Healing In Animal Models Research Articles

The use of three-dimensional bioprinting for skin regeneration and wound healing (literature review)

Three-dimensional (3D) bioprinting is rapidly proliferating across many medical disciplines and is making strides towards manufacturing intricate human organs for clinical application. One of the most promising areas in 3D bioprinting is development of bioinks with certain composition and designed properties.The aim of this systematic review was to assess current biomedical research evidence regarding the efficacy of 3D bioprinting for skin regeneration and wound healing. A comprehensive search for all applicable original articles was conducted according to pre-established eligibility criteria. The study employed PubMed, Web of Science, Scopus, Medline Ovid, and ScienceDirect databases.Of the retrieved articles, eighteen satisfied the inclusion criteria, while twenty-three were excluded. A total of 159 animals that had wound defects were considered in all animal-based research. Collagen and gelatin hydrogels were the most commonly employed bioinks. In relation to cellular composition, allogeneic fibroblasts and keratinocytes were predominant. The observation period ranged from one day to six weeks. Complete wound closure was achieved within 2–4 weeks in most animal studies. In vitro and in vivo animal studies have shown a positive effect of printed bioengineered constructs in accelerating wound healing. Notably, the research where bioprinting was performed directly in the wound in situ was of particular interest. Further studies are required to enhance the tissue bioprinting technique to address skin wound healing in animal models. The utilization of standardized parameters may pave the way for human clinical studies.

Fracture Fusion on Fast-Forward: Locally Administered Deferoxamine Significantly Enhances Fracture Healing in Animal Models: A Systematic Review and Meta-Analysis.

Fractures, with a yearly incidence of 1.2%, can lead to healing complications in up to 10% of cases. The angiogenic stimulant deferoxamine (DFO) is recognized for enhancing bone healing when administered into the fracture gap. This systematic review with meta-analysis investigates the effect of local DFO application on bone healing in rat and mouse models. EMBASE, MEDLINE (PubMed), and Web of Science are systematically searched in January 2024. The study is prospectively registered in PROSPERO (CRD42024492533), and the SYRCLE tool is used to assess study quality and risk of bias. Outcome values contain the primary endpoint bone volume fraction (BV/TV) as well as the secondary endpoints bone volume, tissue volume, bone mineral density, trabecular separation, trabecular thickness, vessel formation and the mechanical properties, assessed by µCT, angiography and mechanical strength tests. Out of 21 included studies, 18 qualify for meta-analysis, involving 539 animals. DFO-treated groups exhibit significantly higher BV/TV values (p<0.0001) compared to controls, with similarly significant improvements in secondary outcomes. These findings highlight the substantial benefit of DFO in promoting bone healing, especially after radiotherapy. Rapid clinical implementation is recommended to help patients at high risk of fracture healing complications.

Primary Human Macrophage and Tenocyte Tendon Healing Phenotypes Changed by Exosomes Per Cell Origin.

The high failure rate of surgical repair for tendinopathies has spurred interest in adjunct therapies, including exosomes (EVs). Mesenchymal stromal cell (MSC)-derived EVs (MSCdEVs) have been of particular interest as they improve several metrics of tendon healing in animal models. However, research has shown that EVs derived from tissue-native cells, such as tenocytes, are functionally distinct and may better direct tendon healing. To this end, we investigated the differential regulation of human primary macrophage transcriptomic responses and cytokine secretion by tenocyte-derived EVs (TdEVs) compared with MSCdEVs. Compared with MSCdEVs, TdEVs upregulated TNFa-NFkB and TGFB signaling and pathways associated with osteoclast differentiation in macrophages while decreasing secretion of several pro-inflammatory cytokines. Conditioned media of these TdEV educated macrophages drove increased tenocyte migration and decreased MMP3 and MMP13 expression. In contrast, MSCdEV education of macrophages drove increased gene expression pathways related to INFa, INFg and protection against oxidative stress while increasing cytokine expression of MCP1 and IL6. These data demonstrate that EV cell source differentially impacts the function of key effector cells in tendon healing and that TdEVs, compared with MSCdEVs, promote a more favorable tendon healing phenotype within these cells.

