ReviewEmerging and innovative approaches for wound healing and skin regeneration: Current status and advances
Introduction
Skin wounds represent a major healthcare problem owing to an increasing number of trauma and pathophysiological conditions. Normal wound healing process includes a very well-orchestrated and regulated process consisting of series of events such as haemostasis, inflammation, proliferation and extracellular matrix (ECM) remodelling [1]. The four healing phases involve interactions between various types of cells, bioactive factors and a supporting platform, which is usually the natural ECM secreted by cells [1]. This normal healing process gets severely dysregulated in case of pathophysiological conditions. Large trauma wounds due to burns or accidents result in loss of majority of skin tissue and thus fail to heal [2]. Majority of non-healing wounds are associated with accidents or disease conditions like diabetes. Such conditions hamper the normal healing pattern of skin tissue and has been a major social and financial burden since decades.
The wound healing cascade begins with hemostasis and inflammation. This stage involves recruitment of blood platelets and immune cells to control loss of blood and clearing of pathogens [3]. The initially recruited immune cells play a major role in secreting chemokines and growth factors, which attract cells and thereby lead the healing process to its next phase of proliferation. The proliferation phase comprises of numerous events like granulation tissue development (formation of provisional ECM), angiogenesis (formation of blood vessels) and re-epithelialization (formation of epidermal skin layer), thereby resulting in wound contraction. This particular phase is regulated through crosstalk between various cells, mainly macrophages, fibroblasts, endothelial cells and keratinocytes. The final phase constitutes remodelling event, in which the previously formed matrix is slowly morphed towards forming either a functional skin or a semi/non-functional scar tissue [3].
In case of non-healing wounds, for example diabetic wounds, the healing process gets obstructed at the very initial phase and gradually turns to be chronic due to failure in healing [4]. Depending on the type of chronic wound (like pressure sores, venous ulcers or diabetic wounds), the process may get hindered during any of the four stages. In case of large burn wounds, natural healing is affected due to significant loss of skin tissue or failure to develop a provisional ECM matrix as a result of tissue necrosis [2,5]. Therefore, clinical interventions are essential for healing such wounds. The most successful strategy is to provide an artificial matrix in the form of wound dressing or skin graft, which serves as a provisional matrix, and thereby aid in the healing process [6]. Researchers have been developing numerous types of wound dressing materials or skin substitutes and trying to mimic the healing-wound or skin microenvironment through cutting edge technologies over the years [6]. The natural wound milieu consists of ECM platform having cell adhesive sites, instructive biochemical cues, growth factors and various types of cells [7]. Mimicking the whole microenvironment is very challenging and therefore most tissue engineers focus on the structural framework that is of prime importance in healing.
Significant improvement in the development of bioactive templates and pro-regenerative matrices has been going on because such matrices trigger the key events of natural healing cascade and help in the regeneration of functional skin tissue. Overall, the platform of a wound dressing or skin graft assists in healing the wounds at a faster rate in addition to the inherent healing process as illustrated in the schematic image (Fig. 1). Furthermore, depending on the type of functionalization of matrix, a specific stage or event of healing process can be stimulated by certain biomolecules like growth factors, cytokines, chemokines and cell adhesive peptides [[8], [9], [10]]. The present review will introduce the readers towards recent and emerging technologies being developed for the improvement of skin tissue engineering and wound healing. Herein, we have briefly reviewed scaffold fabrication approaches to fabricate tissue-engineered skin and bioactive wound dressings. In this review, we have started with the discussion about different scaffold design considerations, functionalization, immunomodulation and vascularization strategies. Furthermore, various smart technologies such as portable skin repair devices and spraying technologies developed in recent years in this field have been discussed and reviewed.
Artificial construct not only requires ideal surface, material, structural and mechanical properties but also cell instructive and cell conducive cues to guide the cells for efficient tissue regeneration [[11], [12], [13]]. The bioengineered matrix should be non-immunogenic, biocompatible, bio-resorbable, and porous in structure with sufficient mechanical strength [1,11,14]. Numerous natural biopolymers have been explored in this area within the last 30 years like cellulose, collagen, chitosan, fibrin, gelatin, silk fibroin, silk sericin, hyaluronic acid and many others [[15], [16], [17], [18]]. In addition, synthetic polymers like poly(vinyl alcohol) (PVA), poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polycaprolactone (PCL), nylon and silicone have also significantly contributed in the development of next generation wound dressings [19]. Apart from providing a physical support, the platform of artificial constructs offers barrier properties, moisture retention properties, and aids in tissue ingrowth at the wound site by acting as an artificial provisional matrix. Although various types of commercially available skin grafts are well described in numerous literature, a rational approach towards addressing the recent emerging techniques is of interest in further adopting efficient wound care therapeutics in future. The present study aims to highlight the progress of last few years in developing various types of tissue-engineered constructs with a special focus on vascularized skin grafts and immunomodulation approach.
