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Cutaneous Radiation Injuries: Models, Assessment and Treatments
Abstract
Many cases of human exposures to high-dose radiation have been documented, including individuals exposed during the detonation of atomic bombs in Hiroshima and Nagasaki, nuclear power plant disasters (e.g., Chernobyl), as well as industrial and medical accidents. For many of these exposures, injuries to the skin have been present and have played a significant role in the progression of the injuries and survivability from the radiation exposure. There are also instances of radiation-induced skin complications in routine clinical radiotherapy and radiation diagnostic imaging procedures. In response to the threat of a radiological or nuclear mass casualty incident, the U.S. Department of Health and Human Services tasked the National Institute of Allergy and Infectious Diseases (NIAID) with identifying and funding early- to mid-stage medical countermeasure (MCM) development to treat radiation-induced injuries, including those to the skin. To appropriately assess the severity of radiation-induced skin injuries and determine efficacy of different approaches to mitigate/treat them, it is necessary to develop animal models that appropriately simulate what is seen in humans who have been exposed. In addition, it is important to understand the techniques that are used in other clinical indications (e.g., thermal burns, diabetic ulcers, etc.) to accurately assess the extent of skin injury and progression of healing. For these reasons, the NIAID partnered with two other U.S. Government funding and regulatory agencies, the Biomedical Advanced Research and Development Authority (BARDA) and the Food and Drug Administration (FDA), to identify state-of-the-art methods in assessment of skin injuries, explore animal models to better understand radiation-induced cutaneous damage and investigate treatment approaches. A two-day workshop was convened in May 2019 highlighting talks from 28 subject matter experts across five scientific sessions. This report provides an overview of information that was presented and the subsequent guided discussions.
... Cutaneous radiation injury (CRI) involves skin and subcutaneous tissue lesions after radiation exposure [131]. CRI is a type of deterministic effect dependent on dose, type of radiation, irradiated volume, and exposed individuals' comorbidities [132,133]. ...
... Still, it can lead to skin necrosis, scarring, severe pain, and skin cancer years after initial exposure [139]. Properly assessing the extent and severity of CRI is often difficult because symptoms can develop over days and weeks after radiation exposure [131]. Therefore, comorbidities, radiation dose, dose rates, evaluation of the surface area in addition to the depth of injury, and TBI must be included in medical, clinical assessment, and surgical decision-making [140,141]. ...
... MSCs are injected during surgery and in several sessions following surgery to deliver paracrine factors like anti-inflammatory cytokines, growth factors, and microvesicles that contribute to the healing [132]. Unfortunately, medical treatments and follow-ups sometimes take decades because of the nature of cutaneous radiation injury [131,132]. ...
Radioactivity is a process in which the nuclei of unstable atoms spontaneously decay, producing other nuclei and releasing energy in the form of ionizing radiation in the form of alpha (α) and beta (β) particles as well as the emission of gamma (γ) electromagnetic waves. People may be exposed to radiation in various forms, as casualties of nuclear accidents, workers in power plants, or while working and using different radiation sources in medicine and health care. Acute radiation syndrome (ARS) occurs in subjects exposed to a very high dose of radiation in a very short period of time. Each form of radiation has a unique pathophysiological effect. Unfortunately, higher organisms—human beings—in the course of evolution have not acquired receptors for the direct “capture” of radiation energy, which is transferred at the level of DNA, cells, tissues, and organs. Radiation in biological systems depends on the amount of absorbed energy and its spatial distribution, particularly depending on the linear energy transfer (LET). Photon radiation with low LET leads to homogeneous energy deposition in the entire tissue volume. On the other hand, radiation with a high LET produces a fast Bragg peak, which generates a low input dose, whereby the penetration depth into the tissue increases with the radiation energy. The consequences are mutations, apoptosis, the development of cancer, and cell death. The most sensitive cells are those that divide intensively—bone marrow cells, digestive tract cells, reproductive cells, and skin cells. The health care system and the public should raise awareness of the consequences of ionizing radiation. Therefore, our aim is to identify the consequences of ARS taking into account radiation damage to the respiratory system, nervous system, hematopoietic system, gastrointestinal tract, and skin.
... Study designs, wound assessment approaches and findings. The CRI condition describes radiation injury to the skin after doses 2 Gy, and over the course of 2 weeks to 1 year, can present as reactions ranging from transient erythema, epilation, moist desquamation, edema, acute ulceration, and dermal atrophy, to induration and necrosis (42). One compound under investigation as a potential mitigator of CRI is BP-C2 (S. ...
... One of these models uses Göttingen minipigs to study CRI. While initial investigation into the mechanisms of CRI often begins in small animal models such as rodents, porcine skin better reflects the physiology of human skin and thus is more suitable for understanding the biological impact of CRI and the efficacy of drugs being tested (42). Historical documentation of cutaneous radiation injuries goes back to the late 1800s. ...
... While CRI is similar to thermal burns, they differ in that the onset is usually delayed with CRI (from days to months) and can continue for years due to persistent waves of inflammation. The time course and severity of CRI wounds depend on the dose and type of radiation received and the location and size of the exposed area (42). The development of the CRI model at AFRRI was based on a documented human radiation accident involving cutaneous injuries, which occurred at an industrial facility in Maryland in 1991 (56). ...
The U.S. Government is committed to maintaining a robust research program that supports a portfolio of scientific experts who are investigating the biological effects of radiation exposure. On August 17 and 18, 2023, the Radiation and Nuclear Countermeasures Program, within the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), partnered with the National Cancer Institute, NIH, the National Aeronautics and Space Administration, and the Radiation Injury Treatment Network to convene a workshop titled, Advanced Technologies in Radiation Research (ATRR), which focused on the use of advanced technologies under development or in current use to accelerate radiation research. This meeting report provides a comprehensive overview of the research presented at the workshop, which included an assembly of subject matter experts from government, industry, and academia. Topics discussed during the workshop included assessments of acute and delayed effects of radiation exposure using modalities such as clustered regularly interspaced short palindromic repeats (CRISPR) – based gene editing, tissue chips, advanced computing, artificial intelligence, and immersive imaging techniques. These approaches are being applied to develop products to diagnose and treat radiation injury to the bone marrow, skin, lung, and gastrointestinal tract, among other tissues. The overarching goal of the workshop was to provide an opportunity for the radiation research community to come together to assess the technological landscape through sharing of data, methodologies, and challenges, followed by a guided discussion with all participants. Ultimately, the organizers hope that the radiation research community will benefit from the workshop and seek solutions to scientific questions that remain unaddressed. Understanding existing research gaps and harnessing new or re-imagined tools and methods will allow for the design of studies to advance medical products along the critical path to U.S. Food and Drug Administration approval.
... Fathi et al. [10] developed a hybrid fiber scaffold containing chitosan, PVA, and silk using an electrospinning technique to assess their combined impact on the wound healing process. The hybrid chitosan-PVA + silk fiber scaffold exhibited notably enhanced mechanical properties and achieved desired swelling characteristics, along with creating a more hydrophilic microenvironment compared to pure PVA and chitosan-PVA fibers. ...
... The incorporation of blended chitosan and electrospun silk within the PVA-based fibrous scaffold notably improved cell adhesion and proliferation when compared to both neat PVA and chitosan-PVA fibers. The in vivo investigation revealed that the composite chitosan-PVA + silk fibrous mats, in the presence of MSC-derived keratinocytes, effectively promoted wound healing and facilitated the regeneration of skin tissue [10]. ...
... Fathi et al. [10] devised an electrospun hybrid scaffold composed of polyvinyl alcohol (PVA), chitosan (Ch), and silk fibers. They assessed its wound healing potential via in vitro implantation of keratinocytes derived from bone marrow mesenchymal stem cells (MSCs) and further evaluated it in vivo. ...
The skin is subject to damage from the surrounding environment. The repair of skin wounds can be very challenging due to several factors such as severe injuries, concomitant infections, or comorbidities such as diabetes. Different drugs and wound dressings have been used to treat skin wounds. Tissue engineering, a novel therapeutic approach, revolutionized the treatment and regeneration of challenging tissue damage. This field includes the use of synthetic and natural biomaterials that support the growth of tissues or organs outside the body. Accordingly, the demand for polymer-based therapeutic strategies for skin tissue defects is significantly increasing. Among the various 3D scaffolds used in tissue engineering, hydrogel scaffolds have gained special significance due to their unique properties such as natural mimicry of the extracellular matrix (ECM), moisture retention, porosity, biocompatibility, biodegradability, and biocompatibility properties. First, this article delineates the process of wound healing and conventional methods of treating wounds. It then presents an examination of the structure and manufacturing methods of hydrogels, followed by an analysis of their crucial characteristics in healing skin wounds and the most recent advancements in using hydrogel dressings for this purpose. Finally, it discusses the potential future advancements in hydrogel materials within the realm of wound healing.
... 44 Although CRI alone does not result in mortality (not to be confused with Cutaneous Radiation Syndrome, a much larger and more significant injury), the morbidity with associated pathologies can manifest as disfigurement, recurring wounds and fibrosis, and unrelenting chronic pain requiring constant and lifelong medical interventions. 42 Therefore, it is critical to understand how to manage this injury in the event of a radiological or nuclear event. ...
