Acceleration of chronic wound healing by bio-inorganic polyphosphate: In vitro studies and first clinical applications

Diabetic wound infections caused by conventional antibiotic-resistant Staphylococcus aureus strains are fast emerging, leading to life-threatening situations (e.g., high costs, morbidity, and mortality) associated with delayed healing and chronic inflammation. Electrospinning is one of the most widely used techniques for the fabrication of nanofibers (NFs), induced by a high voltage applied to a drug-loaded polymer solution. Particular attention is given to electrospun NFs for pharmaceutical applications (e.g., original drug delivery systems) and tissue regeneration (e.g., as tissue scaffolds). However, there is a paucity of reports related to their application in diabetic wound infections. Therefore, we prepared eco-friendly, biodegradable, low-immunogenic, and biocompatible gelatin (GEL)/polyvinyl alcohol (PVA) electrospun NFs (BNFs), in which we loaded the broad-spectrum antibiotic cephradine (Ceph). The resulting drug-loaded NFs (LNFs) were characterized physically using ultraviolet-visible (UV-Vis) spectrophotometry (for drug loading capacity (LC), drug encapsulation efficiency (EE), and drug release kinetics determination), thermogravimetric analysis (TGA) (for thermostability evaluation), scanning electron microscopy (SEM) (for surface morphology analysis), and Fourier-transform infrared spectroscopy (FTIR) (for functional group identification). LNFs were further characterized biologically by in-vitro assessment of their potency against S. aureus clinical strains (N = 16) using the Kirby–Bauer test and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, by ex-vivo assessment to evaluate their cytotoxicity against primary human epidermal keratinocytes using MTT assay, and by in-vivo assessment to estimate their diabetic chronic wound-healing efficiency using NcZ10 diabetic/obese mice (N = 18). Thin and uniform NFs with a smooth surface and standard size (<400 nm) were observed by SEM at the optimized 5:5 (GEL:PVA) volumetric ratio. FTIR analyses confirmed the drug loading into BNFs. Compared to free Ceph, LNFs were significantly more thermostable and exhibited sustained/controlled Ceph release. LNFs also exerted a significantly stronger antibacterial activity both in-vitro and in-vivo. LNFs were significantly safer and more efficient for bacterial clearance-induced faster chronic wound healing. LNF-based therapy could be employed as a valuable dressing material to heal S. aureus-induced chronic wounds in diabetic subjects.

Download Full-text

Effect of platelet-rich fibrin on cell proliferation, migration, differentiation, inflammation, and osteoclastogenesis: a systematic review of in vitro studies

Clinical Oral Investigations ◽

10.1007/s00784-019-03156-9 ◽

2019 ◽

Vol 24 (2) ◽

pp. 569-584 ◽

Cited By ~ 9

Author(s):

Franz-Josef Strauss ◽

Jila Nasirzade ◽

Zahra Kargarpoor ◽

Alexandra Stähli ◽

Reinhard Gruber

Keyword(s):

Systematic Review ◽

Cell Proliferation ◽

Wound Healing ◽

Bone Regeneration ◽

Therapeutic Potential ◽

In Vitro Studies ◽

Bioactive Molecules ◽

Platelet Rich Fibrin ◽

Regenerative Dentistry

Abstract Objective To systematically assess the effects of platelet-rich fibrin (PRF) on in vitro cellular behavior. Methods A systematic electronic search using MEDLINE database was performed. In vitro studies using PRF were considered and articles published up to June 31, 2018 were screened. Eligible studies were selected based on the use of human PRF. Results In total, 1746 titles were identified with the search terms, from these 37 met the inclusion criteria and were chosen for data extraction. In addition, 16 new studies, mainly published in 2019, were also included in the analysis resulting in 53 studies. No meta-analysis could be performed due to the heterogeneity of study designs. Included studies show that PRF enhances proliferation, migration, adhesion, and osteogenic differentiation on a variety of cell types along with cell signaling activation. Furthermore, PRF reduces inflammation, suppresses osteoclastogenesis, and increases the expression of various growth factors in mesenchymal cells. Summary and conclusions Despite some notable differences of the studies, the overall findings suggest a positive effect of PRF on cell proliferation, migration, adhesion, differentiation, and inflammation pointing towards a therapeutic potential in regenerative dentistry. Clinical relevance PRF serves as a reservoir of bioactive molecules to support wound healing and bone regeneration. Although the cellular mechanisms by which PRF supports the clinical outcomes remain unclear, in vitro research provides possible explanations. This systematic review aims to provide an update of the existing research on how PRF affects basic physiological processes in vitro. The overall findings suggest that PRF induces cell proliferation, migration, adhesion, and differentiation along with possessing anti-inflammatory properties further supporting its therapeutic potential in wound healing and bone regeneration.