Evaluating the efficacy of topical Centella asiatica in accelerating burn healing in animal models: A systematic review

Centella asiatica (CA), a medicinal plant with historical use in traditional medicine, is rich in bioactive compounds like asiaticoside, madecassoside, and asiatic acid, which are known for their anti-inflammatory, antioxidant, and collagen-boosting properties. These compounds are especially beneficial in addressing the complexities of burn healing, which involves a balance between inflammation, tissue regeneration, and scarring. The review covers experimental studies focusing in CA in burn animal model from 2014 to 2024, focusing on various outcomes in the aspects of gross, histology, and markers. Results indicate that CA significantly accelerates healing by enhancing tissue repair processes and improving wound quality while reducing scar formation. However, variations in experimental methods, including differences in burn induction, CA formulation, and outcome measurements, highlight a need for standardized research protocols. Findings suggest that CA holds promise as a low-cost, effective therapeutic option for burn treatment, particularly valuable in low-resource settings. This review underlines the importance of further clinical trials to confirm CA’s therapeutic potential, with the goal of developing accessible and effective treatments for burn injuries in humans.

Discovery of Cell Number-Interstitial Fluid Volume (CIF) Ratio Reveals Secretory Autophagy Pathway to Supply eHsp90α for Wound Healing.

Cell secretion repairs tissue damage and restores homeostasis throughout adult life. The extracellular heat shock protein-90alpha (eHsp90α) has been reported as an exosome cargo and a potential driver of wound healing. However, neither the mechanism of secretion nor the genetic evidence for eHsp90α in wound healing has been substantiated. Herein, we show that tissue injury causes massive deposition of eHsp90α in tissues and secretion of eHsp90α by cells. Sequential centrifugations of conditioned medium from relevant cell lines revealed the relative distributions of eHsp90α in microvesicle, exosome and trypsin-sensitive supernatant fractions to be approximately <2%, <4% and >95%, respectively. Establishing the cell-number-to-interstitial-fluid-volume (CIF) ratio for the microenvironment of human tissues as 1 × 109 cells: 1 mL interstitial fluid enabled us to predict the corresponding tissue concentrations of eHsp90α in these fractions as 3.74 μg/mL, 5.61 μg/mL and 178 μg/mL. Remarkably, the 178 μg/mL eHsp90α matches the previously reported 100-300 μg/mL of recombinant eHsp90α whose topical application promotes maximum wound healing in animal models. More importantly, we demonstrate that two parallel secretory autophagy-regulating gene families, the autophagy-regulating (AR) genes and the Golgi reassembly-stacking protein (GRASP) genes work together to mediate the secretion of the physiological concentration of eHsp90α to promote wound healing. Thus, utilization of the CIF ratio-based extrapolation method may enable investigators to rapidly predict biomarker targets from cell-conditioned-medium data.

Extracellular Matrix-Mimetic Intrinsic Versatile Coating Derived from Marine Adhesive Protein Promotes Diabetic Wound Healing through Regulating the Microenvironment.

The management of diabetic wound healing remains a severe clinical challenge due to the complicated wound microenvironments, including abnormal immune regulation, excessive reactive oxygen species (ROS), and repeated bacterial infections. Herein, we report an extracellular matrix (ECM)-mimetic coating derived from scallop byssal protein (Sbp9Δ), which can be assembled in situ within 30 min under the trigger of Ca2+ driven by strong coordination interaction. The biocompatible Sbp9Δ coating and genetically programmable LL37-fused coating exhibit outstanding antioxidant, antibacterial, and immune regulatory properties in vitro. Proof-of-concept applications demonstrate that the coating can reliably promote wound healing in animal models, including diabetic mice and rabbits, ex vivo human skins, and Staphylococcus aureus-infected diabetic mice. In-depth mechanism investigation indicates that improved wound microenvironments accelerated wound repair, including alleviated bacterial infection, lessened inflammation, appearance of abundant M2-type macrophages, removal of ROS, promoted angiogenesis, and re-epithelialization. Collectively, our investigation provides an in situ, convenient, and effective approach for diabetic wound repair.

