Hyaluronan in wound healing: Rediscovering a major player

Wound healing involves a series of carefully modulated steps, from initial injury and blood clot to the final reconstituted tissue or scar. A dynamic reciprocity exists throughout between the wound, blood elements, extracellular matrix, and cells that participate in healing. Multiple cytokines and signal transduction pathways regulate these reactions. A major component throughout most of the process is hyaluronan, a straight‐chain carbohydrate extracellular matrix polymer. Hyaluronan occurs in multiple forms, chain length being the only distinguishing characteristic between them. Levels of hyaluronan in its high–molecular‐weight form are prominent in the earliest stages of wound repair. Progressively more fragmented forms occur in a manner not previously appreciated. We outline here steps in the wound healing cascade in which hyaluronan participates, as well as providing a review of its metabolism. Although described by necessity in a series of quantum steps, the healing process is constituted by a smooth continuum of overlapping reactions. The prevalence of hyaluronan in the wound (initially termed “hexosamine‐containing mucopolysaccharide”), particularly in its early stages, was pointed out over half a century ago by the Harvard surgeon J. Engelbert Dunphy. It appears we are now returning to where we started.     

Plasminogen activator/plasmin system: A major player in wound healing?

The role of the plasminogen activator/plasmin system in fibrinolysis has been well established. Indeed, clinicians worldwide have successfully utilized recombinant tissue-type plasminogen activator as first-line treatment of acute myocardial infarction for almost 2 decades. Outside the field of cardiology, there has been increasing excitement regarding the possible contribution of this system in many other important biological processes, including cell adhesion, cell migration, cell-cell signaling, tumor invasion and metastasis, ovulation, and wound healing. In this review, we present evidence in the current literature that the plasminogen activator/plasmin system does have a role in wound healing, looking at both normal and abnormal healing. Furthermore, the invaluable insights provided by numerous transgenic animal experiments are summarized.     

Cyclosporine A impairs wound healing in rats

Cellular immune responses may play an important role in the early inflammatory and cellular phases of wound healing. Cyclosporine A (CSA), a new immunosuppressive agent, impairs cellular immunity and T-cell-dependent humoral immunity. Therefore, the effect of CSA-induced immunosuppression in a rat wound-healing model was studied. Sprague-Dawley rats underwent a standardized skin incision and subcutaneous implantation of sterile polyvinyl alcohol sponges. CSA was dissolved in olive oil and given by gavage to one group of animals at a total dose of 125 mg/kg/10 days. The control group received an equivalent volume of olive oil. Ten-day-old wounds were weaker in CSA-treated animals, both in the fresh state (282 +/- 19 g vs 380 +/- 27 g, P less than 0.01), and after formalin fixation (1111 +/- 74 g vs 1419 +/- 57 g, P less than 0.01). In addition, CSA-treated rats accumulated significantly less hydroxyproline in the wound sponge granuloma, an index of reparative collagen deposition. The impairment in wound healing occurred without differences in body weight gain or organ weights. There was a profound immunosuppression in the animals receiving CSA as determined by thymic lymphocyte blastogenesis in response to Con A and PHA. These findings suggest that immunosuppression in otherwise healthy animals impairs wound healing.     

Biofilms in wound healing: A bibliometric and visualised study

Bibliometric analyses are often used as a means of visualising the knowledge base and associated trends and patterns in a target scientific field based on a quantitative review of the corresponding literature. In this study, we explore the current status of research pertaining to biofilms in wound healing and elucidate trends in this research space. Through this process, we gain insight into findings from papers indexed in the Web of Science Core Collection. These references were then analysed and plotted using Microsoft Excel 2019, VOSviewer, and CiteSpace V. The results provide a fresh perspective regarding global trends and hotspots in biofilm-related wound healing research. These findings also offer a foundation that researchers can use to identify active hotspots of scientific interest to guide further research endeavours.     

Inflammation and wound healing: the role of bacteria in the immuno-regulation of wound healing

Wound healing is a sequence of complex events, an imbalance of which can result in a failure of the wound to heal, with significant implications for patients and health care services alike. Although the exact mechanism that underlies these events is not fully understood, inflammatory processes and the innate immune system play a vital role, not only in normal wound healing but also in the pathophysiology of delayed wound healing. These defense mechanisms are affected by underlying disease states and medical conditions, for example, diabetes, venous insufficiency, and the inflammation associated with acute trauma. Importantly, however, these processes are also modulated in health by bacteria within the wound. This article examines the role of the mediators of inflammation involved in the wound-healing process and discusses the function of these mediators when normal healing fails. The reaction of the wound to bacterial contamination and the effect of bacteria on wound healing are also discussed.     