... 45 The resulting pathophysiology of this injury can include vascular dilation, increased capillary permeability, microhemorrhage, and platelet consumption. 42 Neutrophil and lymphocyte infiltrates can result in perivascular edema, cell hypoxia, and cell death. CRI pathophysiology and injuries progress through early "prodrome" inflammatory responses, followed by "latent phase" anti-inflammatory response, accompanied by macrophage activation, formation of reactive oxygen and nitrogen species, and elevated proinflammatory cytokine production. ...
... To improve radiation skin injury treatment options, current gaps in the field must first be addressed. 42 There is currently no standard of care, but surgical interventions include manual removal via serial bronchoscopy, lobectomy, thoracic duct ligation, Fontan fenestration, heart transplant, and heart function optimization. Pharmaceutical interventions include tPA, heparin, azithromycin, and sildenafil/tadalafil. 106 A retrospective analysis of SM-exposed patients showed that 23% presented with airway casts. ...
Purpose
To summarize presentations and discussions from the 2022 trans-agency workshop titled “Overlapping Science in Radiation and Sulfur Mustard (SM) Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures.”
Methods
Summary on topics includes: 1) an overview of the radiation and chemical countermeasure development programs and missions; 2) regulatory and industry perspectives for drugs and devices; 3) pathophysiology of skin and lung following radiation or SM exposure; 4) mechanisms of action/targets, biomarkers of injury; and 5) animal models that simulate anticipated clinical responses.
Results
There are striking similarities between injuries caused by radiation and SM exposures. Primary outcomes from both types of exposure include acute injuries, while late complications comprise chronic inflammation, oxidative stress, and vascular dysfunction, which can culminate in fibrosis in both skin and lung organ systems. This workshop brought together academic and industrial researchers, medical practitioners, U.S. Government program officials and regulators to discuss lung-, and skin-specific animal models and biomarkers, novel pathways of injury and recovery, and paths to licensure for products to address radiation or SM injuries.
Conclusions
Regular communications between the radiological and chemical injury research communities can enhance the state-of-the-science, provide a unique perspective on novel therapeutic strategies, and improve overall U.S. Government emergency preparedness.
... 5 Current literature proposes radiation dermatitis (RD) as a research model for the study of ARS/ CRI, despite a difference in exposure conditions due to identical biological pathophysiology. 4 RD occurs in 95% of patients receiving radiation therapy (RT) for cancer treatment, affecting 800 million patients annually. 6 Tumor sites most related to RD include the breast, brain, head and neck, soft tissue, perineum, and anal canal. ...
... Although CRI events usually involve a single high dose radiation exposure, unlike the fractionated exposure during RT, the clinical presentation of the skin reactions is similar. 4 Therefore, information from RISREAC cohort could potentially serve as a control cohort in radiation dermatitis trials and aid in countermeasures development for CRI in the field. The peak RD assigned to our RISREAC cohort was at the end-RT point. ...
... Therefore, N is included at each week in the plot. 4 A Ghaffar et al. ...
Objective:
Radiation dermatitis (RD) occurs in 95% of patients receiving radiation therapy (RT) for cancer treatment, affecting 800 million patients annually. We aimed to demonstrate the feasibility of developing a historical RD cohort, Radiation Induced Skin Reactions (RISREAC) cohort.
Methods:
This retrospective study evaluated RD-related clinical documentation for 245 breast cancer patients who received RT at the University of Rochester Medical Center, to understand the RD progression, scoring, and management. All statistical analyses were performed at 0.05 level of significance.
Results:
Clinician-documented RD severity was observed for 169 (69%) patients with a mean severity of 1.57 [1.46, 1.68]. The mean descriptor-based severity score of 2.31 [2.18, 2.45] moderately correlated (r = 0.532, P < 0.0001) with documented RD grade. Most patients (91.8%) received skin care treatment during RT, with 66.7% receiving more than 2 modalities.
Conclusions:
The RISREAC cohort is the first retrospective cohort established from clinical documentation of radiation-induced skin changes for the study of RD and cutaneous radiation injury (CRI). RD symptom descriptors were more reliably documented and suitable for all skin types compared to Radiation Therapy Oncology Group (RTOG) or Common Toxicity Criteria for Adverse Events (CTCAE) grades. A new descriptor-based scoring tool would be useful for RD and CRI.
... The available literature included cutaneous radiation injuries (Parrish and Seda 2019;DiCarlo et al. 2020), armed conflicts (Haverkamp et al. 2019, parties/concerts/discos Lin et al. 2019;Tseng et al. 2019;, communication accidents (Ewbank et al. 2018), terrorist attacks (Konwinski et al. 2016;Ozoilo et al. 2010;Sheridan et al. 2017, Hunt et al. 2020, mass chemical casualties (Zhang et al. 2015), petroleum and LPG explosions (Kumar 2013;Carlsonet al. 2015), earthquakes (Kearns and Holmes 2014), indoor fires (Koning et al. 2015), forest fires (Seifman et al. 2011), and mine explosions (Allister and Hamilton et al. 1983). ...
... term 'capacity' includes the availability of burn beds, burn surgeons, burn nurses, other support staff, operating rooms, equipment, supplies, and related resources (Haller et al. 2017), which could include a suitable amount of material for human allogeneic skin graft materials. Historically the phrase mass burn casualty disaster included radiation injuries, terrorist attacks, indoor fires, club/disco fires, transport accidents, chemical burns, explosions (including industrial) etc. (Allister and Hamilton 1983;Seifman et al. 2011;Kumar 2013;Kearns et al. 2014;Carlson et al. 2015;Koning et al. 2015;Zhang et al. 2015;Konwinski et al. 2016;Ozoilo et al. 2010;Haller et al. 2017;Sheridan et al. 2017;Ewbank et al. 2019;Hunt, 2017;Chen et al. 2019;Haverkamp et al. 2019;Lin et al. 2019;Tseng et al. 2019;Parrish and Seda 2019;DiCarlo et al. 2020). From recent history in Poland, mass burn casualty disasters included mainly accidents in the carbon mines located in the Śląskie Voivodship (Southern Poland). ...
... 56% TBSA. It may be remarked that an average TBSA of more than 50% is characteristic for mass burn disasters, as reported by many authors (Allister and Hamilton 1983;Seifman et al. 2011;Kumar 2013;Kearns et al. 2014;Carlson et al. 2015;Koning et al. 2015;Zhang et al. 2015;Konwinski et al. 2016;Ozoilo et al. 2010;Haller et al. 2017;Sheridan et al. 2017;Ewbank et al. 2019;Hunt 2017;Chen et al. 2019;Haverkamp et al. 2019;Lin et al. 2019;Tseng et al. 2019;Parrish & Seda 2019;DiCarlo et al. 2020). According to that data the approximate burn area for the model profile of a burn casualty was estimated at 60% TBSA. ...
A burn is a sudden injury which immediate or long-term consequences may be life-threatening for the patient. A mass disaster event may involve large numbers of severely burned patients. Patients of this type typically have a limited area of healthy, unburned skin from which an autologous split thickness skin graft could be collected. In a clinical situation of this type, it is necessary to use a particular skin substitute. Non-viable allogeneic human skin graft materials might be considered as the most suitable skin substitutes in the treatment of such patients. At present, Poland does not have a sufficient supply of human allogeneic skin graft materials to meet the needs arising from a sudden and unforeseen mass disaster. This study involved an analysis of selected mass disasters. From this an estimate was made from a verified casualty profile of the necessary minimum stock of human allogeneic skin graft materials. An insufficient amount of skin results from an inadequate number of skin donors, which in turn results from the current tissue donation system. Therefore, a proposal has been made for the organizational, legal and systemic changes required to improve the situation in Polish transplantology, with particular emphasis on skin donation. In order to achieve a strategic stock of human skin grafts, a tissue collecting transplantation team should be organized. The rights and obligations of the non-physician transplant team member should be extended. Proposals have been made for awareness campaigns (adverts, posters etc.) and educational schemes (educational video, lectures during transplant coordinator training, etc.). Finally, a proposal has been made for possible methods to deal with the logistic management of the allogeneic skin stock. The required, essential stock of human allogeneic skin in the event of a mass disaster has been estimated at 600,000 cm².
... Kerastat completed a clinical trial in 2018 (NCT03559218) and was cleared for a radiation dermatitis indication in 2020. The company continues to advance the product for treatment of CRI/LRI during a radiological or nuclear incident, using a large white pig model [133]. ...
... These approaches range from nutraceuticals such as oral or topical curcumin [114,141,142] and drugs targeting the vasculature [143] to advanced wound care (Silverlon® dressings) and structural (KeraStat® cream) products. Detailed information about many of the approaches discussed here has been previously published [133]. ...
