Chronic wounds are a health problem that have devastating consequences for patients and contribute major costs to healthcare systems and societies. To understand the magnitude of this health issue, a systematic review was undertaken. Searches were conducted in MEDLINE, EMBASE, EBM Reviews and Cochrane library, CINAHL, EBSCO, PsycINFO, and Global Health databases for articles published between 2000 and 2015. Included publications had to target adults (≥18 years of age), state wound chronicity (≥3 weeks) and/or label the wounds as chronic, complex, hard‐to‐heal, or having led to an amputation. The review excluded studies that did not present data on generic health‐related quality of life and/or cost data, case studies, randomized controlled trials, economic modeling studies, abstracts, and editorials. Extracted data were summarized into a narrative synthesis, and for a few articles using the same health‐related quality of life instrument, average estimates with 95% confidence intervals were calculated. Thirty articles met the inclusion criteria. Findings revealed that health‐related quality of life was lowest for physical pathologies, and based on average estimates were scores most inferior in the domain physical role for both patients with chronic wounds and for those with wound‐related amputations. The cost burden was mainly attributed to amputations for patients also comorbid with diabetes, where the cost for hospitalization ranged from US$12,851 to US$16,267 (median) for this patient group. Patients with chronic wounds have poor health‐related quality of life in general and wound‐related costs are substantial. Development and implementation of wound management strategies that focus on increasing health‐related quality of life and effectively reduce costs for this patient group are urgently needed.

Engineering synthetic hydrogels on a molecular basis to introduce natural features that are important in instructing cell behavior is becoming increasingly crucial in biomaterial-based approaches for regenerative medicine and in cell biology to study cell-matrix interactions in three-dimensions (3D). Here, we used collagen gels and exploited the design flexibility of the biological, biochemical and physical characteristics offered by a PEG-based hydrogel system to systematically study the effect of specific extracellular microenvironments on the behavior of primary human fibroblasts in 3D. We firstly found that the proliferation profiles of fibroblasts from different patients cultured within collagen gels (3D) differed significantly from their behavior observed on tissue culture plastic (2D). Furthermore, using the biomimetic PEG-based matrix we showed that cell proliferation in 3D could be selectively manipulated via alteration of the gel characteristics. In particular, this study revealed that, in spite of matrix sensitivity to proteases (e.g. MMP) and the presence of cell-integrin binding sites, at high stiffness (elastic modulus, G' >1200 Pa) the matrix acts as a barrier for cells cultured in 3D. Finally, a comparison between the biomimetic PEG-based and collagen gels indicated that differences in their viscoelastic behaviours, determined by the nature of network structures and cross-links, may influence the mechanism(s) cells employ to remodel their 3D extracellular microenvironment. In conclusion, these studies highlight that for proliferation in 3D, compared to 2D, cells require strategies to overcome the physical impediment posed by the matrix. We also demonstrate that by exploiting the design flexibility of the characteristics offered by these biomimetic hydrogels, it is possible to separately investigate complex aspects characterizing the cell-matrix interactions in 3D; this has the potential to have great impact in regenerative medicine, as well as in cell biology and cancer research. Abstract Engineering synthetic hydrogels on a molecular basis to introduce natural features that are important in instructing cell behavior is becoming increasingly crucial in biomaterial-based approaches for regenerative medicine and in cell biology to study cell-matrix interactions in three-dimensions (3D). Here, we used collagen gels and exploited the design flexibility of the biological, biochemical and physical characteristics offered by a PEG-based hydrogel system to systematically study the effect of specific extracellular microenvironments on the behavior of primary human fibroblasts in 3D. We firstly found that the proliferation profiles of fibroblasts from different patients cultured within collagen gels (3D) differed significantly from their behavior observed on tissue culture plastic (2D). Furthermore, using the biomimetic PEG-based matrix we showed that cell proliferation in 3D could be selectively manipulated via alteration of the gel characteristics. In particular, this study revealed that, in spite of mat...