The opioid growth regulatory system and naltrexone in diabetes: One side makes you taller and the other side makes you smaller

This article provides an overview of research into the inhibitory role of the Opioid Growth Regulatory System (OGRS), which is characterized by its mediator, Opioid Growth Factor (OGF), [Met 5 ]-enkephalin, and its specific receptor (OGFr), in the pathobiology of diabetic complications involving the ocular surface. Additionally, involvement of the OGRS in systemic diabetic complications is illustrated by its role in poor diabetic cutaneous wound healing. The title of this paper is derived from Lewis Carroll’s Alice’s Adventures in Wonderland in which Alice is invited by the caterpillar to eat either side of a mushroom with powerful growth inducing characteristics. In the context of this review, this metaphor highlights the antagonistic relationship between the OGRS and naltrexone (NTX), which blocks the binding of OGF to OGFr thereby preventing or reversing the deleterious effects of the OGRS in the pathobiology of diabetic complications such as dry eye, keratopathy (delayed corneal epithelial wound healing and decreased corneal sensitivity) and delayed cutaneous wound healing in animal models of type 1 and type 2 diabetes. In addition, we will show that topical NTX treatment has been demonstrated to be safe in early phase studies performed in humans. We believe these data support further clinical trials of NTX in the treatment of diabetic ocular surface disease and delayed cutaneous wound healing. Finally, our findings may have implications for the evaluation of the OGRS in the pathobiology of other systemic diabetic complications.

Bimetallic oxide Cu–Fe3O4 nanoclusters with multiple enzymatic activities for wound infection treatment and wound healing

Infections and oxidative stress complicate wound healing. In recent years, nanomaterials with natural enzymatic activities have enabled the development of new antibacterial pathways. In this study, Cu-Fe3O4 nanoclusters with multienzyme properties were synthesised. Interestingly, they exhibited activity similar to that of horseradish peroxidase (POD) in acidic environments but their functions resembled superoxide dismutase and catalase in neutral or weakly alkaline environments. In vitro studies have demonstrated the good free-radical scavenging activity of Cu-Fe3O4 nanoclusters in a neutral environment. Under acidic conditions, Cu-Fe3O4 nanoclusters combined with H2O2 demonstrated good antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli). The combination of Cu-Fe3O4 and H2O2 was found to be effective in preventing MRSA infections and promoting wound healing in animal models. RNA sequencing (RNA-seq) technology revealed that chemodynamic therapy (CDT) using nanoparticles can interfere with metabolic processes such as galactose metabolism in MRSA bacteria, destroy the transport system on the surface of MRSA, and affect quorum sensing to hinder the formation of biofilms, thus achieving effective antibacterial efficacy. The use of Cu-Fe3O4 nanoclusters as a novel class of multi-catalytically active nanozymes in the anti-infection of disease-causing pathogens and wound healing has significant potential. STATEMENT OF SIGNIFICANCE: Cu-Fe3O4 nanoclusters with multienzyme properties were successfully prepared by a solvothermal method. Cu-Fe3O4 nanoclusters exhibited horseradish peroxidase (POD)-like activity in acidic environments and also showed synergistic effects similar to superoxide dismutase peroxidase in neutral or weakly basic environments. More importantly, these Cu-Fe3O4 nanoclusters showed high biosafety with no apparent in vivo toxicity. Chemodynamic therapy (CDT) using Cu-Fe3O4 nanoclusters was revealed by RNA sequencing (RNA-Seq) technology to interfere with the metabolic processes of MRSA bacteria, such as galactose metabolism, disrupt the MRSA surface transport system, and impede biofilm formation, resulting in effective antibacterial efficacy. The use of Cu-Fe3O4 nanoclusters for anti-infection and wound healing of pathogenic pathogens has significant potential as a novel class of multi-catalytic active nanoclusters.

Facile and eco-friendly fabrication of biocompatible hydrogel containing CuS@Ser NPs with mechanical flexibility and photothermal antibacterial activity to promote infected wound healing

Bacterial infections can significantly impede wound healing and pose a serious threat to the patient’s life. The excessive use of antibiotics to combat bacterial infections has led to the emergence of multi-drug-resistant bacteria. Therefore, there is a pressing need for alternative approaches, such as photothermal therapy (PTT), to address this issue. In this study, for the first time, CuS NPs with photothermal properties were synthesized using sericin as a biological template, named CuS@Ser NPs. This method is simple, green, and does not produce toxic and harmful by-products. These nanoparticles were incorporated into a mixture (XK) of xanthan gum and konjac glucomannan (KGM) to obtain XK/CuS NPs composite hydrogel, which could overcome the limitations of current wound dressings. The composite hydrogel exhibited excellent mechanical flexibility, photothermal response, and biocompatibility. It also demonstrated potent antibacterial properties against both Gram-positive and negative bacteria via antibacterial experiments and accelerated wound healing in animal models. Additionally, it is proved that the hydrogel promoted tissue regeneration by stimulating collagen deposition, angiogenesis, and reducing inflammation. In summary, the XK/CuS NPs composite hydrogel presents a promising alternative for the clinical management of infected wounds, offering a new approach to promote infected wound healing.