Neovascularisation in wound healing

Through the process of angiogenesis, vasculogenesis or arteriogenesis, the vascular network regenerates and viable tissue fills the wound bed. Research has attempted to determine how this knowledge can be applied into the clinical setting.     

Microdeformation in wound healing

Mechanical forces greatly influence cellular organization and behavior. Cells respond to applied stress by changes in form and composition until a suitable state is reestablished. However, without any mechanical stimuli cells stop proliferating, discontinue migration, go into cell‐cycle arrest, and eventually die. Hence, one can assume that pathologies closely depending on cell migration like cancer or atherosclerosis might be governed by biophysical parameters. Moreover, mechanical cues will have fundamental effects in wound healing. Especially negative pressure wound therapy has the potential to endorse wound healing by induction of both macrodeformation (wound contraction) and microdeformation (tissue reactions at microscopic level). So far, the capacity for researchers to study the link between mechanical stimulation and biological response has been limited by the lack of instrumentation capable of stimulating the tissue in an appropriate manner. However, first reports on application of micromechanical forces to wounds elucidate the roles of cell stretch, substrate stiffness, and tissue deformation during cell proliferation and differentiation. This review deals with their findings and tries to establish a link between the current knowledge and the questions that are essential to clinicians in the field: What is the significance of mirodeformations for wound healing? Does “dead space” impede propagation of mechanical cues? How can microdeformations induce cell proliferation? What role do fibroblasts, myofibroblasts, and mesenchymal stem cells play in chronic wounds with regard to micromechanical forces?     

Telemedicine in wound healing

Better care for patients and improved health care depends on the availability of good information which is accessible when and where it is needed. The development of technology, more specifically the Internet, has expanded the means whereby information can be acquired and transmitted over large distances enabling the concept of telemedicine to become a reality. Telemedicine, defined as the practise of medicine at a distance, encompasses diagnosis, education and treatment. It is a technology that many thought would expand rapidly and change the face of medicine. However, this has not happened and during the last decade although certain telemedicine applications, such as video-consulting and teleradiology, have matured to become essential health care services in some countries, others, such as telepathology, remain the subject of intensive research effort. Telemedicine can be used in almost any medical specialty although the specialties best suited are those with a high visual component. Wound healing and wound management is thus a prime candidate for telemedicine. Development of a suitable telemedical system in this field could have a significant effect on wound care in the community, tertiary referral patterns and hospital admission rates.     

Honey: An immunomodulator in wound healing

Honey is a popular natural product that is used in the treatment of burns and a broad spectrum of injuries, in particular chronic wounds. The antibacterial potential of honey has been considered the exclusive criterion for its wound healing properties. The antibacterial activity of honey has recently been fully characterized in medical‐grade honeys. Recently, the multifunctional immunomodulatory properties of honey have attracted much attention. The aim of this review is to provide closer insight into the potential immunomodulatory effects of honey in wound healing. Honey and its components are able to either stimulate or inhibit the release of certain cytokines (tumor necrosis factor‐α, interleukin‐1β, interleukin‐6) from human monocytes and macrophages, depending on wound condition. Similarly, honey seems to either reduce or activate the production of reactive oxygen species from neutrophils, also depending on the wound microenvironment. The honey‐induced activation of both types of immune cells could promote debridement of a wound and speed up the repair process. Similarly, human keratinocytes, fibroblasts, and endothelial cell responses (e.g., cell migration and proliferation, collagen matrix production, chemotaxis) are positively affected in the presence of honey; thus, honey may accelerate reepithelization and wound closure. The immunomodulatory activity of honey is highly complex because of the involvement of multiple quantitatively variable compounds among honeys of different origins. The identification of these individual compounds and their contributions to wound healing is crucial for a better understanding of the mechanisms behind honey‐mediated healing of chronic wounds.     

A review of microvascular measurements in wound healing

The microcirculatory evaluation in patients affected by arteriopathic or venous ulcers is usually carried out using laser Doppler flowmetry, transcutaneous oxygen (transcutaneous pressure of oxygen, TcPO(2)), and carbon dioxide (transcutaneous pressure of carbon dioxide, TcPCO(2)) measurements and capillaroscopy. These techniques provide significant pathophysiologic and prognostic information. TcPO(2) and TcPCO(2) diagnose and classify the extent of arterial disease in the leg ulcers caused by arterial disease; the prognostic value is recognized, though doubts about its prognostic potential exist in the case of leg ulcer. Laser Doppler flowmetry is able to identify the first functional impairment in the early stages of the arterial disease and in the complicated venous insufficiency. Capillaroscopy gives us morphological and quantitative parameters of the capillary bed that is damaged in arteriopathic and venous ulcers; nevertheless, it does not provide us with definite prognostic indexes. Combining the 3 methods may contribute to yield objective measures in the clinical management of lower extremity ulcers.