With all the advances in tissue engineering for construction of fully functional skin tissue, complete regeneration of chronic wounds is still challenging. Since immune reaction to the tissue damage is critical in regulating both the quality and duration of chronic wound healing cascade, strategies to modulate the immune system are of importance. Generally, in response to an injury, macrophages switch from pro-inflammatory to an anti-inflammatory phenotype. Therefore, controlling macrophages' polarization has become an appealing approach in regenerative medicine. Recently, hydrogels-based constructs, incorporated with various cellular and molecular signals, have been developed and utilized to adjust immune cell functions in various stages of wound healing. Here, the current state of knowledge on immune cell functions during skin tissue regeneration is first discussed. Recent advanced technologies used to design immunomodulatory hydrogels for controlling macrophages' polarization are then summarized. Rational design of hydrogels for providing controlled immune stimulation via hydrogel chemistry and surface modification, as well as incorporation of cell and molecules, are also dicussed. In addition, the effects of hydrogels' properties on immunogenic features and the wound healing process are summarized. Finally, future directions and upcoming research strategies to control immune responses during chronic wound healing are highlighted.

Rational Design of Immunomodulatory Hydrogels for Chronic Wound Healing.

Chronic wounds: Current status, available strategies and emerging therapeutic solutions.

Given their severity and non-healing nature, diabetic chronic wounds are a significant concern to the 30.3 million Americans diagnosed with diabetes mellitus (2015). Peripheral arterial diseases, neuropathy, and infection contribute to the development of these wounds, which lead to an increased incidence of lower extremity amputations. Early recognition, debridement, offloading, and controlling infection are imperative for timely treatment. However, wound characterization and treatment are highly subjective and based largely on the experience of the treating clinician. Many wound dressings have been designed to address particular clinical presentations, but a prescriptive method is lacking for identifying the particular state of chronic, non-healing wounds. The authors suggest that recent developments in wound dressings and biosensing may allow for the quantitative, real-time representation of the wound environment, including exudate levels, pathogen concentrations, and tissue regeneration. Development of such sensing capability could enable more strategic, personalized care at the onset of ulceration and limit the infection leading to amputation. This review presents an overview of the pathophysiology of diabetic chronic wounds, a brief summary of biomaterial wound dressing treatment options, and biosensor development for biomarker sensing in the wound environment.

https://www.mdpi.com/2306-5354/5/3/51/pdf

Smart Wound Dressings for Diabetic Chronic Wounds.

Hyaluronic acid (HA), as one of the main components of the extracellular matrix (ECM), plays a significant role in a multitude of biological processes involving cell migration, proliferation, differentiation, wound healing and inflammation. Thanks to its excellent biocompatibility, biodegradability and hygroscopic properties, HA has been used in its natural form for joint lubrication and ocular treatment. The chemical structure of HA can be easily modified by direct reaction with its carboxyl and hydroxyl groups. Recently, HA derivatives have been synthesised with the aim of developing HA-based materials with increased mechanical strength, improved cell interactions and reduced biodegradation and studied for regenerative medicine purposes, including cell therapy and tissue engineering. In this context, the present manuscript reviews HA applications from a basic point of view - including chemical modifications and cellular biology aspects related to clinical translation - and future perspectives of using biofabrication technologies for regenerative medicine. A detailed description of current clinical trials, testing advanced therapies based on combination of stem cells and HA formulations, is included. The final goal was to offer an integral portrait and a deeper comprehension of the current applications of HA from bench to bedside.

/pdf/advances-of-hyaluronic-acid-in-stem-cell-therapy-and-tissue-1u4erw15hg.pdf

Advances of hyaluronic acid in stem cell therapy and tissue engineering, including current clinical trials.