... In addition to the approaches mentioned above, both BARDA and NIAID have supported contracts for other novel approaches to treat CRI/LRI. These have included investments in TP508 (Chrysalis Biotherapeutics), a thrombin peptide that targets the vasculature to provide mitigation of radiation injuries to the skin [143], Granexin gel, a product with an active ingredient consisting of the aCT1 peptide, which targets connexin 43 protein, downregulates inflammation, and is in late-stage human trials for a variety of indications (FirstString Research) [133], and Nor Leu 3-A(1-7) (US Biotest Inc.), an angiotensin analog that has shown promise in accelerating healing of severe radiation-induced lesions [122]. ...
The threat of a large-scale radiological or nuclear (R/N) incident looms in the present-day climate, as noted most recently in an editorial in Scientific American (March 2021). These large-scale incidents are infrequent but affect large numbers of people. Smaller-scale R/N incidents occur more often, affecting smaller numbers of people. There is more awareness of acute radiation syndrome (ARS) in the medical community; however, ionizing radiation-induced injuries to the skin are much less understood. This article will provide an overview of radiation-induced injuries to the skin, deeper tissues, and organs. The history and nomenclature; types and causes of injuries; pathophysiology; evaluation and diagnosis; current medical management; and current research of the evaluation and management are presented. Cutaneous radiation injuries (CRI) or local radiation injuries (LRI) may lead to cutaneous radiation syndrome (CRS), a sub-syndrome of ARS. These injuries may occur from exposure to radioactive particles suspended in the environment (air, soil, water) after a nuclear detonation (ND), an improvised nuclear detonation (IND), a nuclear power plant (NPP) incident, or an encounter with a radioactive dispersal or exposure device (RDD/RED). These incidents may also result in a radiation-combined injury (RCI); a chemical, thermal, or traumatic injury, with radiation exposure. Skin injuries from medical diagnostic and therapeutic imaging, medical misadministration of nuclear medicine or radiotherapy, occupational exposures (including research) to radioactive sources are more common but are not the focus of this manuscript. Diagnosis and evaluation of injuries are based on the scenario, clinical picture, and dosimetry, and may be assisted through advanced imaging techniques. Research-based multidisciplinary therapies, both in the laboratory and clinical trial environments, hold promise for future medical management. Great progress is being made in recognizing the extent of injuries, understanding their pathophysiology, as well as diagnosis and management; however, research gaps still exist.
... US Government funding agency scientists frequently communicate with investigators about the Animal Rule, and work collaboratively to anticipate and mitigate regulatory challenges. To that end, NIAID, BARDA and FDA have co-sponsored many successful scienti c conferences focused on topics such as animal model development and organ-speci c [52][53][54][55] and radiation combined injuries [56], MCM advancement and repurposing [57][58][59][60], biodosimetry [61] and regulatory issues [59]. At each step of the process, RNCP program sta have interacted frequently with investigators in the funded research portfolio, to help accelerate the development process, in the hopes of advancing promising candidates toward FDA approval. ...
... Although the rst four drugs approved for H-ARS were drugs that were repurposed from other clinical indications [59] (primarily oncology and hematology), there is a robust pipeline of approaches that target many pathways for H-ARS, as well as other sub-syndromes, including, but not limited to, GI-ARS [81][82][83][84][85], skin injuries [52], late lung [53] and kidney complications [67,[86][87][88], cardiovascular [55], central nervous system [69,[89][90][91] and radiation combined injuries [92][93][94]. It would be challenging to list all the products that are being investigated for potential use as radiation MCMs; however, given the multi-organ dysfunction known to occur a er radiation exposure, products targeting each of the a ected organs (see Table 1) have been widely studied. ...
... It would be challenging to list all the products that are being investigated for potential use as radiation MCMs; however, given the multi-organ dysfunction known to occur a er radiation exposure, products targeting each of the a ected organs (see Table 1) have been widely studied. These approaches have been reviewed elsewhere [52,53,[56][57][58][59]95]. ...
The USA has experienced one large-scale nuclear incident in its history. Lessons learned during the Three-Mile Island nuclear accident provided government planners with insight into property damage resulting from a low-level release of radiation, and an awareness concerning how to prepare for future occurrences. However, if there is an incident resulting from detonation of an improvised nuclear device or state-sponsored device/weapon, resulting casualties and the need for medical treatment could overwhelm the nation’s public health system. After the Cold War ended, government investments in radiation preparedness declined; however, the attacks on 9/11 led to re-establishment of research programs to plan for the possibility of a nuclear incident. Funding began in earnest in 2004, to address unmet research needs for radiation biomarkers, devices and products to triage and treat potentially large numbers of injured civilians. There are many biodosimetry approaches and medical countermeasures (MCMs) under study and in advanced development, including those to address radiation-induced injuries to organ systems including bone marrow, the gastrointestinal (GI) tract, lungs, skin, vasculature and kidneys. Biomarkers of interest in determining level of radiation exposure and susceptibility of injury include cytogenetic changes, ‘omics’ technologies and other approaches. Four drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of acute radiation syndrome (ARS), with other licensures being sought; however, there are still no cleared devices to identify radiation-exposed individuals in need of treatment. Although many breakthroughs have been made in the efforts to expand availability of medical products, there is still work to be done.
... Indeed, as clinical manifestations are dose and time-dependent, fibrosing inflammatory flares and necrotic recurrences may occur months or years after exposure for the most serious cases 8,9 . Thus, healing of LRI is a long process where pain induced by the injury remains resistant to opiates 10 . Access to a tool for early diagnosis of LRI would be therefore particularly useful for the management of a radiological emergency consecutive to mass accident. ...
... For a clinical use in a case of emergency, interesting biomarkers should be stable, collected with a minimally invasive method (a simple blood test for example) and analyzed easily at a reasonable cost 10 . In this regard, circulating microRNAs (miRNAs) constitute promising candidates as biomarkers of radiation induced biological effects. ...
A radiological accident, whether from industrial, medical, or malicious origin, may result in localized exposure to high doses of ionizing radiations, leading to the development of local radiation injury (LRI), that may evolve toward deep ulceration and necrosis of the skin and underlying tissues. Early diagnosis is therefore crucial to facilitate identification and management of LRI victims. Circulating microRNAs (miRNA) have been studied as potential diagnostic biomarkers of several diseases including hematological defects following whole-body irradiation (WBI). This study aims to identify a blood miRNA signature associated with LRI in a preclinical C57BL/6J mouse model of hindlimb irradiation using different 10-MV X-ray doses that lead to injuries of different severities. To this end, we first performed broad-spectrum plasma miRNA profiling, followed by a targeted validation step, on two independent animal cohorts. Using a multivariate sparse partial least square discriminant analysis, we identified a panel of eight circulating miRNAs able to segregate mice according to LRI severity. Interestingly, these miRNAs were previously associated with WBI (miR-150-5p, miR-342-3p, miR-146a-5p), inflammation (miR-18a-5p, miR-148b-3p, miR-532-5p) and skin diseases (miR-139-5p, miR-195-5p). Our results suggest the use of circulating miRNAs as suitable molecular biomarkers for LRI prognosis and diagnosis.
... They usually appear after a specific dose (threshold dose or threshold of clinical effects), being more severe the higher the amount received [1,[4][5][6]. Skin lesions and lens opacities are examples of deterministic effects after radiation exposure [7][8][9][10]. ...
... There is no threshold dose, and effects can occur at low doses. The development of malignancy is the most common stochastic effect of radiation exposure [7][8][9][10]. Stochastic effects often appear years after exposure. ...
In the past decades, we have witnessed tremendous developments in endovascular surgery. Nowadays, highly complex procedures are performed by minimally invasive means. A key point is equipment improvement. Modern C-arms provide advanced imaging capabilities, facilitating endovascular navigation with an adequate open surgical environment. Nevertheless, radiation exposure remains an issue of concern. This study aims to analyze radiation used during endovascular procedures according to complexity, comparing a mobile X-ray system with a hybrid room (fixed X-ray system). This is an observational and prospective study based on a cohort of non-randomized patients treated by endovascular procedures in a Vascular Surgery department using two imaging systems. The study is planned for a 3-year duration with a recruitment period of 30 months (beginning 20 July 2021) and a 1-month follow-up period for each patient. This is the first prospective study designed to describe the radiation dose according to the complexity of the procedure. Another strength of this study is that radiologic variables are obtained directly from the C-arm and no additional measurements are required for feasibility benefit. The results from this study will help us determine the level of radiation in different endovascular procedures, in view of their complexity.
... В последнее время всё чаще гамма-облучение находит применение в биопромышленности при получении вакцин, антигенов и других биологических препаратов. Более широко для этих целей используются гамма-излучающие изотопы кобальта-60 и цезия-137, а также ускоренные электроны [7,8]. ...