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Wound healing involves a complex series of biochemical events and has traditionally been managed with 'low tech' dressings and bandages. The concept that diagnostic and theranostic sensors can complement wound management is rapidly growing in popularity as there is tremendous potential to apply this technology to both acute and chronic wounds. Benefits in sensing the wound environment include reduction of hospitalization time, prevention of amputations and better understanding of the processes which impair healing. This review discusses the state-of-the-art in detection of markers associated with wound healing and infection, utilizing devices imbedded within dressings or as point-of-care techniques to allow for continual or rapid wound assessment and monitoring. Approaches include using biological or chemical sensors of wound exudates and volatiles to directly or indirectly detect bacteria, monitor pH, temperature, oxygen and enzymes. Spectroscopic and imaging techniques are also reviewed as advanced wound monitoring techniques. The review concludes with a discussion of the limitations of and future directions for this field.

Oxygen is a potent modulator of cell function and wound repair in vivo. The lack of oxygen (hypoxia) can create a potentially lethal environment and limit cellular respiration and growth or, alternatively, enhance the production of the specific extracellular matrix components and increase angiogenesis through the hypoxia-inducible factor-1 pathway. For the in vitro generation of clinically relevant tissue-engineered grafts, these divergent actions of hypoxia should be addressed. Diffusion through culture medium and tissue typically limits oxygen transport in vitro, leading to hypoxic regions and limiting the viable tissue thickness. Approaches to overcoming the transport limitations include culture with bioreactors, scaffolds with artificial microvasculature, oxygen carriers, and hyperbaric oxygen chambers. As an alternate approach, angiogenesis after implantation may be enhanced by incorporating endothelial cells, genetically modified cells, or specific factors (including vascular endothelial growth factor) into the scaffold or exposing the graft to a hypoxic environment just before implantation. Better understanding of the roles of hypoxia will help prevent common problems and exploit potential benefits of hypoxia in engineered tissues.

In view of these results, it is hypothesized that a specific inhibitor of MMP-9 could potentially be more therapeutically effective than general MMP inhibitors in modulating chronic ulcers towards a healing state.

Cutaneous wound healing is the process by which skin repairs itself. It is generally accepted that cutaneous wound healing can be divided into 4 phases: haemostasis, inflammation, proliferation, and remodelling. In humans, keratinocytes re-form a functional epidermis (reepithelialization) as rapidly as possible, closing the wound and reestablishing tissue homeostasis. Dermal fibroblasts migrate into the wound bed and proliferate, creating “granulation tissue” rich in extracellular matrix proteins and supporting the growth of new blood vessels. Ultimately, this is remodelled over an extended period, returning the injured tissue to a state similar to that before injury. Dysregulation in any phase of the wound healing cascade delays healing and may result in various skin pathologies, including nonhealing, or chronic ulceration. Indigenous and traditional medicines make extensive use of natural products and derivatives of natural products and provide more than half of all medicines consumed today throughout the world. Recognising the important role traditional medicine continues to play, we have undertaken an extensive survey of literature reporting the use of medical plants and plant-based products for cutaneous wounds. We describe the active ingredients, bioactivities, clinical uses, formulations, methods of preparation, and clinical value of 36 medical plant species. Several species stand out, including Centella asiatica, Curcuma longa, and Paeonia suffruticosa, which are popular wound healing products used by several cultures and ethnic groups. The popularity and evidence of continued use clearly indicates that there are still lessons to be learned from traditional practices. Hidden in the myriad of natural products and derivatives from natural products are undescribed reagents, unexplored combinations, and adjunct compounds that could have a place in the contemporary therapeutic inventory.

Melt electrospinning in a direct writing mode is a recent additive manufacturing approach to fabricate porous scaffolds for tissue engineering applications. In this study, we describe porous and cell-invasive poly (ε-caprolactone) scaffolds fabricated by combining melt electrospinning and a programmable x-y stage. Fibers were 7.5 ± 1.6 µm in diameter and separated by interfiber distances ranging from 8 to 133 µm, with an average of 46 ± 22 µm. Micro-computed tomography revealed that the resulting scaffolds had a highly porous (87%), three-dimensional structure. Due to the high porosity and interconnectivity of the scaffolds, a top-seeding method was adequate to achieve fibroblast penetration, with cells present throughout and underneath the scaffold. This was confirmed histologically, whereby a 3D fibroblast-scaffold construct with full cellular penetration was produced after 14 days in vitro. Immunohistochemistry was used to confirm the presence and even distribution of the key dermal extracellular matrix proteins, collagen type I and fibronectin. These results show that melt electrospinning in a direct writing mode can produce cell invasive scaffolds, using simple top-seeding approaches.