Background There is not an ideal biomaterial for tissue-engineered skin substitutes (TESSs), and most of the studies or existing therapies use xenogeneic origin natural biomaterials or biosynthetic scaffolds. Objective To analyse clinical, histological integration and homeostasis parameters of a human TESS manufactured with fibrin-hyaluronic acid biomaterial (HA-Skin), grafted in immunodeficient mice for 8 weeks, and compared with the gold standard treatment (Autograft), a human TESS manufactured with fibrin-agarose biomaterial (AG-Skin) and secondary wound healing dressings. Methods Human TESSs and autografts were implanted into BALB/c mice after surgical excision. Secondary wound healing approach was achieved with biosynthetic collagen wound dressing (Biobrane® ) and fibrin-hyaluronic acid or fibrin-agarose biomaterial without cells (Total N = 44). Clinical integration and homeostasis parameters were evaluated every two weeks for two months. Histological and immunohistochemical analyses were performed four and eight weeks after grafting. Results HA-Skin, AG-Skin and Autograft groups showed a proper clinical integration and epithelization eight weeks later. Scar evaluation revealed better results for Autograft and HA-Skin. Homeostasis analysis indicated similar values of transepidermal water loss and elasticity between HA-Skin (6.42 ± 0.75 g/h/m2 , 0.42 ± 0.08 AU), Autograft (6.91 ± 1.28 g/h/m2 , 0.40 ± 0.08 AU) and healthy mouse skin (6.40 ± 0.43 g/h/m2 , 0.35 ± 0.03 AU). Histological results showed that human TESSs and autografts presented better skin structuration and higher expression of cytokeratins. Conclusions This study suggests that human TESS based on fibrin-hyaluronic acid biomaterial could be suitable for clinical application in the treatment of several dermatological pathologies (wound healing).

Hyaluronic acid biomaterial for human tissue-engineered skin substitutes: Preclinical comparative in vivo study of wound healing.

The choice of which surgical dressing to use is an important step in the postoperative care of orthopaedic patients. This decision is influenced in part by the patient's level of activity prior to surgery, medical history, wound classification, and cost. As orthopaedic wounds are inherently complex, often overlying bony prominences, it is imperative that orthopaedic providers are aware of the dressings available and how best to deploy them. Classified into three categories (passive, active, and interactive), orthopaedic surgical dressings can vary based upon their mechanism of action, absorptive capacity, and ability to provide wound protection. Through the activation or promotion of one of the four stages of wound healing, orthopaedic surgical dressings act to optimize postoperative wound care, leading to improved patient outcomes and a decrease in associated complications. The combined use of multiple dressings, with varying attributes, provides the ultimate method for obtaining the ideal orthopaedic surgical dressing. Choosing the appropriate dressing and subsequent care regimen can prevent unnecessary hospitalizations and additional costs associated with complex wound care. Future prospective trials aimed at evaluating specific dressings and their utility in orthopaedics is warranted.

Orthopaedic surgical dressings

Norepinephrine is used in the acute care setting to establish and maintain hemodynamic stability in patients with hypotension. Although it is often a lifesaving medication, norepinephrine may lead to profound vascular insufficiency in the extremities, resulting in dry gangrene and skin necrosis. The purpose of this article is to present a case series of skin complications related to treatment with norepinephrine and review the pathophysiology behind these complications. The authors also explore risk stratification as it relates to history and clinical presentation with subsequent focus on contingencies to mitigate the adverse effects of vasoconstriction on peripheral tissues.

Norepinephrine-Induced Peripheral Ischemia Leading to Gangrene: A Case Series.

Objectives: To analyze the efficacy of a hyaluronic acid--based matrix in the treatment of lesions where the extracellular matrix was lost. Methods: Prospective, noncomparative clinical case series. Results: Twelve patients with 12 serious surgical wounds of different etiologies participated in this project. Many defects showed exposed muscle, tendons, and/or bone. After thorough debridement, a hyaluronic acid--based matrix, with a removable, semipermeable silicone top layer, was applied for the purpose of generating a neodermis. In a number of cases, the matrix was combined with negative pressure wound therapy. All wounds developed granulation tissue. Nine wounds were subsequently closed with a split-skin autograft. There was no graft failure. Three wounds healed by secondary intention. All wounds showed complete reepithelialization. Discussion: Lesions with exposed tendon and bone are difficult to heal. Providing a granulation tissue through the use of an extracellular matrix in which cellular repopulation leads to the development of granulation tissue has been shown to be beneficial with regard to the speed and quality of healing. In this case series, the use of a hyaluronic acid--based matrix was shown to provide a granulation tissue and all lesions healed completely. Conclusion: This case series shows a strong trend for Hyalomatrix to play an important role in supporting wound healing in complex, surgical wounds.

Use of Hyaluronic Acid-Based Biological Bilaminar Matrix in Wound Bed Preparation: A Case Series.

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Orthopaedic surgical dressings

Norepinephrine-Induced Peripheral Ischemia Leading to Gangrene: A Case Series.

Use of Hyaluronic Acid-Based Biological Bilaminar Matrix in Wound Bed Preparation: A Case Series.