Download Full-text

Electrical Stimulation for Wound Healing: A Review of Evidence From In Vitro Studies, Animal Experiments, and Clinical Trials

The International Journal of Lower Extremity Wounds ◽

10.1177/1534734605275733 ◽

2005 ◽

Vol 4 (1) ◽

pp. 23-44 ◽

Cited By ~ 200

Author(s):

Luther C. Kloth

Keyword(s):

Wound Healing ◽

Clinical Trials ◽

Electrical Stimulation ◽

Animal Experiments ◽

In Vitro Studies

Download Full-text

KLF4 Promotes Diabetic Chronic Wound Healing by Suppressing Th17 Cell Differentiation in an MDSC-Dependent Manner

Journal of Diabetes Research ◽

10.1155/2021/7945117 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Xiong Yang ◽

Bryan J. Mathis ◽

Yu Huang ◽

Wencheng Li ◽

Ying Shi

Keyword(s):

Wound Healing ◽

Th17 Cell ◽

Th17 Cells ◽

Chronic Wound ◽

Suppressor Cells ◽

Dependent Manner ◽

Diabetic Wound ◽

Diabetic Wound Healing ◽

Th17 Differentiation

Objectives. Diabetic wound inflammation deficiencies lead to ulcer development and eventual amputation and disability. Our previous research demonstrates that myeloid-derived suppressor cells (MDSCs) accumulate during inflammation and promote chronic wound healing via the regulation of Kruppel-like factor 4 (KLF4). In this study, we aimed to investigate the potential roles of MDSCs and KLF4 in diabetic wound healing. Methods. An ob/ob mouse pressure ulcer (PU) model was used to evaluate the process of wound healing. The expression levels of KLF4 and IL-17A were measured by real-time PCR, and the population of MDSCs and Th17 cells was measured by flow cytometry. The levels of cytokines were determined by an immunosuppression assay. Results. KLF4 deficiency in the diabetic PU model resulted in decreased accumulation of MDSCs, increased expansion of Th17 cells, and significantly delayed wound healing. Conversely, KLF4 activation by APTO-253 accelerated wound healing accompanied by increased MDSC populations and decreased numbers of Th17 cells. MDSCs have been proven to mediate Th17 differentiation via cytokines, and our in vitro data showed that elevated KLF4 expression in MDSCs resulted in reduced Th17 cell numbers and, thus, decreased levels of cytokines indispensable for Th17 differentiation. Conclusions. Our study revealed a previously unreported function of KLF4-regulated MDSCs in diabetic wound healing and identified APTO-253 as a potential agent to improve the healing of pressure ulcers.

Download Full-text

Metal doped calcium silicate biomaterial for skin tissue regeneration in vitro

Journal of Biomaterials Applications ◽

10.1177/0885328220962607 ◽

2020 ◽

pp. 088532822096260

Author(s):

K Mohamed Abudhahir ◽

R Murugesan ◽

R Vijayashree ◽

N Selvamurugan ◽

Tze-Wen Chung ◽

...

