, and sustained biological activity. Experiments on wound healing in vivo demonstrated that the hydrogel can hasten the healing process and may find utility as a wound dressing.

It has been discovered that hydrogels containing collagen induce neovascularization, alleviate pain, and expedite the healing of burn lesions, rendering them more effective than conventional methods like paraffin dressings [52]. A collagen hydrogel containing curcumin has also been found to promote burn wound healing through its antioxidant and anti-inflammatory properties [53]. Moreover, Chakrabarti et al. [54] suggested that their bFGF-collagen-silver sulfadiazine hydrogel accelerates burn healing by promoting fibroblast proliferation. In an in vivo study, using hydrogels led to a faster wound closure, with nearly complete epithelialization in 16 days, compared to standard and control groups. The accelerated healing was attributed to increased re-epithelialization and granulation tissue formation facilitated by collagen and growth factors. The results of numerous investigations on collagen-based hydrogels and their uses in wound healing are compiled in Table 1.

Materials	Experimental method	Outcome	Study
Collagen, Cysteine-modified ϵ-poly(l-lysine), In situ-polymerized polypyrrole	In vitro	Enhanced tissue adhesion, low cytotoxicity, improved cell migration, blood coagulation, and accelerated full-thickness wound healing.	[55]
Human placental collagen/adipose-derived stem cells (ADSCs)	In vivo	Significant wound healing and contraction with enhanced fibroblast proliferation, angiogenesis, and collagen deposition.	[56]
Curcumin-loaded liposomes, Lysine–collagen	In vitro and in vivo	Improved wound healing efficacy with sustained drug release and enhanced tissue regeneration.	[57]
Collagen, Laccase-protocatechuic aldehyde, Fe^3+	In vitro and in vivo	Enhanced mechanical properties, antioxidant activity, cell proliferation, and accelerated wound healing.	[58]
Recombinant human collagen type III, Multifunctional antibacterial nanoparticles	In vitro and in vivo	Programmed release of antibacterial nanoparticles and collagen type III for accelerated wound healing.	[59]
Collagen and polyethylene glycol, umbilical cord stem cell factor	In vitro and in vivo	Injectable, self-healing hydrogel promoting cell response, collagen deposition, and angiogenesis for diabetic wound repair.	[60]
Methacrylated collagen, 2-hydroxypropyl-beta-cyclodextrin/triclosan complex	In vitro and in vivo	Improved wound healing with controlled release of triclosan and enhanced antibacterial activity.	[61]
Collagen	In vivo	Super-ductile, injectable, self-healing hydrogels with accelerated wound-repair properties.	[62]
Human amnion, Rabbit collagen, Carboxymethyl cellulose sodium salt, Citric acid, Prawn shell chitosan	In vitro and in vivo	Rapid burn wound healing, improved re-epithelialization, and wound contraction when covered with a membrane.	[63]

Table 1.

Collagen-based hydrogels for accelerating wound healing.

3.2 Nanofibers

The integration of nanofibers and collagen, which possess advantageous characteristics including high porosity, exceptional bioactive agent delivery capacity, superior surface-area-to-volume ratio, and enhanced mechanical properties, has the potential to facilitate wound healing and stimulate skin regeneration [64]. Regenerative medicine and wound healing benefit from nanofibers due to their ability to mimic ECM and promote cellular proliferation and migration [65, 66]. In a rat model, electrospun tilapia collagen nanofibers were found to promote rapid and effective cutaneous wound healing, according to a study by Zhou et al. [67]. Collagen nanofibers accelerated wound healing in vivo, thereby substantially stimulating re-epithelialization [68]. It has been reported that appropriately dense nanofiber scaffolds hasten the healing of skin wounds, promote re-epithelialization, and generate cutaneous skin appendages in the skin [69]. Xie et al. [69] have shown that the utilization of nanofiber scaffolds significantly expedites the process of wound healing through the reduction of collagen I/collagen III and TGF-β1 ratios, which ultimately leads to a decrease in collagen deposition. Fibrosis was inhibited by polycaprolactone (PCL)/gelatin nanofiber scaffolds via the TGF-1/ tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) pathway and in a manner dependent on TGF-1. By facilitating granulation tissue formation, sustaining re-epithelialization, and stimulating angiogenesis, nanofiber systems may hasten the process of wound healing [69]. Nevertheless, further research is needed to determine the specific impacts of nanofiber scaffolds on collagen synthesis and scar formation.

