Advanced drug delivery systems and artificial skin grafts for skin wound healing☆
Graphical abstract
Introduction
As the largest organ of the human body, skin plays a pivotal role in maintaining homeostasis as well as protecting the internal organs from the external environment. Cutaneous injuries, especially chronic wounds, burns, and skin wound infection, require painstakingly long-term treatment with an immense financial burden to healthcare systems worldwide. An aging population coupled with escalating rates of diabetes and obesity continue to increase the prevalence of chronic wounds. It has been estimated that 1–2% of the population in developed countries will experience a chronic wound in their lifetime [1]. In the US, chronic wounds affect 6.5 million patients, with about 18% of diabetic patients over the age of 65 suffer from non-healing foot ulcers [2]. Non-healing wounds such as large-area burns, full-thickness wounds, infected wounds, and chronic wounds not only impair the physiological functions of the skin barrier but can also inflict morbidity and even death [3]. Those wounds require intensive and long-term care with costly wound care products [4,5]. Unfortunately, despite of intense investigation to improve cutaneous wound care, clinical management of chronic wounds remains unsatisfactory in many cases.
Various strategies including growth factor and gene delivery as well as cell therapy have been used to enhance the healing of non-healing wounds. Drug delivery systems across the nano, micro, and macroscales can extend half-life, improve bioavailability, optimize pharmacokinetics, and decrease dosing frequency of drugs and genes. Nanoparticle-mediated delivery would be needed for protein and nucleic acid therapeutics to access the intracellular targets. On the other hand, microparticle-mediated delivery would offer a more sustained therapeutic effect if only extracellular delivery is required because the lower surface-to-volume ratio would slow the release kinetics [6]. Microcapsules or microgels may also be used for cell delivery [7,8]. Among various drug delivery systems, macro-system delivery through tissue-engineered scaffolds is particularly relevant to wound healing as they can serve as a depot for incorporating therapeutics. Furthermore, they can physically protect the wounds as wound dressings [[9], [10], [11]]. Therefore, drug-incorporated scaffolds are particularly promising for synergistically accelerating the healing process of chronic wounds.
Although many bioactive approaches based on bioengineered acellular scaffolds have been explored to improve non-healing wound care, many have proved ineffective in clinical trials [[12], [13], [14], [15]]. The innate wound healing ability of skin is largely depended on the type of wound, patient's accompanying diseases or injury state [[12], [13], [14], [15], [16], [17], [18]]. For advanced wound healing, replacement of the damaged skin tissue with cellular skin substitutes is particularly effective for restoration of the barrier and regulatory functions of the skin at the wound site. Cellular scaffolds incorporating fibroblasts, keratinocytes, stem/progenitor cells, or reprogrammed cells have shown promising results for accelerating in vivo wound healing and reducing scar formation [[19], [20], [21], [22], [23]]. In particular, stem cell-based approaches show increasing promise by acting through immune modulation, paracrine effects, and differentiation into epidermal and dermal cells to replace the damaged skin [24]. Bone marrow-derived mesenchymal stem cells (BM-MSC) as well as MSCs isolated from adipose tissues, skin tissues (epidermal stem cells), umbilical cord, and blood, have been explored in wound healing delivery systems [19,[25], [26], [27]]. In addition, induced pluripotent stem cells (iPSCs) from somatic cells can be an attractive alternative as autologous cell sources [22,23,28,29]. However, the poor viability of stem cells in wound beds characterized by a harsh inflammatory environment often decreases the therapeutic potential of the cells [[30], [31], [32]]. Thus, cell engineering and reprogramming via genetic modification are exciting strategies for advanced wound healing by improving the survival of the transplanted cells, controlling the secretion of therapeutic factors and enhancing the biological functions in vivo [21,33,34]. Recently, genome editing/correction of cells from patients with chronic wounds or skin disorders have also drawn attention for the potential of patient-specific wound therapy [[35], [36], [37], [38], [39]].
Cell-laden bioengineered scaffolds have been produced as skin substitutes mimicking the morphological and biological features of the skin tissue. Conventional approaches to skin tissue engineering have focused on imitating the layer-by-layer structure of skin, but simplifying the complexity of the skin tissue to two major compartments, epidermis and dermis [[40], [41], [42], [43]]. Although the first few generations of skin constructs have produced acceptable results in many cases, there remains ample room for improvement with advanced skin constructs possessing control over cellular composition and spatial distribution to recapitulate the complicated architecture and functions of native skin tissues.