Purpose: To study clinical, hematologic and immunologic parameters in assessing the anti-radiation efficacy of the therapeutic agent based on the microorganism Fusobacterium necrophorum. Material and methods: The studies on determination of the anti-radiation efficacy of the strains of microorganisms killed by gamma-irradiation were carried out on sexually mature sexless white mice and white rats with live weight of 18–20 and 180–200 g, respectively, divided into experimental and control groups according to the principle of analogs. Modeling of acute radiation sickness was carried out on a Puma gamma unit with a radioactive source of cesium-137 at a dose of LD100/30. As potential anti-radiation drugs we used inactivated by irradiation on the gamma unit Explorer preparations of microbial origin F. necrophorum strain 8. necrophorum strain 8TS630501 at doses of 15, 20, 25 and 30 kGy. The tested preparations were injected subcutaneously in the volume of 0.2 cm3 to white mice and 2.0 cm3 to white rats 3 days after radiation exposure. Results: It was experimentally established that complete sterilization of the microbe occurs at doses of 25 and 30 kGy. The culture of F. necrophorum, irradiated at doses of 25 and 30 kGy and administered to animals 3 days after external radiation exposure, promoted survival, preservation of 60 to 80 % of lethally irradiated white mice and rats. At the same time the recovery of leukocytes and hemoglobin number was slow and continued until the end of the study. In animals treated with the developed therapeutic agents, there was also a decrease in the number of T-cells, but it was less pronounced than in the irradiation control group. The number of B-lymphocytes was affected similarly to T-lymphocytes. The minimum of the number of B-lymphocytes in the experimental groups was noted at 14 days. Studies on the intensity of the process of lipid peroxidation (LPO) in the content of malonic dialdehyde in peripheral blood of gamma-irradiated, treated and intact rats, it was found that in the irradiated control group there is a significant increase in the LPO index in blood in relation to biological control and treatment groups. Conclusion: It has been established that the highest anti-radiation efficacy is possessed by a therapeutic agent of microbial origin (RNF-30), which was obtained by gamma-irradiation at a dose of 30 kGy of the culture of F. necrophorum.
... This technique was first used in 1970 in Russia (54). In this method, the optical fiber is inserted into a vein by a catheter (54,55). patients show that UV stimulation leads to activating a cytokine cascade including prostaglandin 2, IL-4, and IL-10, that is associated with suppression of IF-γ production and reduced cytokine storm (78,82). ...
The pandemic outbreak of Coronavirus disease 2019 (COVID-19) which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), is a new viral infection in all countries around the world. An increase in inflammatory cytokines, fever, dry cough, and pneumonia are the main symptoms of COVID-19. A shared of growing clinical evidence confirmed that cytokine storm correlates with COVID-19 severity which is also a crucial cause of death from COVID-19. The success of anti-inflammatory therapies in the recovery process of COVID-19 patients has been well established. Over the years, phototherapy (PhT) has been identified as a promising non-invasive treatment approach for inflammatory conditions. New evidence suggests that PhT as an anti-inflammatory therapy may be effective in treating acute respiratory distress syndrome (ARDS) and COVID-19. This review aims to a comprehensive overview of the direct and indirect effects of anti-inflammatory mechanisms of PhT in ARDS and COVID-19 patients.
... В случае чрезвычайных ситуаций, связанных с радиоактивными выбросами и влиянием на природные очаги инфекционных болезней (сибирская язва, бруцеллез, чума крупного рогатого скота, свиней и т.д.), возможно радиационно-биологическое, радиационно-термическое поражение сельскохозяйственных животных [5][6][7][8]. В условиях современных крупных животноводческих комплексов при концентрации значительного количества животных на ограниченных территориях возрастает опасность заражения и быстрого распространения инфекционных заболеваний, среди которых значительный экономический ущерб скотоводству в Российской Федерации и во всем мире причиняет пастереллез, вызывающий массовое распространение болезни у молодняка и взрослых животных со значительным смертельным исходом [9][10][11][12]. ...
Purpose: Simulate radiation-pasteurellosis lesions in the body. Material and methods: Modeling of radiation and pasteurellosis lesions caused by the action of physical and biological factors on the organism Modeling of acute radiation disease (ARD) of animals was carried out by gamma-irradiation at the “Puma” facility with an exposure dose rate of 2.36×10-5 A/kg. Pasteurella multocida, the causative agent of pasteurellosis, as one of the most frequently occurring pathogenic agents, was used as a model biological agent to reproduce the experimental biological lesion. Modeling of radiation-pasteurellosis lesion was carried out on rabbits and on white mice with live weight of 2.8‒3.4 kg and 18‒20 g, respectively. Results: In experiments on white mice to determine the optimal doses of the affecting agents it was found that the minimum doses of gamma rays and the causative agent of pasteurellosis are 6.0 Gy and 4.5×103 microbial cells per kg (m.k./kg), 3.9 Gy and 9.0×103 m.k./kg, which leads to the development of pasteurellosis infection and radiation sickness in acute form with death of all animals, mainly on the first and second days after exposure to the affecting agents. k./kg, which leads to the development of pasteurellosis infection and radiation disease in acute form with death of all animals, mainly on the first and second days after combined exposure to the affecting agents. It was found that gamma-irradiation of rabbits at a dose of 8.0 Gy, followed by infection with Pasteurella at a dose of 4.5×103 m.k./kg, aggravated the course of the pasteurellosis process, contributed to its generalization and accelerated the death of animals. Conclusion: Radiation-pasteurellosis affection proceeded rapidly. Animals died on 2‒13 days after the onset of the disease with an average life expectancy of 6.3 days. Exposure of rabbits to non-lethal doses of the studied agents at the indicated doses led to aggravation of the course of radiation sickness and pasteurellosis infection, causing death of all animals from radiation-pasteurellosis pathology. At autopsy of corpses of animals, which died from acute course of radiation-pasteurellosis pathology, swelling of subcutaneous tissue in the area of pharynx and intermandibular space of neck, hyperemia and enlargement of lymph nodes, numerous hemorrhages on serous and mucous membranes and in tissues of parenchymatous organs ‒ serous or serous-fibrinous exudate in thoracic and abdominal areas, pulmonary edema were found.
... Epidermal and follicular keratinocytes interact with multiple immune cells to shape, amplify and regulate inflammatory responses, thus creating the first line of defense against environmental threats [7]. Over the past few years, technical advances in molecular biology and the use of innovative experimental models have led to a better understanding of the pathogenesis of numerous dermatological diseases, including cutaneous radiation injuries [8][9][10]. In this review, we describe the pathomechanisms of radiation-induced skin damage based on the latest findings, with a particular focus on the structural and immunological barrier function of the epidermis. ...
An important hallmark of radiation dermatitis is the impairment of the mitotic ability of the stem/progenitor cells in the basal cell layers due to radiation-induced DNA damage, leading to suppressed cell renewal in the epidermis. However, this mechanism alone does not adequately explain the complex pathogenesis of radiation-induced skin injury. In this review, we summarize the latest findings on the complex pathogenesis of radiation dermatitis and correlate these with the clinical features of radiation-induced skin reactions. The current studies show that skin exposure to ionizing radiation induces cellular senescence in the epidermal keratinocytes. As part of their epithelial stress response, these senescent keratinocytes secrete pro-inflammatory mediators, thereby triggering skin inflammation. Keratinocyte-derived cytokines and chemokines modulate intercellular communication with the immune cells, activating skin-resident and recruiting skin-infiltrating immune cells within the epidermis and dermis, thereby orchestrating the inflammatory response to radiation-induced tissue damage. The increased expression of specific chemoattractant chemokines leads to increased recruitment of neutrophils into the irradiated skin, where they release cytotoxic granules that are responsible for the exacerbation of an inflammatory state. Moreover, the importance of IL-17-expressing γδ-T cells to the radiation-induced hyperproliferation of keratinocytes was demonstrated, leading to reactive hyperplasia of the epidermis. Radiation-induced, reactive hyperproliferation of the keratinocytes disturbs the fine-tuned keratinization and cornification processes, leading to structural dysfunction of the epidermal barrier. In summary, in response to ionizing radiation, epidermal keratinocytes have important structural and immunoregulatory barrier functions in the skin, coordinating interacting immune responses to eliminate radiation-induced damage and to initiate the healing process.
... 5 Depending on an individual patient's injury scenario, biodosimetry techniques such as gamma H2AX assay of hair follicles, DSB markers (53BP), protein signatures, and EPR of hard tissues may help better define the scope of the radiation damage. 8 Grading scales have been developed to describe and categorize the severity of individual cutaneous radiation injuries. The NIH Common Terminology Criteria for Adverse Events (CTCAE) provides 5 grades ranging from light erythema (Grade 1) to ulceration/skin loss (Grade 4) and fatal injuries (Grade 5). 9 Another grading system based on clinical presentation and affected percentage of body surface area is the METREPOL Cutaneous System Grading scale, which provides a broad prediction of prognosis related to injury severity (Table 1). ...
The Radiation Emergency Assistance Center/Training Site (REAC/TS) is one of the US Department of Energy (DOE)/National Nuclear Security Administration (NNSA) Nuclear Emergency Response Team (NEST) assets and has been responding to radiological incidents since 1976. REAC/TS is in the Oak Ridge Institute for Science and Education (ORISE). A critical part of the REAC/TS mission is to provide emergency response, advice, and consultation on injuries and illnesses caused from ionizing radiation. Fortunately, radiation injuries are not frequent, but when they occur, they are more likely to be cutaneous radiation injuries (CRI) or internal contamination. In this paper, we will review selected cases from the REAC/TS experience in order to illustrate cutaneous patterns of injury and treatment options.