The potential of biomimetic nanofibrous scaffolds in wound healing applications is further highlighted by their recent achievements. Using graphene oxide quantum dot nanocomposites and collagen crosslinked modified chitosan, Dutta et al. [70] created asymmetric scaffolds by electrospinning. These scaffolds demonstrated superior cytocompatibility, anti-inflammatory properties, and antibacterial activity. Rapid re-epithelialization and collagen deposition were shown in an in vivo assessment using a rat model, highlighting its applicability for quick wound healing. Similarly, nanofibrous membranes based on recombinant human collagen type III were developed by Dong et al. [71] and showed superior mechanical qualities, flexibility, and water absorption. These membranes’ capacity to accelerate wound closure and improve collagen deposition was demonstrated in vivo experiments on a mouse full-thickness wound model, underscoring their effectiveness in skin regeneration. For skin regeneration, Amini et al. [72] introduced a unique biomimetic hybrid scaffold made of decellularized dermis and collagen fibers that included stromal cell-derived factor-1 alpha (SDF-1α). According to this study., the prolonged release of SDF-1α from the scaffold demonstrated a strong capacity to quicken wound healing in diabetic rat models, pointing to its potential for skin tissue engineering.

3.3 Sponges

Collagen sponges possess exceptionally interconnected and porous architectures, allowing them to efficiently absorb blood and wound exudate as efficient wound dressings [73]. Collagen sponges are particularly advantageous in the context of wound healing due to their ability to suture delicate tissue and serve as a template for new tissue due to their wet strength [43]. It is possible to modify the porosity of collagen sponges through the manipulation of collagen content and the freeze-drying process [43, 74]. It is necessary to replace sponge dressings once they become completely saturated with absorbed exudate, with replacement occurring on a weekly or biweekly basis [75].

The efficacy of a collagen-based sponge as an active wound material has been demonstrated in a study by Aravinthan et al. [76] through its ability to promote speedier re-epithelialization. A dry sponge dressing can retain a moist environment for skin repair while absorbing a greater quantity of exudate from the lesion [77]. Wu et al. [77] have produced a Tau@Col sponge that, by incorporating taurine, exhibits anti-inflammatory and antioxidant properties. This is due to the sustained release of taurine, which promotes enhanced wound healing via inhibition of inflammation and stimulation of proliferation. When the Tau@Col sponge was utilized to treat a full-thickness wound model in vivo on rodents, it demonstrated the most rapid closure of the wound, as well as the most effective granulation formation and collagen deposition. Another work was conducted by Yao et al. [78] to assess the safety and effectiveness of employing an absorbable collagen sponge loaded with recombinant basic FGF topically to promote wound repair in cases of traumatic ulcers. Recombinant basic FGF-containing absorbable collagen sponge substantially accelerated the wound healing process, according to the study. Shi et al. [79] developed non-toxic sponge scaffolds using porcine skin-derived collagen (PSC) and fish scale-derived collagen (FSC). In rabbit studies, PSC and FSC scaffolds showed better burn wound healing with no scars compared to gauze and vaseline gauze groups. Table 2 summarizes the current research on collagen sponges.

Materials	Vascular growth	Anti-bacterial	Moist microenvironment	Hemostasis	Study
Tilapia collagen	✓			✓	[80]
Aminated β-Glucan (A-Glu), Type I collagen				✓	[81]
Gentamicin collagen (Genta-Coll)	✓	✓		✓	[82]
Tilapia skin collagen		✓		✓	[83]
Zwitterionic betaine, Collagen			✓	✓	[84]
Hydrolyzed collagen, S-nitrosoglutathione			✓		[85]

Table 2.

Summary of collagen-based sponges in wound repair studies.