Interleukin-6 in Traumatic Brain Injury: A Janus-Faced Player in Damage and Repair.

Traumatic brain injury (TBI) is a common and often devastating illness, with wide-ranging public health implications. In addition to the primary injury, victims of TBI are at risk for secondary neurological injury by numerous mechanisms. Current treatments are limited and do not target the profound immune response associated with injury. This immune response reflects a convergence of peripheral and central nervous system-resident immune cells whose interaction is mediated in part by a disruption in the blood-brain barrier (BBB). The diverse family of cytokines helps to govern this communication and among these, Interleukin (IL)-6 is a notable player in the immune response to acute neurological injury. It is also a well-established pharmacological target in a variety of other disease contexts. In TBI, elevated IL-6 levels are associated with worse outcomes, but the role of IL-6 in response to injury is double-edged. IL-6 promotes neurogenesis and wound healing in animal models of TBI, but it may also contribute to disruptions in the BBB and the progression of cerebral edema. Here, we review IL-6 biology in the context of TBI, with an eye to clarifying its controversial role and understanding its potential as a target for modulating the immune response in this disease.

Mechanical properties and wound healing potential of bacterial cellulose-xyloglucan-dextran hydrogels

Bacterial cellulose (BC) is a promising material for use as an artificial skin in wound healing application, however, its applications are limited due to its poor malleability. Incorporating non-cellulosic polysaccharides such as dextran and xyloglucan (XG) may enhance its respective wound healing and malleability. This study presents a novel in situ biopreparation method to produce BC-based hybrid hydrogels containing dextran (BC-D) and xyloglucan-dextran (BC-XG-D) with unique mechanical and rheological properties. Structural analysis revealed that dextran of different sizes (10k, 70k and 2M of Mw) form micron-sized particles by loosely binding to cellulosic fibres. The addition of xyloglucan resulted acts as a lubricant in mechanical testing. The BC-XG-D hybrid hydrogels showed a reduced Young's modulus of 4MPa and a higher maximum tensile strain of 53% compared to native BC. Moreover, they displayed less plastic but more viscous behaviour under large shear strain deformation. The wound healing animal model experiments demonstrated that the BC-XG-D hybrid hydrogels promoted wound healing process and skin maturation. Overall, these findings contribute to the development of functional BC-based medical materials with desired mechanical and rheological properties that have the potential to accelerate wound healing.

Effective Combination Therapy with Human Amniotic Membrane Mesenchymal Stem Cells and Low-Level Laser Therapy in Wound Healing in Animal Models.

Introduction: Many studies have recognized the importance of new methods in wound healing. This study aims to investigate the healing effects of allograft extra embryonic mesenchymal stem cells (MSCs) with and without low-level diode laser irradiation when grafted into full-thickness skin defects in diabetic animal models. Methods: In this experimental study, in order to make the rats diabetic, we used an intra-peritoneal injection of streptozotocin. Human amniotic membrane derived mesenchymal stem cells (hAMSCs) were irradiated with a low-level diode laser. Two full-thickness excisions were made on the backs of the rats. Next, the rats were divided into the following groups: group 1: low-level laser (LLL) irradiated hAMSCs and group 2: hAMSCs alone transplanted into skin wound. Histopathologic, ultrasound and elasticity evaluations were performed 7, 14 and 21 days after grafting. Results: In the evaluated rats, epithelial formation was on day 7 and increased until day 14. On days 7, 14 and 21, the percentage of epithelial formation in the irradiated cell group was significantly higher than that in the cell group, so that, on day 21, the epithelium in this group completely covered the wound surface while in the control group the wound surface was still not completely covered. In terms of angiogenesis, on day 7, the irradiated cells were significantly lower than the cells. Also, the formation of collagen in the cellular hydrogel group could confirm the effectiveness of amniotic MSCs in collagen production and thus accelerate the wound healing process. In comparison with hAMSCs alone, irradiated hAMSCs increased the thickness and elasticity of the skin. Conclusion: Low-power laser along with MSCs can be effective in improving chronic wound condition in the animal model.