... b Active product development is underway in another ARS subsyndrome, namely gastrointestinal ARS (GI-ARS) and in 2 additional organs affected by radiation, albeit with delayed manifestations of the injury, namely radiation-induced lung injury (RILI), 1 and cutaneous radiation injury (CRI). 2 Drugs for ARS are developed under the Animal Rule because human challenge studies are not ethical and field trials are not feasible. In addition, the demonstration of drug effectiveness in a related condition of use (e.g., in myelosuppression induced by cancer therapies or in immunemediated cytopenia) generally cannot be fully extrapolated to ARS because these conditions do not adequately reflect the ARS pathophysiology. ...
The Food and Drug Administration’s (FDA) approval to market drug products for use as medical countermeasures, to prevent or mitigate injury caused by various threat agents, is commonly based on evidence of efficacy obtained in animals. Animal studies are necessary when human studies are not feasible and challenge studies are not ethical. The successful development of countermeasures to radio-nuclear threats that cause Acute Radiation Syndrome (ARS) provides the opportunity to explore potential areas of overlap in the scientific approaches to studies of injuries caused by radiation and sulfur mustard exposures in animals. The aim is to evaluate the available scientific knowledge for radiation threat agents and sulfur mustard for potential analogies of fundamental mechanisms of organ injury and dysfunction. This evaluation is needed to determine the applicability of regulatory strategies for product development and approval adopted by manufacturers of countermeasures for radiation threat agents. Key elements of an efficient development plan based on animal efficacy studies include characterizing the pathophysiology of organ injury and the mechanism of action (MOA) of the countermeasure; modeling the clinical condition in animals to establish the manifestations of the injury caused by various levels of exposures to the threat agent and the response to various doses of the countermeasure candidate; as well as selecting a maximally effective human dose.
... Therefore, repeated exposure to radiation can induce several radiation-induced diseases, such as cataract, radiation dermatitis, and various cancers, including brain cancer, breast cancer, and skin malignancies. [3][4][5][6][7] Cases of radiation-related complications in medical staff have also been reported. [8] Therefore, proper shielding and efforts to reduce radiation exposure are important for pain physicians. ...
Background
The present study aimed to evaluate the degree of radiation shielding effects according to lead equivalent thickness and distance during C-arm fluoroscopy-guided lumbar interventions.
Methods
The exposure time and air kerma were recorded using a fluoroscope. The effective dose (ED) was measured with and without the shielding material of the lead apron using 2 dosimeters at 2 positions. According to the lead equivalent thickness of the shielding material and distance from the side of the table, the groups were divided into 4 groups: group 1 (lead equivalent thickness 0.6 mm, distance 0 cm), group 2 (lead equivalent thickness 0.6 mm, distance 5 cm), group 3 (lead equivalent thickness 0.3 mm, distance 0 cm), and group 4 (lead equivalent thickness 0.3 mm, distance 5 cm). Mean differences such as air kerma, exposure time, ED, and ratio of EDs (ED with protector/ED without protector) were analyzed.
Results
A total of 400 cases (100 cases in each group) were collected. The ratio of ED was significantly lower in groups 1 and 2 (9.18 ± 2.78% and 9.56 ± 3.29%, respectively) when compared to that of groups 3 and 4 (21.93 ± 4.19% and 21.53 ± 4.30%, respectively). The reductive effect of a 5-cm distance was 33.3% to 36.1% when comparing the ED between groups 1 and 2 and groups 3 and 4.
Conclusions
The 0.3- and 0.6-mm lead equivalent thickness protectors have a radiation attenuation effect of 78.1% to 78.5% and 90.4% to 90.8%, respectively. The 5-cm distance from the side of the table reduces radiation exposure by 33.3% to 36.1%.
... Depending upon the suspected extent of a lesion, other treatment considerations include antimicrobial prophylaxis and treatment, inhibitors of proteolysis, growth factors to enhance granulation and re-epithelialization, and stimulation of the local blood supply with pentoxifylline [15]. Multiple novel countermeasures for CRS and CRI are being evaluated in animal models, these include aCT1 peptide, thrombin peptide, mesenchymal stromal cells, and angiotensin analogues [16]. Following the latent phase, a manifest illness phase will occur due to an irradiated basal layer of the skin. ...
Radiation events such as nuclear war, nuclear reactor incidents, and the deployment of a radioactive dispersal device (dirty bomb) are all significant threats in today’s world. Each of these events would bring significant challenges to clinicians caring for patients with burns and traumatic injuries who are also contaminated or irradiated. The result of a nuclear exchange in a densely populated area could result in thousands of patients presenting with trauma, burns, and combined injury (trauma and burn in an irradiated patient). In this review, we will discuss the three major types of ionizing radiation: alpha, beta, and gamma, and their respective health hazards and biological effects. Additionally, we will discuss the types of burn injuries in a nuclear disaster, caring for the contaminated patient, and managing the combined injury of burn trauma with acute radiation syndrome. The reader will also be left with an understanding of how to prioritize lifesaving interventions, estimate the absorbed dose of radiation, and predict the onset of acute radiation syndrome. While some animal models for morbidity and mortality exist, there is limited modern day human data for patients with combined injury and burns associated with a nuclear disaster due to the infrequent nature of these events. It is extremely important to continue multidisciplinary research on the prevention of, preparedness for, and the response to nuclear events. Furthermore, continued exploration of novel treatments for radiation induced burns and the management of combined injury is necessary.
... «Радиационный отзыв» чаще ассоциирован с традиционными химиотерапевтическими препаратами, однако отмечены случаи, связанные с применением ингибиторов EGFR, ингибиторов BRAF-тирозинкиназы и др. [17,18]. ...
This review highlights the issue of radiation-induced skin reactions (RISR), emphasizes the high frequency of RISR in patients with cutaneous lymphomas undergoing radiation therapy, and analyzes numerous pathological processes that occur in the skin as a result of ionizing radiation exposure. The review systematically examines external and internal factors influencing the development of RISR, compares diagnostic methods, discusses preventive measures and treatments for radiation dermatitis, and describes the mechanisms of action for drugs used in RISR prophylaxis and treatment. RISR remains a significant problem in radiation therapy, characterized by a high frequency, a wide range of clinical manifestations, and an impact on patients quality of life. The mechanisms, diagnosis, prevention, and treatment of RISR are considered.
... Exposure of the subcutaneous tissue to high doses or prolonged radiation exposure may lead to fibrosis, edema, fat necrosis, and infection of the subcutaneous tissue. These phenomena usually occur at higher radiation doses and may lead to severe skin damage or even ulceration[132]. There is no specific therapeutic care for radiation injury to subcutaneous tissues. ...
Radiation skin injury (RSI) is a frequent adverse effect of radiation therapy for malignant tumors. It often leads to problems such as decreased quality of life in patients and interferes with the normal course of radiation therapy (RT). With the rising incidence of tumors and the burgeoning number of patients undergoing RT, the care of RSI is of crucial importance in cancer patient treatment. Currently, drugs and biomaterials are widely used in the care of RSI. However, there is no international consensus on the current protocol for the therapeutic care of RSI. Many drugs and biomaterials cannot be applied to the appropriate type of radiation dermatitis, resulting in unfavorable results in the therapeutic care of RSI. The choice of appropriate drugs and biomaterials for the therapeutic care of the different types of RSI is essential to improving the quality of life of patients. This article first reviews the main mechanisms of acute and chronic RSI. Subsequently, the application of drugs and novel biomaterials in the preventive, acute, and chronic phases of the care of RSI is summarized. Finally, the suggestions and protocols for the application of novel biomaterials in the care of RSI are discussed, as are the current challenges and future prospects for the development of combined biomaterials and integrated care solutions.
... Радіаційні ураження шкіри можна розділити на гострі та пізні (хронічні). Гостре ушкодження виникає протягом кількох годин чи тижнів після радіаційного опромінення, тоді як хронічне ушкодження виникає за місяці чи роки після радіаційного опромінення [4,5]. Найбільш важкі гострі та пізні реакції, що спостерігаються найчастіше після аварійного опромінення у високих дозах. ...
В експериментальній моделі встановлено відновлювальна та протизапальна активність культивованих/кріоконсервованих мезенхімальних стромальних клітин кісткового мозку (МСК КМ) при локальному та/або системному терапевтичному уведенні тваринам з радіаційними ураження шкіри на 14 і 21 добу після опромінення. Терапевтична ефективність МСК КМ визначалася у зниженні в 2,3 рази ступеня тяжкості клінічних реакцій, прискоренні загоювання та зменшенні в 1,6 рази площі уражених ділянок шкіри без виникнення хронічних радіаційних виразок з одночасним зниженням більш ніж у 2,0 рази рівню С-реактивного білка у сироватці крові у період розгортання системних та місцевих запальних реакцій.
... The protection of people, structures, and equipment from harmful radiation impacts is of interest to researchers working in the field of nuclear engineering. To minimize the radiation effect, physicians, technicians, and patients must track some key rules [6]. Primarily, the period of contact must be maintained to the lowest possible, and the sources of radiation must be maintained as far away from persons; in addition, protective material must be utilized, specifically in radiation absorption situations. ...