Keyword(s):

Wound Healing ◽

Calcium Silicate ◽

Soft Tissues ◽

Healing Process ◽

Antibacterial Properties ◽

Clinical Applications ◽

Wound Dressings ◽

Skin Tissue ◽

Wound Healing Process

This study spots light on combined Wound healing process conjoining blood coagulation, inflammation reduction, proliferation and remodeling of the cells. The objective is to overcome the drawbacks of conventional clinically applied wound dressings such as poor rigidity, porosity, mechanical potency and bactericidal activity. As nosocomial infection is a very common condition at the wound site, bio-adhesive materials with intrinsic antibacterial properties are used in clinical applications. Considering the provenability of Wollastonite [Calcium silicate (CaSiO3)] to regenerate the soft tissues by inducing vascularization and regeneration of fibroblast cells And the antibacterial potentiality of zinc in clinical applications, the present study focuses on synthesis of Zn-Ws particles and evaluation of its antimicrobial and wound healing potentialities towards skin tissue engineering applications. The compositional characterization by EDAS and FT-IR spectral analysis have substantiated the presence of major elements and corresponding band stretching associated with the synthesized particles whereas the particles morphology by SEM images have shown the size of the Ws and Zn-Ws to be 370 nm and 530 nm respectively. From the in vitro studies, skin regenerative potential of Zn-Ws was determined on promoting fibroblast cell (NIH3T3) proliferation by providing better adhesiveness, biocompatibility and cytocompatibility. The antibacterial property of Zn-Ws evaluation by minimum inhibitory concentration (MIC) and zone of inhibition (ZOI) methods against clinical isolates of Gram +Ve and Gram –Ve bacterial strains have confirmed that the addition of Zn has diminished the bacterial growth and also helped in degrading the bacterial biofilms. Thus it is summed up that the process of wound healing is expected to occur with reduced risk of post-injury infections by the presence of zinc-doping on wollastonite for skin tissue application.

Download Full-text

Challenges with Wound Infection Models in Drug Development

Current Drug Targets ◽

10.2174/1389450121666200302093312 ◽

2020 ◽

Vol 21 (13) ◽

pp. 1301-1312 ◽

Cited By ~ 1

Author(s):

Sandeep K. Shukla ◽

Ajay K. Sharma ◽

Vanya Gupta ◽

Aman Kalonia ◽

Priyanka Shaw

Keyword(s):

Wound Healing ◽

Wound Infection ◽

Chronic Wound ◽

Wound Care ◽

Infection Model ◽

In Vivo Models ◽

Infection Models

: Wound research is an evolving science trying to unfold the complex untold mechanisms behind the wound healing cascade. In particular, interest is growing regarding the role of microorganisms in both acute and chronic wound healing. Microbial burden plays an important role in the persistence of chronic wounds, ultimately resulting in delayed wound healing. It is therefore important for clinicians to understand the evolution of infection science and its various etiologies. Therefore, to understand the role of bacterial biofilm in chronic wound pathogenesis, various in vitro and in vivo models are required to investigate biofilms in wound-like settings. Infection models should be refined comprising an important signet of biofilms. These models are eminent for translational research to obtain data for designing an improved wound care formulation. However, all the existing models possess limitations and do not fit properly in the model frame for developing wound care agents. Among various impediments, one of the major drawbacks of such models is that the wound they possess does not mimic the wound a human develops. Therefore, a novel wound infection model is required which can imitate the human wounds. : This review article mainly discusses various in vitro and in vivo models showing microbial colonization, their advantages and challenges. Apart from these models, there are also present ex vivo wound infection models, but this review mainly focused on various in vitro and in vivo models available for studying wound infection in controlled conditions. This information might be useful in designing an ideal wound infection model for developing an effective wound healing formulation.

Download Full-text

An EGF- and Curcumin-Co-Encapsulated Nanostructured Lipid Carrier Accelerates Chronic-Wound Healing in Diabetic Rats

Molecules ◽

10.3390/molecules25204610 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4610

Author(s):

Hye-Jin Lee ◽

Moses Jeong ◽

Young-Guk Na ◽

Sung-Jin Kim ◽

Hong-Ki Lee ◽

...