Rock inhibitors and antisense oligonucleotides for Fuchs corneal endothelial dystrophy

AbstractFuchs corneal dystrophy (FECD) is the most common primary cause of corneal endothelial dystrophy. FECD is a complex disease where interaction between multiple genetic and environmental factors results in endothelial cells apoptosis and atypical extracellular matrix deposition. Due to the shortage of donor tissue, and high costs of transplants, a topical therapy for treating corneal endothelial dysfunction is urgently required. The topical treatment of several agents has been investigated as therapies for FECD, by the promotion of endothelial cell proliferation and migration, in experimental models of the disorder. ROCK1 and ROCK2 inhibition promotes cell adhesion, prevents apoptosis, and enhances the proliferation of and human corneal endothelial cells. These therapies have involved the knockdown of connexin by siRNA, the release of cell–cell contact inhibition with EDTA, and inhibition of Rho‐associated protein kinase (ROCK) with Y‐27632. Recently several papers showed that Ripasudil, a rho kinase inhibitor, has been shown to promote corneal endothelial wound healing in animal models and in clinical trials. An antisense oligonucleotide (ASO) has also been developed to target the repetitive RNA. This has been shown to decrease foci formation and reversal of misplacing in ex‐vivo FECD specimens. Antisense oligonucleotides (ASO) reduced the RNA aggregates and their toxic downstream events in patient cells. ASO has to be designed to target a particular genetic mutation. This new medical‐based regenerative therapy may provide a less invasive and more effective method for treating patients with FECD.

Effects of Exercise or Mechanical Stimulation on Bone Development and Bone Repair.

The development and regeneration of the bone are tightly regulated by mechanical cues. Multiple cell types, including osteoblasts, osteocytes, osteoclasts, mesenchymal stem cells (MSCs), and recently found skeletal stem cells (SSCs), are responsible for efficient bone development and injury repair. The immune cells in the environment interact with bone cells to maintain homeostasis and facilitate bone regeneration. Investigation of the mechanism by which these cells sense and respond to mechanical signals in bone is fundamental for optimal clinical intervention in bone injury healing. We discuss the effects of exercise programs on fracture healing in animal models and human patients, which encouragingly suggest that carefully designed exercise prescriptions can improve the result of fracture healing during the remodeling phase. However, additional clinical tracing and date accumulation are still required for the pervasive application of exercise prescriptions to improve fracture healing.

Evaluating the Effectiveness of Aqueous Extract of Persian Oak (Quercus castaneifolia C.A.Mey.) Fruit Hull on Dermal Wound Healing in the Rat Model

Background: Persian oak (Quercus castaneifolia C.A.Mey) belongs to the Fagaceae family. This plant is commonly used in Iranian traditional medicine to treat inflammatory and gastric ulcers. Objectives: This study aimed to assess the efficacy of Persian oak fruit aqueous hull extract on wound healing in rats. Methods: Thirty-five male Wistar rats were randomly divided into five groups, then two full-thickness wounds of 10 mm in diameter were created bilaterally on the back of the animals. The negative control group received saline, the positive control group was treated with phenytoin cream, and three treatment groups received 2%, 4%, and 8% Jaft aqueous extract. The animals received these medicines once daily for 15 days. The percentage of wound healing was evaluated using wound contraction ratio, re-epithelialization, tensile strength, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) content. Histopathological examination was performed on repaired tissues. Results: In the 2%, 4%, and 8% Jaft extract and the phenytoin groups, the wound closure rate was significantly higher than in the saline group. The treatment groups revealed significant healing improvement (P &lt; 0.05) compared to the control group in wound contraction, tensile strength, epithelialization duration, VEGF, and PDGF plasma level. Histopathological investigations also exhibited development in wound healing with Jaft extract. Conclusions: This study shows that the Persian oak fruit hull aqueous extract was effective in wound healing in animal models. Clinical trials are required to prove the efficacy of Q. castaneifolia fruit hull spray in healing various wounds in humans.

Strategies to Minimize Surgical Scarring: Translation of Lessons Learned from Bedside to Bench and Back.