In this study, a series of barium titanate ceramics of the chemical composition BaTiO3 was prepared. The solid-state reaction route was adopted to synthesize the ceramic samples at various sintering temperatures of 1100–1300 °C. X-ray diffraction and FTIR spectroscopy were utilized to examine the structure of the fabricated ceramics. The UV–Vis–reflectance data were recorded to guess the optical bandgap energy of the synthesized ceramics. The ability of the synthesized ceramics to attenuate ionizing radiation was qualified using a Monte Carlo simulation (MCNP code) in the γ-energy interval ranging between 59 keV and 1408 keV. Shielding parameters, including LAC, TF, and RPE, were evaluated. The XRD and FTIR analyses showed the formation of a tetragonal BaTiO3 perovskite structure with the Pmmm space group. The crystallite size and the relative density increased, whereas the porosity decreased, with increasing sintering temperatures. Optical bandgap energy (Eg) values decreased as the sintering temperatures increased. The radiation shielding results depicted that raising the sintering temperature between 1100 °C and 1300 °C resulted in a slight increase in the µ values by a factor of ≈8 %. The mentioned increase in the µ values caused a reduction in the Δeq and Δ0.5, and TF values for the fabricated BaTiO3 ceramic samples, while the RPE values increased with increasing sintering temperatures between 1100 °C and 1300 °C.
... e study of the combined radiation lesions in peacetime in practical conditions is impossible due to the absence of this type of injury, so researchers need to refer to the method of modeling CRL on laboratory animals. Given that in the case of the use of nuclear weapons, up to 80-85% of those affected with CRL are expected, treating the pathology takes one of the leading places [22,23]. In the immediate period after exposure to the damaging factors of a nuclear explosion or accident, it is precisely the timely complete medical manifestations that determine the survival prognosis [24]. ...
Since the search for the effective medication in combined lesions includes the selection of an optimal experimental model for such injuries, there is actually a study aimed at developing an optimal model of combined radiation-biology (Pasteurella) lesions. The pathogen Pasteurella multocida (as one of the most frequent pathogenic agents involved in both isolated and combined radiation-biology lesions of agricultural animals) was used as a model of a biological agent to reproduce experimental biological research. We employed the “Chinchilla” rabbits of 2.5–3.0 kg body weight as a biological model for doing combined radiation Pasteurella lesion. When determining the optimal model of combined radiation-biology (Pasteurella) lesion, we consider that in the joint action of various pathological agents on the organism, there is a synergistic effect of explosion agents, previously specifying minimal doses of external γ-radiation and pasteurellosis pathogen that in the joint action of nonfatal doses would be lethal. The first stage of the experiments determined the minimal doses of gamma rays and pasteurellosis pathogen that in joint action causes combined radiation-biology pathology. We examined 66 rabbits divided into 11 groups of 6 animals each to determine minimal doses of infectious agent-pasteurellosis pathogen. The animals of the first 9 groups were given subcutaneously Pasteurella species at doses 1·109, 1·108, 1·107, 1·106, 1·105, 1·104, 1·103, 1·102, and 1·101 of microbial cells per animal of 0.3 ml suspension in volume; the 10th group of animals were given saline solution; the 11th served as a biological control group. In determining the minimal doses of gamma rays, we conducted experimental tests on 36 rabbits, which have been exposed to external γ-radiation in the “PUMA” system with a 137Cs radiation source of the exposure dose of 5.38 R/min at doses 2.0, 4.0, 6.0, 8.0, 10, and 12 Gy. To specify the optimal model of radiation-pasteurellosis lesion, we used the rabbits subjected to a combined radiation-biology effect using minimal doses of gamma rays and pasteurellosis agent, leading to a lethal effect during their complex action. The researches revealed that 50% of the death of rabbits infected with pasteurellosis occurs using Pasteurella at a dose of 3.7·104 microbial cells per kilogram (LD50 = 3.7∙104 m.c./kg), and 50% of radiation death in rabbits occurs when irradiated their gamma rays at a dose of 8.0 Gy (LD50 = 8.0 Gy). The combined effect of nonlethal doses of the studied agents in the indicated doses on rabbits led to the aggravation of the course of radiation and pasteurellosis infection, causing the death of animals from combined radiation-pasteurellosis pathology. The model combined radiation-pasteurellosis disease ran its course rapidly, and the animals died 3 to 6 days after the onset. The autopsy of the animals that died from acute radiation-pasteurellosis pathogen had found swelling of the subcutaneous tissue in the pharynx and intermaxillary space of the neck, hyperemia, lymphoid nodular hyperplasia, numerous hemorrhages on the serous and mucous membranes and in the tissues of the parenchymal organs, serous or serous-fibrinous exudate, and in the chest and abdominal regions, pulmonary edema. The research stated that gamma radiation of rabbits at a dose of 8.0 Gy conducted before exposure with Pasteurella at LD50 (3.7·104 m.c./kg) declined the course of the pasteurellosis process, facilitated its generalization, and fastened the death of animals. Combined radiation-pasteurellosis infection ran its course rapidly, and the animals died within 3 to 6 days after the onset of the disease. The autopsy showed the pathologicoanatomic factors of the acute pasteurellosis: swelling of the subcutaneous tissue, purulent-catarrhal bronchopneumonitis, and pulmonary edema.
... αCT1 is a 25-AA peptide that is currently in pivotal-stage clinical trials for surgical scar reduction and skin radiation injury (DiCarlo et al., 2020;Montgomery et al., 2021). This 25mer comprises a 16-AA antennapedia cell penetration sequence and the last 9 AAs of the gap junction protein connexin 43 (Hunter et al., 2005). ...
Current medicinal treatments for diseases comprise largely of two categories: small molecule (chemical) drugs (e.g., aspirin) and larger molecules (peptides/proteins, e.g., insulin). Whilst both types of therapeutics can effectively treat different diseases, ranging from well-understood (in view of pathogenesis and treatment) examples (e.g., flu), to less-understood chronic diseases (e.g., diabetes), classical small molecule drugs often possess significant side-effects (a major cause of drug withdrawal from market) due to their low- or non-specific targeting. By contrast, therapeutic peptides, which comprise short sequences from naturally occurring peptides/proteins, commonly demonstrate high target specificity, well-characterized modes-of-action, and low or non-toxicity in vivo. Unfortunately, due to their small size, linear permutation and lack of tertiary structure, peptidic drugs are easily subject to rapid degradation or loss in vivo through chemical and physical routines, thus resulting in a short half-life and reduced therapeutic efficacy, a major drawback that can reduce therapeutic efficiency. However, recent studies demonstrate that the short half-life of peptidic drugs can be significantly extended by various means, including use of enantiomeric or non-natural amino acids (AAs) (e.g., L-AAs replacement with D-AAs), chemical conjugation [e.g., with polyethylene glycol], and encapsulation (e.g., in exosomes). In this context, we provide an overview of the major in vivo degradation forms of small therapeutic peptides in the plasma and anti-degradation strategies. We also update on the progress of small peptide therapeutics that are either currently in clinical trials or are being successfully used in clinical therapies for patients with non-infectious diseases, such as diabetes, multiple sclerosis, and cancer.
... Radiation-induced cutaneous ulcers following accidental or intentional acute exposure to high doses of ionizing radiation are a challenging medical problem [1]. Radiationinduced cutaneous ulcers are characterized by the occurrence of unpredictable cycles of inflammation that extend beyond the initial damage, increasing the affected area on the epidermis and deeper tissues, owing to delayed tissue necrosis and repair failure [2,3]. Radiation considerably contributes to inflammation and cell senescence of the investigated tissue, and targeting senescent cells is a potential therapeutic strategy for skin radiation ulcers [4][5][6]. ...
Radiation-induced cutaneous ulcers are a challenging medical problem for patients receiving radiation therapy. The inhibition of cell senescence has been suggested as a prospective strategy to prevent radiation ulcers. However, there is no effective treatment for senescent cells in radiation ulcers. In this study, we investigated whether zileuton alleviated radiation-induced cutaneous ulcer by focusing on cell senescence. We demonstrate increased cell senescence and senescence-associated secretory phenotype (SASP) in irradiated dermal fibroblasts and skin tissue. The SASP secreted from senescent cells induces senescence in adjacent cells. In addition, 5-lipoxygenase (5-LO) expression increased in irradiated dermal fibroblasts and skin tissue, and SASP and cell senescence were regulated by 5-LO through p38 phosphorylation. Finally, the inhibition of 5-LO following treatment with zileuton inhibited SASP and mitigated radiation ulcers in animal models. Our results demonstrate that inhibition of SASP from senescent cells by zileuton can effectively mitigate radiation-induced cutaneous ulcers, indicating that inhibition of 5-LO might be a viable strategy for patients with this condition.
... contrast to the untreated irradiated wounds which were much thinner and are known to suffer from reduced granulation tissue formation and a thinner neoepidermis in other studies as well [11]. Both of these factors likely contribute to the clinically well-documented fragility and unpredictability of irradiated wounds [11,36]. ...