3.4 Films

Primarily as a barrier, collagen films have been utilized in tissue engineering and wound healing. Collagen solutions can be used to cast and air-dry films with a thickness of approximately 0.1–0.5 mm, as with ophthalmological shields [43]. Collagen films produced via wind drying or freeze drying exhibit a supple and flexible texture, thereby enhancing their convenience of use and improving their ability to adhere to the wound. Furthermore, the thinness and transparency of these materials facilitate easy observation of the lesion, thereby enabling more accurate monitoring of the healing process [86]. They offer a more comfortable fit, are flexible and soft, and promote better wound adhesion [87]. Collagen possesses the ability to exert direct control over the wound microenvironment, facilitate cellular attachment and function by acting as a scaffold, and transport biologically active agents or antimicrobials to promote wound healing [21]. Rathod et al. [88] have demonstrated that collagen film infused with calendula flower extract has an enhanced capacity for wound healing. Incorporating collagen into wound healing can help speed up the recovery process as an additional measure [89].

3.5 Composites

In contrast to alternative types of wound dressings, collagen-based composites present a multitude of benefits. They promote tissue regeneration by modulating the wound microenvironment and providing an environment conducive to cell growth [90]. More importantly, it is imperative to comprehend the distinct physiological characteristics of each patient and the characteristics of the wound to determine the most suitable wound dressing for specific instances [91]. A study by Grigore et al. [92] has yielded a collagen-nanoparticle composite scaffold that exhibits promise in facilitating tissue regeneration and wound healing while also controlling infections. Another work by Sun et al. [93] has produced a bi-layered composite dressing composed of non-crosslinked collagen with the potential to expedite the inflammatory response during the initial phases of wound healing. For wound healing, a research study by Lakra et al. [42] has developed a collagen scaffold that is reinforced with furfural. This scaffold offers both mechanical support and protection against the external environment. Information on several collagen-based composites for accelerating wound healing is compiled in Table 3.

Materials	Form	Outcome	Study
Type I collagen, silver nanoparticles	Nanocomposite	Antimicrobial, non-toxic, and biocompatible with skin cells and fibroblasts	[94]
Collagen, zinc oxide nanoparticles, polydopamine	Nanocomposite	Broad-spectrum antimicrobial, anti-inflammatory, promotes blood vessel generation and collagen deposition	[95]
Curcumin, PCL, collagen	Electrospun fibers	Increased mechanical properties, effective against S. aureus, suitable for wound management	[96]
Biogenic nano-zinc oxide, collagen	Membrane	Enhanced wound healing activity, reduced MMP-9, TNF-α, MPO, NAG, increased IL-10, comparable to standard group	[97]
Mussel-inspired scaffold with collagen and hyaluronic acid	Porous scaffold	Reduced inflammation, sustained growth factor release, excellent swelling ability, potential for diabetic wound treatment	[98]
Fish collagen, hyaluronate, sodium alginate	Lyophilized scaffolds	Multifunctional wound dressing, enhanced water absorption, controlled drug release, biocompatible	[99]
Collagen, carboxymethylcellulose, silver nanoparticles	Freeze-dried composites	Prevented infection, prospective wound healing, biocompatible, no cytotoxic effects	[100]

Table 3.

Collagen-based composites for accelerating wound healing.

3.6 Collagen nano- and micro-particles for drug/protein/peptide delivery

For accelerating wound healing, collagen nanoparticles and microparticles have demonstrated promise in the delivery of proteins, drugs, and peptides. These particles have the potential to be utilized in a multitude of medicinal domains, encompassing cosmetic purposes and the regeneration of nerve tissue, articular cartilage, skin, and bone [101]. Collagen nanoparticles possess the ability to penetrate skin lesions with relative ease, rendering them optimal candidates for therapeutic delivery under control [102]. It has been demonstrated that nanoparticles, including collagen nanoparticles, enhance the quality of wound healing and promote its progression as a result of their high ratio of surface area to volume, which enables more effective drug encapsulation and controlled release [103]. In addition, these particles possess benefits for wound healing applications [104] because their complex release profiles, which are unattainable with alternative delivery systems, can be modified via a multitude of parameters including material type, particle size, surface charge, encapsulation method, etc.