Technological advancements in the last 2-3 decades have resulted in many Food and Drug Administration (FDA) approved bioengineered scaffolds and wound dressings, which are commercially available for wound healing applications [20]. This has increased the survival rates of burn and trauma patients. However, ‘cost to heal factor’ is still a major concern because most of the advancements in wound care therapeutics are highly expensive. Burn injuries and chronic wounds affect more than 11 million and 6.5 million people respectively every year; and the estimated healthcare cost may go beyond $14 billion considering the present situation [21]. Bridging the gap between number of patients and available wound care regimens is the ultimate aim of most researchers in order to treat millions of affected patients. This has motivated researchers to develop different cost-effective wound care solutions since the last decade [10,22,23]. Here, we critically appraise the research efforts concerned with the cutting-edge technologies for wound repair and regeneration. We would also touch upon the most recent advances in skin tissue engineering like development of pre-vascularized grafts, immunomodulatory constructs and siRNA/miRNA based therapeutics, which represent the next generation wound care technology. The review also provides an updated overview on improvisation on the autologous cell delivery with special dedicated discussions on portable bioprinters, spray devices and in situ hydrogels for immediate first-aid. Finally, we aim to provide an insight on the future directions and perspective of the improved wound healing technology and their possible impact in clinical practice.
Section snippets
Recent innovative strategies in wound healing and skin regeneration
Skin tissue engineering is a complex process involving appropriate choice of biomaterial, cell selection and designing of suitable platform in order to mimic structural and functional properties of skin [6,19]. In last five years, fabrication of a pro-regenerative construct has been a major focus of research in wound repair and regeneration [[24], [25], [26]]. The principal aim is to develop scaffolds containing cell instructive cues to restore the damaged skin in a regenerative manner as
Immunomodulation and vascularization based approach
Principal goals in wound management include vascularization in the regenerated tissue to achieve rapid wound healing and skin regeneration. Many pioneering approaches have utilized cellular and molecular biology for the development of pre-vascularized skin grafts over the past decade [17,29]. During the course of development of advanced cellular therapies, a greater comprehension of basic biology has been considered by the researchers in recent years. Targeting immune system for enhanced
SiRNA based skin therapeutics
Among the nucleic acid based wound healing strategies, utilization of siRNA and miRNA based wound healing has gained momentum over the past few years. Small interfering RNA is a small, synthetic RNA of 21–25 nucleotides length that can specifically carry out silencing of intended genes through knockdown of messenger RNA (mRNA) specific to the gene of interest [112]. Both the siRNA and miRNA are short stretches of nucleotide RNA duplex and holds potential to inhibit mRNA translation through
MicroRNA based skin therapeutics
The discussion on nucleotide-based treatments relevant in wound healing is incomplete without incorporating the context of miRNAs. Although both miRNA and siRNA share similar structures (~25 nucleotide RNA duplex with 2 nucleotides 3'overhang), their mode of action is different [127]. Unlike siRNAs that are designed prioritizing specificity for binding, miRNAs are comparatively imprecise in terms of complementarity to their target and hence can target multiple genes as depicted in Fig. 8.Ia [127
An update on the clinical trials
The clinical implementation of technology is necessary to validate proof of concept and pre-clinical studies performed in animal models. Clinical study not only reveals the treatment outcomes, but also unfolds the basic information like cost of treatment, patient safety and risks involved during the particular treatment. Efficacy of wound dressings and skin grafts have been constantly under evaluation through the regulated clinical trials on patients in multiple clinical set-ups over a period
Conclusion and future scope
Wound chronicity and poor healing associated with diabetic and trauma wounds are serious clinical problems, affecting millions of people around the world. Expensive treatments and long-term hospital-stays further worsen the situation, thus creating a major economic burden on the healthcare system. Tissue engineering concept together with recent technological advancements has led to obtaining efficient fabrication processes, which ultimately aim towards affordability when produced in large
Acknowledgment
BBM thankfully acknowledges funding support from Department of Biotechnology (DBT) & Department of Science and Technology (DST), Government of India.
Abbreviations
- 3D
- 3 dimensional
- RNA
- ribonucleic acid
- miRNA
- micro RNA
- siRNA
- small interfering RNA
- ECM
- extracellular matrix
- PVA
- poly(vinyl alcohol)
- PGA
- poly(glycolic acid)
- PLA
- poly(lactic acid)
- PCL
- polycaprolactone
- FDA
- food and drug administration
- CEA
- cultured epithelial autografts
- BMSCs
- bone marrow derived stem cells
- ADMSCs
- adipose derived mesenchymal stem cells
- TGF-β1
- transforming growth factor-beta 1
- α-SMA
- alpha smooth muscle actin
- HDF
- human dermal fibroblast
- NHDF
- normal human dermal fibroblasts
- HUVEC
- human umbilical vein endothelial cells
- DRT
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