Significance: An understanding of the physiology of wound healing and scarring is necessary to minimize surgical scar formation. By reducing tension across the healing wound, eliminating excess inflammation and infection, and encouraging perfusion to healing areas, surgeons can support healing and minimize scarring. Recent Advances: Preoperatively, newer techniques focused on incision placement to minimize tension, skin sterilization to minimize infection and inflammation, and control of comorbid factors to promote a healing process with minimal scarring are constantly evolving. Intraoperatively, measures like layered closure, undermining, and tissue expansion can be taken to relieve tension across the healing wound. Appropriate suture technique and selection should be considered, and finally, there are new surgical technologies available to reduce tension across the closure. Postoperatively, the healing process can be supported as proliferation and remodeling take place within the wound. A balance of moisture control, tension reduction, and infection prevention can be achieved with dressings, ointments, and silicone. Vitamins and corticosteroids can also affect the scarring process by modulating the cellular factors involved in healing. Critical Issues: Healing with no or minimal scarring is the ultimate goal of wound healing research. Understanding how mechanical tension, inflammation and infection, and perfusion and hypoxia impact profibrotic pathways allows for the development of therapies that can modulate cytokine response and the wound extracellular microenvironment to reduce fibrosis and scarring. Future Directions: New tension-off loading topical treatments, laser, and dermabrasion devices are under development, and small molecule therapeutics have demonstrated scarless wound healing in animal models, providing a promising new direction for future research aimed to minimize surgical scarring.

Pulsed Electro-Magnetic Field (PEMF) Effect on Bone Healing in Animal Models: A Review of Its Efficacy Related to Different Type of Damage.

Simple SummaryPulsed electromagnetic fields (PEMFs) are a type of biophysical stimulation that has been shown to be effective in improving bone regeneration and preventing bone loss. Their use dates back to the 1970s, but a gold standard treatment protocol has not yet been defined. PEMF efficacy relies on the generation of biopotentials, which activate several molecular pathways. There is currently no clear understanding of the effects on bone healing and, in addition, there are several animal models relevant to this issue. Therefore, drawing guidelines and conclusions from the analysis of the studies is difficult. In vivo investigations on PEMF stimulation are reviewed in this paper, focusing on molecular and morphological improvements in bone. Currently, there is little knowledge about the biological mechanism of PEMF and its effect on bone healing. This is due to the variability of crucial characteristics of electro-magnetic fields, such as amplitude and exposure frequency, which may influence the type of biological response. Furthermore, a different responsiveness of cells involved in the bone healing process is documented. Heterogeneous setting parameters and different outcome measures are considered in various animal models. Therefore, achieving comparable results is difficult.Biophysical energies are a versatile tool to stimulate tissues by generating biopotentials. In particular, pulsed electromagnetic field (PEMF) stimulation has intrigued researchers since the 1970s. To date, many investigations have been carried out in vivo, but a gold standard treatment protocol has not yet been defined. The main obstacles are represented by the complex setting of PEMF characteristics, the variety of animal models (including direct and indirect bone damage) and the lack of a complete understanding of the molecular pathways involved. In the present review the main studies about PEMF stimulation in animal models with bone impairment were reviewed. PEMF signal characteristics were investigated, as well as their effect on molecular pathways and osseous morphological features. We believe that this review might be a useful starting point for a prospective study in a clinical setting. Consistent evidence from the literature suggests a potential beneficial role of PEMF in clinical practice. Nevertheless, the wide variability of selected parameters (frequency, duration, and amplitude) and the heterogeneity of applied protocols make it difficult to draw certain conclusions about PEMF effectiveness in clinical implementation to promote bone healing. Deepening the knowledge regarding the most consistent results reported in literature to date, we believe that this review may be a useful starting point to propose standardized experimental guidelines. This might provide a solid base for further controlled trials, to investigate PEMF efficacy in bone damage conditions during routine clinical practice.

Oral 11β-HSD1 inhibitor AZD4017 improves wound healing and skin integrity in adults with type 2 diabetes mellitus: a pilot randomized controlled trial.

BackgroundChronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by the enzyme 11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1) impair wound healing.ObjectivesEfficacy, safety, and feasibility of 11β-HSD1 inhibition for skin function and wound healing.DesignInvestigator-initiated, double-blind, randomized, placebo-controlled, parallel-group phase 2b pilot trial.MethodsSingle-center secondary care setting. Adults with type 2 diabetes mellitus without foot ulcers were administered 400 mg oral 11β-HSD1 inhibitor AZD4017 (n = 14) or placebo (n = 14) bi-daily for 35 days. Participants underwent 3-mm full-thickness punch skin biopsies at baseline and on day 28; wound healing was monitored after 2 and 7 days. Computer-generated 1:1 randomization was pharmacy-administered. Analysis was descriptive and focused on CI estimation. Of the 36 participants screened, 28 were randomized.ResultsExploratory proof-of-concept efficacy analysis suggested AZD4017 did not inhibit 24-h ex vivoskin 11β-HSD1 activity (primary outcome; difference in percentage conversion per 24 h 1.1% (90% CI: −3.4 to 5.5) but reduced systemic 11β-HSD1 activity by 87% (69–104%). Wound diameter was 34% (7–63%) smaller with AZD4017 at day 2, and 48% (12–85%) smaller after repeat wounding at day 30. AZD4017 improved epidermal integrity but modestly impaired barrier function. Minimal adverse events were comparable to placebo. Recruitment rate, retention, and data completeness were 2.9/month, 27/28, and 95.3%, respectively.ConclusionA phase 2 trial is feasible, and preliminary proof-of-concept data suggests AZD4017 warrants further investigation in conditions of delayed healing, for example in diabetic foot ulcers.Significance statementStress hormone activation by the enzyme 11β-HSD type 1 impairs skin function (e.g. integrity) and delays wound healing in animal models of diabetes, but effects in human skin were previously unknown. Skin function was evaluated in response to treatment with a 11β-HSD type 1 inhibitor (AZD4017), or placebo, in people with type 2 diabetes. Importantly, AZD4017 was safe and well tolerated. This first-in-human randomized, controlled, clinical trial found novel evidence that 11β-HSD type 1 regulates skin function in humans, including improved wound healing, epidermal integrity, and increased water loss. Results warrant further studies in conditions of impaired wound healing, for example, diabetic foot ulcers to evaluate 11β-HSD type 1 as a novel therapeutic target forchronic wounds.

Antibacterial Zeolite Imidazole Frameworks with Manganese Doping for Immunomodulation to Accelerate Infected Wound Healing.

Numerous nanomedicines currently emerge to reduce the dramatic threat in antibiotics resistance for antibacterial application against severe bacterial infections, while it is restricted by over-reacted immune response to pathogenic bacteria. Herein, enzymatic activity is introduced into the zeolitic imidazolate framework-8 (ZIF-8) to achieve sterilization by releasing Zn ions, as well as inflammation regulation through the variable valence of Mn ions that are uniformly doped into its framework. Within this simple metal organic framework (MOF) structure design, Mn-ZIF-8 possesses the co-existence of Mn2+ /Mn4+ to endow the nanocomposite with the anti-inflammatory capabilities, which can be adjusted through the redox environment. The enzymatic activity of Mn ions and superiority of pore structure of ZIF-8 are effectively combined to realize the substrate selection via reactant molecular size and high-efficiency internal catalytic performance. By such design, this nanocomposite would not only exhibit an excellent antibacterial performance against pathogenic bacteria, but also reshape the inflammatory immunity by regulating macrophage polarization to suppress over-reacted inflammation, leading to a favorably therapeutic efficiency on bacteria-infected wound healing in animal models. Taken together, this nanoplatform provides effective approach for accelerating infected wound healing via bacteria killing and inflammation modulation, and may be extended for the therapy of other severe bacteria-induced infections.

Gas Plasma-Augmented Wound Healing in Animal Models and Veterinary Medicine.

The loss of skin integrity is inevitable in life. Wound healing is a necessary sequence of events to reconstitute the body’s integrity against potentially harmful environmental agents and restore homeostasis. Attempts to improve cutaneous wound healing are therefore as old as humanity itself. Furthermore, nowadays, targeting defective wound healing is of utmost importance in an aging society with underlying diseases such as diabetes and vascular insufficiencies being on the rise. Because chronic wounds’ etiology and specific traits differ, there is widespread polypragmasia in targeting non-healing conditions. Reactive oxygen and nitrogen species (ROS/RNS) are an overarching theme accompanying wound healing and its biological stages. ROS are signaling agents generated by phagocytes to inactivate pathogens. Although ROS/RNS’s central role in the biology of wound healing has long been appreciated, it was only until the recent decade that these agents were explicitly used to target defective wound healing using gas plasma technology. Gas plasma is a physical state of matter and is a partially ionized gas operated at body temperature which generates a plethora of ROS/RNS simultaneously in a spatiotemporally controlled manner. Animal models of wound healing have been vital in driving the development of these wound healing-promoting technologies, and this review summarizes the current knowledge and identifies open ends derived from in vivo wound models under gas plasma therapy. While gas plasma-assisted wound healing in humans has become well established in Europe, veterinary medicine is an emerging field with great potential to improve the lives of suffering animals.