Keyword(s):

Wound Healing ◽

Chronic Wounds ◽

Chronic Wound ◽

Healing Process ◽

Double Emulsion ◽

Average Diameter ◽

Diabetic Rats ◽

Wound Healing Process ◽

Nanostructured Lipid Carrier

Nanostructured lipid carriers (NLC) are capable of encapsulating hydrophilic and lipophilic drugs. The present study developed an NLC containing epidermal growth factor (EGF) and curcumin (EGF–Cur-NLC). EGF–Cur-NLC was prepared by a modified water-in-oil-in-water (w/o/w) double-emulsion method. The EGF–Cur-NLC particles showed an average diameter of 331.8 nm and a high encapsulation efficiency (81.1% and 99.4% for EGF and curcumin, respectively). In vitro cell studies were performed using two cell types, NIH 3T3 fibroblasts and HaCaT keratinocytes. The results showed no loss of bioactivity of EGF in the NLC formulation. In addition, EGF–Cur-NLC improved in vitro cell migration, which mimics the wound healing process. Finally, EGF–Cur-NLC was evaluated in a chronic wound model in diabetic rats. We found that EGF–Cur-NLC accelerated wound closure and increased the activity of antioxidant enzymes. Overall, these results reveal the potential of the NLC formulation containing EGF and curcumin to promote healing of chronic wounds.

Download Full-text

Dissolved oxygen from microalgae-gel patch promotes chronic wound healing in diabetes

Science Advances ◽

10.1126/sciadv.aba4311 ◽

2020 ◽

Vol 6 (20) ◽

pp. eaba4311 ◽

Cited By ~ 5

Author(s):

Huanhuan Chen ◽

Yuhao Cheng ◽

Jingrun Tian ◽

Peizheng Yang ◽

Xuerao Zhang ◽

...

Keyword(s):

Cell Proliferation ◽

Wound Healing ◽

Dissolved Oxygen ◽

Oxygen Delivery ◽

Chronic Wounds ◽

Chronic Wound ◽

Superior Performance ◽

Gaseous Oxygen ◽

Promote Cell Proliferation

Chronic wounds in diabetes undergo a lifetime risk of developing into diabetic foot ulcers. Oxygen is crucial to wound healing by regulating cell proliferation, migration, and neovascularization. However, current oxygen therapies, including hyperbaric oxygen (HBO) and topical gaseous oxygen (TGO), mainly employ gaseous oxygen delivery, which is much less effective in penetrating the skin. Here, we introduce an oxygen-producing patch, made of living microalgae hydrogel, which can produce dissolved oxygen. The superior performance of the patch that results from its dissolved oxygen delivery is >100-fold much more efficient than TGO penetrating the skin. Further experiments indicate that the patch could promote cell proliferation, migration, and tube formation in vitro, and improve chronic wound healing and the survival of skin grafts in diabetic mice. We believe that the microalgae-gel patch can provide continuous dissolved oxygen to improve chronic wound healing.

Download Full-text

Nano-in-Micro Dual Delivery Platform for Chronic Wound Healing Applications

Micromachines ◽

10.3390/mi11020158 ◽

2020 ◽

Vol 11 (2) ◽

pp. 158 ◽

Cited By ~ 3

Author(s):

Jana Zarubova ◽

Mohammad Mahdi Hasani-Sadrabadi ◽

Lucie Bacakova ◽

Song Li

Keyword(s):

Wound Healing ◽

Network Formation ◽

Chronic Wound ◽

Wound Care ◽

Healing Process ◽

Microfluidic System ◽

Wound Healing Process ◽

Delivery Platform ◽

Endothelial Growth Factor

Here, we developed a combinatorial delivery platform for chronic wound healing applications. A microfluidic system was utilized to form a series of biopolymer-based microparticles with enhanced affinity to encapsulate and deliver vascular endothelial growth factor (VEGF). Presence of heparin into the structure can significantly increase the encapsulation efficiency up to 95% and lower the release rate of encapsulated VEGF. Our in vitro results demonstrated that sustained release of VEGF from microparticles can promote capillary network formation and sprouting of endothelial cells in 2D and 3D microenvironments. These engineered microparticles can also encapsulate antibiotic-loaded nanoparticles to offer a dual delivery system able to fight bacterial infection while promoting angiogenesis. We believe this highly tunable drug delivery platform can be used alone or in combination with other wound care products to improve the wound healing process and promote tissue regeneration.

Download Full-text