Background
Radiation-induced skin injury is a well-known risk factor for impaired wound healing. Over time, the deleterious effects of radiation on skin produce a fibrotic, hypovascular dermis poorly suited to wound healing. Despite increasing understanding of the underlying pathophysiology, therapeutic options remain elusive. Deferoxamine (DFO), an iron-chelating drug, has been shown in prior murine studies to ameliorate radiation-induced skin injury as well as improve wound healing outcomes in various pathologic conditions when administered transdermally. In this preclinical study, we evaluated the effects of deferoxamine on wound healing outcomes in chronically irradiated murine skin.
Methods
Wild-type mice received 30 Gy of irradiation to their dorsal skin and were left to develop chronic fibrosis. Stented excisional wounds were created on their dorsal skin. Wound healing outcomes were compared across 4 experimental conditions: DFO patch treatment, vehicle-only patch treatment, untreated irradiated wound, and untreated nonirradiated wounds. Gross closure rate, wound perfusion, scar elasticity, histology, and nitric oxide assays were compared across the conditions.
Results
Relative to vehicle and untreated irradiated wounds, DFO accelerated wound closure and reduced the frequency of healing failure in irradiated wounds. DFO augmented wound perfusion throughout healing and upregulated angiogenesis to levels observed in nonirradiated wounds. Histology revealed DFO increased wound thickness, collagen density, and improved collagen fiber organization to more closely resemble nonirradiated wounds, likely contributing to the observed improved scar elasticity. Lastly, DFO upregulated inducible nitric oxide synthase and increased nitric oxide production in early healing wounds.
Conclusion
Deferoxamine treatment presents a potential therapeutic avenue through which to target impaired wound healing in patients following radiotherapy.
... 30 National Institute of Allergy and Infectious Diseases has been developing radioprotectors, therapeutics, and mitigators as medical countermeasures in accidental/intentional radiation exposures. 31 Drugs from this program are evaluated to decrease the AEs of RT. 32 The effect of microbiome on differences in radiation response was also recently reviewed among patients, and exploiting such differences to modulate radiation response before, during, and after chemoradiotherapy is of interest. 33 Therapy-induced senescence and its relationships with cell death, resistance to therapy, cancer stemness, and plasticity is a dynamic area. ...
... Currently, specialists in various fields of biology and medicine pay considerable attention to the prevention and treatment of RT complications. The objects of such research are an extremely wide range of compounds with various pathophysiological and pharmacological activities, which are capable of limiting radiation alteration, modulating the processes of repair and cell death, the course of immune-inflammatory reactions and fibrogenesis, etc. [28][29][30]. ...
The radioprotective effects of a new 1-isobutanoil-2-isopropylisothiourea derivative named T1082 are presented. Research methods included toxic characteristics, radioprotective activity (Till–McCulloch’s test and 30-day survival test) in γ-ray total-body-irradiated mice, and a clinical and histological study of the effect of T1082 on acute radiation skin reactions (RSR) in rats after a single or fractionated β-ray local irradiation. T1082 is more effective than its analogue, the NOS inhibitor T1023, at low concentrations and doses (1/12–1/8 LD10), both parenterally and intragastrically. In this case, its therapeutic index (LD50/ED50) reaches 30, and the optimal radioprotective doses (ED84–98—141–224 mg/kg) are an order less than the maximum tolerated doses—1/16–1/10 LD10. These properties allowed T1082, at a low intragastrical dose (160 mg/kg; 1/14 LD10), to significantly limit the severity of acute RSR after single (40 Gy) and fractionated (78 Gy) β-ray irradiation. The results confirm T1082 as one of the safest emergency radioprotectors and indicate the prospects for its further development as a pharmacological agent for the prevention of RT complications.
... For example, it may be advisable to provide higher-end support such as the administration of growth factors in an NHP to allow survival past H-ARS and monitoring of other complications like GI-or lung-driven morbidity or mortality. As for cutaneous radiation injury, porcine skin is considered to be very similar to human skin (20); therefore, a cutaneous radiation injury model was developed in Yorkshire swine exposed at focal areas to increasing doses of radiation. Scoring of resulting skin damage (e.g., erythema and dry or moist desquamation) was used to better understand the dose response and time course response of when the injuries occur in the model, how they present and progress, and how scoring of the injury sites can be done. ...
The Radiation and Nuclear Countermeasures Program within the National Institute of Allergy and Infectious Diseases (NIAID), is tasked with the mandate of identifying biodosimetry tests to assess exposure and medical countermeasures (MCMs) to mitigate/treat injuries to individuals exposed to significant doses of ionizing radiation from a radiological/nuclear incident, hosted. To fulfill this mandate, the Radiation and Nuclear Countermeasures Program (RNCP), hosted a workshop in 2018 workshop entitled "Policies and Regulatory Pathways to U.S. FDA licensure: Radiation Countermeasures and Biodosimetry Devices." The purpose of the meeting was to facilitate the advancement of MCMs and biodosimetry devices by assessing the research devices and animal models used in preclinical studies; government policies on reproducibility, rigor and robustness; regulatory considerations for MCMs and biodosimetry devices; and lessons learned from sponsors of early stage MCM or biodosimetry devices. Meeting presentations were followed by a NIAID-led, open discussion among academic investigators, industry researchers and U.S. government representatives.
... Many small animal (e.g., mouse, rat, guinea pig) models of radiation are detailed in the literature, which include: total-body irradiation (TBI) for hematopoietic acute radiation syndrome (H-ARS) (5), and gastrointestinal (GI)-ARS (6); partial-body irradiation (PBI) for GI-ARS and lung injuries (7); whole thorax lung irradiation (WTLI) exposure for lung effects (8); and PBI for renal and other delayed effects of acute radiation exposure (DEARE) (9). Large animal models [e.g., nonhuman primate (NHP), minipig (MP), full-size pig (Yorkshire Swine), or canine] have also been developed for TBI H-ARS (10) or GI-ARS (6), PBI GI-ARS (11,12), WTLI for lung (13), TBI kidney 2 (14), and cutaneous radiation injury (CRI) (15). Since large animal resources are limited and costly, preliminary efficacy and dosing studies should be completed in small animal studies. ...
INTRODUCTION
The Radiation and Nuclear Countermeasures Program (RNCP), which is part of the National Institute of Allergy and Infectious Diseases (NIAID), within the National Institutes of Health (NIH) sponsored a workshop on “Policies and Regulatory Pathways to Food and Drug Administration (FDA) Licensure: Radiation Countermeasures and Biodosimetry Devices” that was held on October 9–10, 2018, in Bethesda, MD. This meeting was attended by U.S. Government (USG), academic, and industry researchers involved in the development of radiation medical countermeasures (MCMs) and biodosimetry tools. The objectives of this meeting were to: 1. discuss current policies and regulatory pathways to aid in the advancement of radiation MCM and biodosimetry tools, 2. identify resources, guidance, and gaps in research practices and existing policies, and 3. provide a platform for an open and informal dialogue among scientists and government partners with expertise in MCM or biodosimetry development. Discussion topics centered on: 1. defining the context for deployment of MCMs and biodosimetry platforms, 2. animal models of irradiation developed in response to the FDA Animal Rule and Biodosimetry Guidance (1), 3. NIH policy and support for MCM development and biodosimetry advancement, and 4. lessons learned from industry frontrunners. More detailed information can be found in the full meeting report available online ( https://doi.org/10.1667/RADE-21-00157.1)
DEFINING THE CONTEXT FOR DEPLOYMENT OF MCMS AND BIODOSIMETRY PLATFORMS
After a nuclear incident, the USG response relies on scenario modeling at the federal, state, and local level. Responders will likely be resource-limited; therefore, to address screening needs during a radiation public health emergency, a USG interagency working group developed the radiation-specific TRiage, TReatment, TRansport (RTR) system (2). This effort is designed to optimize resource allocation (material and personnel) to the most appropriate staging zones. Inherent to this planning is the need to provide continuous monitoring. Triage will direct scarce resources to those individuals who will benefit the most from medical care, whereas others will be released for observation or provided palliative care, depending on the severity of the exposure. If more help is needed at the local level, a federally sponsored National Disaster Medical System (NDMS) is available. The NDMS deploys personnel and augments the local response and health care systems with Veterans Administration hospitals and hospitals within the NDMS network, including the Radiation Injury Treatment Network (RITN) (3). Any response to a nuclear disaster will require a large and coordinated effort by local responders and providers, up to and including regional and national receivers, to care for patients.
ANIMAL MODELS TO SUPPORT RADIATION MCM DEVELOPMENT
Animal models. Animal models serve as surrogates in situations where it is not ethical to conduct human studies, as is the case for radiation studies. The animal models selected should model the disease of interest, and a drug's anticipated mechanism of action. Studies must be adequate and well-controlled, and the effect of the challenge agent in the laboratory model should be predictive of the human condition. For drug and biological product MCM development, the US FDA Animal Rule (AR) guidance should be followed (21 CFR 314.610(a) for drugs, and 21 CFR 601.91(a) for biological products) (4). Given the complexity of the AR, developers are encouraged to consult early and often with the US FDA to ensure that the critical path selected to move an approach forward is acceptable to the agency.