This review covers comprehensively the advanced treatment strategies to improve the quality of cutaneous wound healing and further explores techniques for cell engineering and skin tissue engineering to develop cellular skin substitutes.
Section snippets
Phases of normal wound healing
Cutaneous wound healing consists of three partially overlapping phases: hemostasis and inflammation, new tissue formation, and tissue remodeling (Fig. 1). Within these broad phases, there exist a series of tightly regulated event involving chemotaxis, phagocytosis, neocollagenesis, collagen degradation, and collagen remodeling [44]. In addition, wound healing in human is a complicated biological process requiring the coordinated migration and proliferation of both keratinocytes and fibroblasts,
Guidelines for wound assessment and management
As mentioned above, chronic wounds are commonly caused by an underlying pathologic process, such as infection or vascular insufficiency, that produces repeated and prolonged insults to the tissues. Failure to correct or control the underlying pathology can result in a persistent cycle of injury that causes repetitive tissue damage. Consequently, the care for chronic wounds aims at not only removing or ameliorating the etiologic causes, but also addressing the underlying systemic and metabolic
Advanced delivery systems for wound healing
This section introduces the most recent and advanced drug delivery systems based on nanoparticles, microcarriers and tissue-engineered scaffolds for wound healing (Fig. 2). Nano-sized carriers are required for delivery of biologics that act intracellularly, such as peptides or nucleic acids. Small size would favor an improved drug penetration into wound beds and an increased intracellular uptake. On the other hand, micro-sized carriers offer a slower extracellular drug release due to a low
Microcarriers
When intracellular delivery is not required, microspheres are advantageous because of better control of the drug release profile, particularly with low burst release. As gentamycin sulfate (GS) was incorporated to gelatin microspheres (GMs), and then embedded in a silk fibroin (SF) scaffolds, the drug release rate of GS-incorporated GM/SF (GS/GM/SF) scaffolds was significantly slower than that of GS-incorporated SF (GS/SF) scaffolds without microencapsulation [217]. Furthermore, the GS/GM/SF
Wound dressing materials
Ideal wound dressing exhibits good biological compatibility, biodegradability, water adsorption and retention properties, low cytotoxicity, nonstick ability, and antibacterial effects. It prevents the wound from being infected, allows gas exchange, could be removed easily, adsorbs excrescent wound exudate, and remains a part of the exudate to maintain local moisture of the wound, which accelerates wound healing. Moreover, the materials can serve as a depot for delivering a diversity of
Cellular skin substitutes
Cell-based therapy approaches for wound healing are advantageous over delivering single soluble factors in that administered cells can respond to the local environment and release multiple factors.
Skin equivalents
The limitation of current biomaterial-based skin substitutes is poor vascularization, which incurs long healing period and unsatisfactory cosmetic outcome [334]. Stem cells hold great potential for tissue regeneration as they have excellent immunocompatiblity, secrete numerous growth factors, and produce matrices. Therefore, skin equivalents can be developed by using stem cells and their complexes with biomaterials. In this part, we summarize the skin equivalents generated with cells or through
Summary and perspectives
Among various innovative strategies of drug delivery for the cutaneous wound healing, scaffold-mediated drug delivery approaches are particularly suited for improving wound healing because the scaffold can act as a barrier to protect against infections and to maintain moisture environment in addition to serving as a drug reservoir to provide wound-stage specific biochemical cues and drugs. Cell-laden scaffold can further bring the power of cell therapy and tissue engineering to bear, and it is
Acknowledgement
The authors thank Dr. Dan Shao for his technical assistance. We also thank Dr. Chinmaya Mahapatra for finding literature and critical discussion on this manuscript. This work was supported by NIH (AR073935 and HL140275), Global Research Laboratory Program (Korean NRF: 2015032163), Global Research Development Center Program (Korean NRF: 2018K1A4A3A01064257), Basic Science Research Program (Korean NRF: 2016R1A6A3A03012178), National Key R&D Program of China (2018YFC1105704, 2017YFC1103304,
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This review is part of the Advanced Drug Delivery Reviews theme issue on "Perspectives and review articles on nanomedicine from NanoDDS'17"
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Co-first author.