In the study by Li et al., the injectable granular hydrogel composed of collagen microparticles and hydroxyapatite nanoparticles connected with tannic acid demonstrated dynamic reversibility, making it effective in promoting wound healing and suppressing inflammatory responses [105]. Conversely, despite being evaluated as prospective grafting materials, collagen-type I scaffolds incorporating Aloe vera and gelatin-collagen microparticles failed to demonstrate a substantial enhancement in wound healing in the study by Gil-Cifuentes et al. [106]. This lack of improvement may be attributed to the scaffolds’ low biodegradability. For the treatment of full-thickness burn infections, the curcumin-loaded microspheres encased in collagen-cellulose nanocrystal scaffolds by Guo et al. [107], exhibited encouraging outcomes in terms of preventing local inflammation and accelerating dermal regeneration. The aforementioned results collectively emphasize the adaptability and potential of collagen microparticles and nanoparticles in promoting strategies for wound healing.

4. Synthetic collagen-mimetic peptides

As wound healing is a complex biological process, it is crucial to develop novel approaches to facilitate this process. Synthetic peptides known as collagen mimetic peptides (CMPs) are engineered to simulate the characteristics and operations of endogenous collagen. Their capacity to expedite the process of wound healing has attracted considerable interest. The purpose of collagen CMPs is to replicate the appearance and functionality of collagen, a significant ECM protein that is indispensable for wound healing and physiological processes [108, 109]. The capacity of CMPs to aggregate into triple helices resembling collagen allows them to bind to partially denatured collagen, potentially playing a role in their efficacy as wound healing agents [110].

Hwang et al. [111] devised a method to deliver controlled vancomycin via elastin-like peptide and collagen-like peptide nanovesicles (ECnVs) affixed to collagen-containing matrices, to advance antibiotic therapeutics. The research conducted by the authors revealed that vancomycin exhibited improved entrapment efficacy, resulting in prolonged antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, Chattopadhyay et al. [112] brought attention to the effectiveness of a bifunctional peptide that promotes wound closure in mice and facilitates collagen deposition by clustering TGF-β receptors on damaged collagen. Moreover, Baratta et al. found that CMPs can accelerate corneal lesion healing and promote regeneration of corneal epithelial cells [109].

Deng et al. [113] investigated advancements in hydrogel formulations intended for wound repair. They created a thermosensitive hydrogel composed of chitosan conjugated with recombinant collagen-peptide. This hydrogel demonstrated exceptional mechanical strength and facilitated both cell infiltration and wound healing. Mistry et al. [114] investigated the potential of nutraceutical collagen peptides for cutaneous wound healing. Their findings revealed that significant wound closure was achieved in both young and aged fibroblasts via increased cellular proliferation and migration. Thapa et al. [115] developed vancomycin-containing liposomes tethered to collagen-based hydrogels as an advancement in wound infection control via CMP-tethered liposomes. By its sustained vancomycin release and enhanced antibacterial effects against MRSA, this method offers the potential for a topical formulation that can be utilized to prevent MRSA wound infections. The wound-healing potential of collagen peptides derived from the epidermis of Tilapia nilotica and Salmo salar was investigated by Mei et al. [116]. They found that altered wound microflora colonization was associated with accelerated healing rates.

5. Collagen and extracellular vesicles

Extracellular vesicles (EVs) are vital intermediaries of intercellular communication; they are secreted by a variety of cells and perform indispensable functions in processes that promote regeneration [117]. EVs serve as mediators that enable communication between parent and recipient cells; they actively participate in the complex processes of wound healing, which encompass remodeling, hemostasis, inflammation, and proliferation [117]. The potential for harnessing the intrinsic capabilities of EV-based signaling during each of these stages of wound healing indicates a viable approach to stimulating compromised healing processes.

Extracellular vesicles (EVs) originating from a wide range of sources, including blood, skin cells, stem cells, immune cells, and epithelial cells, have exhibited the capacity to stimulate the deposition of ECM, remodel tissue, and contract wounds [118]. For example, EVs derived from mesenchymal stem cells (MSCs) and fibroblasts have been shown to promote wound healing by optimizing the functions of endothelial and fibroblast cells [119, 120]. Furthermore, EVs derived from MSCs exhibit considerable promise in facilitating the process of wound healing due to their favorable characteristics, including minimal immunogenicity, exceptional stability, and diverse therapeutic impacts on skin regeneration [120]. An unprecedented approach to managing chronic wounds involves the integration of bioactive molecules, including miRNAs and pharmaceuticals, with transformed EVs [121]. MSCs-derived nanovesicles imitate EVs secreted by cells in nature; these nanovesicles promote wound repair in vitro and in vivo [122].

Efforts to optimize the efficiency of wound healing encompass novel approaches, including the integration of collagen and EVs, as well as hydrogel dressings that provide sustained EV release [123]. The potential of this method is illustrated by the application of collagen III protein hydrogels that release EVs for an extended period, thereby facilitating angiogenesis-dependent cutaneous wound healing [124]. The collaboration between EV release and collagen synthesis to expedite wound healing is illustrated in Figure 2. This process involves an inflammatory response, cellular ingestion of vesicles, and improved cell functions that ultimately result in tissue repair.

Figure 2.

Accelerating wound healing with collagen and EVs.

6. Collagen’s regulation

Collagen, a crucial protein, actively regulates various regenerative processes such as proliferation, differentiation, inflammation, and angiogenesis. In terms of cell proliferation and cycle progression, monomeric collagen is implicated in promoting cell cycle advancement by suppressing endogenous p21 levels, thereby releasing the “regulatory brake” on the cell cycle [125]. Regarding angiogenesis, collagen fibers offer guidance for endothelial cell migration, with collagen I supporting migration and collagen IV ensuring proper lumen formation and vascular integrity [126]. Notably, collagen and fibrin collaboratively influence sprout angiogenesis, while the collagen-derived inhibitor Arresten suppresses squamous cell carcinoma invasion [127, 128]. In the realm of cell differentiation, fibroblast-derived collagens, particularly type VI collagen, play a pivotal role in modulating key steps in cancer development, including apoptosis, proliferation, angiogenesis, invasion, and metastasis [129].

The induction of collagen synthesis involves both physical and chemical factors. Physical factors like mechanical stress, electrical stimulation, and ultrasound, along with chemical factors such as ascorbic acid, copper, and retinoic acid, contribute to this process. Various studies reveal that physical and biological factors can either stimulate or hinder collagen biosynthesis at different gene expression levels. For instance, during muscle wound healing, an increase in collagen synthesis rate is observed, indicating that collagen deposition is primarily achieved through heightened synthesis during this process [130, 131]. Neocollagenesis and neoelastinogenesis are recognized for their significant roles in addressing esthetic conditions like cutaneous aging and scarring [132].

6.1 Physical factors

The process of collagen synthesis is subject to strict regulation at the transcriptional level by various cytokines [133]. A multitude of trans-acting protein factors and cis-acting regulatory elements participate in the control of collagen gene expression [133, 134]. As an illustration, the synthesis of type I collagen fibers is controlled by a variety of positive or negative transcription factors in reaction to distinct signaling pathways [133].

Although the available evidence does not explicitly discuss the precise impacts of ultrasound, mechanical stress, and electrical stimulation on collagen synthesis and regulation, it is established that such stimuli can alter cellular behavior and gene expression, including collagen gene expression. However, additional research may be necessary to determine the precise mechanisms and effects of these physical factors on collagen synthesis and regulation. It has been shown that electrical stimulation can direct the formation of new collagen, even in the absence of neural influences [135]. The results of this study indicate that electrical stimulation has a substantial impact on the regulation of collagen synthesis in the course of wound healing. Additionally, the studies emphasize the significance of mechanical stress in regulating collagen synthesis. There is a suggestion that when using electrical stimulation at levels that affect both motor and sensory functions, the resulting mechanical environment might not completely mimic the natural stress and strain that collagen fibers typically experience during regular daily activities. In other words, the effects of electrical stimulation may not precisely replicate the usual conditions that contribute to the maturation and cross-linking of collagen fibers in the body [136].

Similarly, recent studies investigate the impact of ultrasound on the synthesis and regulation of collagen. It has been demonstrated that ultrasound can induce fibroblast proliferation and migration, thereby stimulating collagen secretion and augmenting the tensile strength of connective tissues [133]. Research on porcine lesions has documented that the application of low-amplitude ultrasound promotes increased collagen deposition and density, suggesting that it has a beneficial effect on the healing process [137]. Furthermore, it has been discovered that therapeutic ultrasound can alter the biological and mechanical characteristics of fibroblasts, thereby impacting the phases of wound healing involved in regeneration and remodeling. Research has shown that the application of high-intensity ultrasound therapy can substantially enhance the synthesis of ECM constituents, such as collagen type I and fibronectin, which are indispensable for the processes of tissue regeneration and wound repair [138]. In addition, a clinical trial revealed that an ultrasonic surgery system stimulated collagen synthesis, demonstrating its potential to improve wound healing [139].

6.2 Chemical factors

A multitude of chemical factors, such as cytokines, ascorbic acid, glucocorticoids, and signaling pathways, regulate collagen synthesis. These factors are of paramount importance in the control of collagen gene synthesis and expression, which has serious implications for tissue morphogenesis, fibrosis, and even cancer.

The intricate regulation of type I collagen gene expression encompasses a multitude of cytokines operating at the level of transcription. Skin lesions, including scleroderma, may result from an overproduction and accumulation of collagen in different tissues [133]. It has been shown that ascorbic acid significantly enhances collagen synthesis while leaving other protein synthesis unaffected; furthermore, this effect seems to be unrelated to its function as a cofactor in the hydroxylation of lysine and proline [140]. Glucocorticoids inhibit collagen synthesis specifically at micro-molar concentrations, whereas cancer cells utilize mutated genes, transcription factors, signaling pathways, and receptors to modulate collagen biosynthesis [141]. Furthermore, the regulation of collagen can be achieved through the use of various inhibitory agents that target biosynthesized processes and distribution arrangements. Furthermore, indirect methods of collagen modification are also possible and are partially ascribed to other complex signaling pathways and interrelated molecular mechanisms [141].

7. Limitations and future trends

Collagen-based therapeutics, such as wound dressings containing diverse polymers, are indispensable for the process of wound healing. These scaffolds enable effective drug delivery, tissue engineering, and hemostatics through their ability to modulate the wound microenvironment and support cellular processes. Despite these advantages, collagen-based therapies have significant drawbacks, such as a dearth of high-quality research and randomized control trials substantiating their clinical utility, an absence of agreement regarding the most effective treatment approaches, and financial considerations that might impede patient access [142, 143].

Future developments in collagen-based therapies aim to overcome current limitations and enhance effectiveness, thus addressing present challenges. An example of this is the investigation of combination therapies, which entail the integration of collagen-based products with additional components for wound healing, including stem cells, EVs, and growth factors [144, 145]. Another promising approach involves using electrospun nanofibrous membranes made of recombinant human collagen type III. These membranes have demonstrated effectiveness in promoting the healing of skin wounds [145]. Furthermore, current investigations are concentrated on the advancement of innovative collagen-based products, such as a collagen-like protein formed via elastin-like polypeptide fusion, which seeks to enhance the efficacy of wound healing [145]. In brief, while collagen-based therapies show promise in accelerating wound healing, the ongoing pursuit of advancements and novel methodologies, such as the development of combination therapies and new products, highlights the constantly evolving nature of this field.

8. Conclusion

Collagen is crucial to tissue preservation and regeneration, and this chapter covered wound healing in detail. Collagen coordinates tissue regeneration and repair as a dynamic conductor during ECM remodeling. The chapter covers collagen’s basic activities in matrix remodeling and its many wound-healing applications, including scaffolds, micro/nanoparticles, synthetic peptides, and EV interactions. The chapter also examines collagen’s regulatory role in cellular processes and collagen production stimulation methods. It looks ahead to collagen-based wound healing medicines and their potential. This chapter aims to contribute to the ongoing wound healing dialog by providing a thorough overview of current advancements and potential directions, inspiring further research and innovation in collagen-based therapeutic interventions for patients and healthcare practices.