Many small animal (e.g., mouse, rat, guinea pig) models of radiation are detailed in the literature, which include: total-body irradiation (TBI) for hematopoietic acute radiation syndrome (H-ARS) (5), and gastrointestinal (GI)-ARS (6); partial-body irradiation (PBI) for GI-ARS and lung injuries (7); whole thorax lung irradiation (WTLI) exposure for lung effects (8); and PBI for renal and other delayed effects of acute radiation exposure (DEARE) (9). Large animal models [e.g., nonhuman primate (NHP), minipig (MP), full-size pig (Yorkshire Swine), or canine] have also been developed for TBI H-ARS (10) or GI-ARS (6), PBI GI-ARS (11, 12), WTLI for lung (13), TBI kidney² (14), and cutaneous radiation injury (CRI) (15). Since large animal resources are limited and costly, preliminary efficacy and dosing studies should be completed in small animal studies. The adequate design of preclinical studies is critical as this research feeds into more advanced development funded either by NIAID/RNCP or the Biomedical Advanced Research and Development Authority (BARDA).
Advanced product development. BARDA incorporates flexible authorities, such as multi-year support, promotion of innovation, industry partnerships, and cutting-edge expertise to develop MCMs and biodosimetry tools for radiation injury. To date, BARDA's Project BioShield (16) has supported 27 radiation products; of which eight products advanced to the U.S. FDA for approval/licensure/clearance, and fourteen were acquired for the Strategic National Stockpile (SNS). Stockpiled agents include ThyroShield® (potassium iodide oral solution), calcium- and zinc-diethylenetriamine penta-acetic acid (DTPA), Neupogen®, Neulasta®, and Leukine®.³ BARDA also supports a robust radiation biodosimetry portfolio, which includes point of care (POC) triage screening tests to discern individuals needing medical evaluations from those who can evacuate, as well as high throughput laboratory tests, which more accurately report individual absorbed radiation dose, and inform medical care. BARDA is also working on the development of thermal burn products, since combined radiation injuries are expected (17). Developing biodosimetry tools is challenging since regulatory strategies are still being developed. Nonetheless, BARDA has advanced four of these products into validation and clinical testing, with one pre-Emergency Use Authorization (EUA) data package filed.⁴ The end goal is to obtain U.S. FDA-cleared triage tools to help separate concerned citizens from individuals with medically significant radiation doses, and to assist physicians in determining who requires administration of life-saving treatments.
NIH POLICY AND FDA REGULATORY GUIDANCE
NIH policy to enhance reproducibility through rigor and transparency. Advancing products through licensure and commercialization requires an understanding of the regulations governing drug development. The goal of the regulations (and their governing statutes) is to ensure that end-users receive the safest and most effective products currently available for the specified indication. For a drug, it means that it will reproducibly address a pathology as a therapeutic or prophylactic medication. For a device, it will reproducibly function as intended, be it an instrument of life support, a diagnostic kit, or a tool for conducting the practice of medicine. Above all, it must be safe, and the potential for adverse events (i.e., side-effects or failure modes) should be understood and controlled, if possible. The concept of quality should be incorporated into every facet of drug and device development, from research through clinical trials and post-marketing surveillance. Investigators are responsible for managing key resources that are tantamount to improving rigor and transparency. The NIH Office of Extramural Research provides policy guidelines for Rigor and Reproducibility.⁵ Additionally, NIH training modules are available.⁶
Radiation biodosimetry development and validation challenges: a regulatory perspective. Radiation biodosimetry devices are a subset of in vitro diagnostics (IVDs) that can be used to estimate the absorbed radiation dose received by individuals (18). Use of these IVDs can range from field triage settings (POC) to confirmatory testing and clinical evaluation (high throughput). The regulatory path to market and identification of pivotal validation studies that need to be conducted can be a challenge. Some instruments, including biodosimetry devices, may qualify for an EUA. The EUA permits the use of an unapproved product during a declared emergency (life-threatening or serious condition) where no alternative is available, and there is insufficient time to obtain FDA clearance, approval, or licensing under the Federal Food, Drug, and Cosmetic Act.⁷ Requests for EUAs go to the FDA Office of the Commissioner; however, the path had been somewhat obscure until the recent EUAs issued for COVID-19 diagnostic tests. To determine the best path forward, developers should refer to the available FDA guidance document, “Radiation Biodosimetry Medical Countermeasure Devices Guidance for Industry and Food and Drug Administration Staff” (1). For a successful IVD development project, the FDA recommends early and frequent interactions, careful consideration of the path to market, attention to special controls for De Novo submissions, and preparation of a pre-EUA submission.
Development of therapeutics for radiological and nuclear emergencies. If an approved/licensed drug is being repurposed as an MCM, an extensive safety profile in humans will likely already be available through clinical experience and post-marketing studies. If not, a traditional Investigational New Drug (IND) application will be required to conduct Phase 1 studies in healthy volunteers with appropriate age, sex and race considerations. As with all drug development, preclinical safety and toxicology studies will also need to be addressed in animal models. MCM products may be eligible for fast-track, priority review, or breakthrough therapy programs, which can considerably reduce the review time for approval or licensure. Orphan product designations and grant programs are also available for indications that affect less than 200,000 patients per year in the U.S. Finally, in the absence of adequate, approved, and available alternatives, an EUA can also be used for unapproved products or indications for use in public health emergencies.
GOVERNMENT SUPPORT FOR ADVANCEMENT OF MCMS AND BIODOSIMETRY TECHNOLOGIES
The mission of the NIAID/RNCP program is to support early through late-stage research to develop radiation/nuclear MCMs and biodosimetry tools (19). NIAID/RNCP has funded the development of rodent and NHP models of H-and GI-ARS (7, 20, 21). In addition, animal models for DEARE continue to be developed for GI and lung injury (22, 23). Rat and canine models have also been established to test radionuclide decorporation agents (24, 25). NIAID/RNCP efforts have directly led to three INDs for oral decorporation agents and a cellular MCM, the manufacture or reformulation of three MCMs, and the FDA approval of three MCMs for H-ARS – Neupogen and Neulasta (2015), and Nplate® (2021). In 2018, BARDA-funded studies led to the FDA approval of Leukine (sargramostim) for H-ARS. The NIAID/RNCP also helps advance biodosimetry tools by providing valuable NHP biological samples to developers for proof of principle analysis (26–29). This pipeline is fueled by a company engagement pathway that begins with an introductory teleconference with NIAID, followed by a Radiation and Nuclear Group – Advanced Product Development (RNG-APD) interagency meeting, with participation from several government partners and testing facilities. The RNG-APD allows for early-stage feedback and establishes the best drug development pathway for the product.
BARDA also employs subject matter experts who have experience in a variety of areas in product development. Generally, contracts are used to develop products as a public-private partnership. Other innovative programs such as the Division of Research, Innovation, and Ventures (DRIVe)⁸ and Early Notification to Act, Control and Treat (ENACT)⁹ are also used to accelerate the development of products. From 2007–2020, BARDA, in its entirety, has had over 59 FDA approvals, licensures, and clearances spanning a variety of health threats.¹⁰ BARDA's biodosimetry program started in 2009 with the funding of 11 technologies in the areas of proteomics, gene expression, and DNA damage.
LESSONS LEARNED FROM THE FRONTRUNNERS
The FDA has approved four MCMs to date for H-ARS, but no biodosimetry test or device has been cleared as of the time of this publication. Therefore, lessons learned from developers of candidate MCMs and biodosimetry tools, including challenges and advances in their journey toward U.S. FDA licensure, can be informative for other researchers.
Application of the FDA Animal Rule for the development of Neupogen, Neulasta, and Nplate as radiation MCMs. Amgen worked closely with USG partners to successfully advance Neupogen, Neulasta, and Nplate as hematopoietic radiation MCMs. Careful adherence to the considerations laid forth by the AR guidance played an important role in these successes (4). Prior to their consideration for H-ARS, these drugs were approved for medical use in over 100 countries and were part of large clinical trials; with 26,421 (8.8 M individuals) and 5,419 (4.4 M individuals) clinical trials for Neupogen and Neulasta, respectively. Therefore, the extensive medical use and well-understood tolerability profiles of these drugs also played a role in their success.
To support the radiation indication, pivotal studies were conducted in mice and NHPs. NHPs were exposed to a lethal dose of 7.5 Gy [LD50/60] of linear accelerator (LINAC) photon irradiation. Neupogen (administered daily, starting at 24 h postirradiation)-treated groups demonstrated higher survival compared to the vehicle-treated cohort, and duration of neutropenia was also significantly reduced (30). Similarly, Neulasta demonstrated efficacy in irradiated mice and NHPs exposed to 7.5 Gy TBI. Neulasta treatment resulted in a 91% survival as compared to 48% survival in the control group, and also decreased the median duration of neutropenia (31).
Although the FDA approval of romiplostim (Nplate) was made after the meeting described herein, it is included to provide an up-to-date accounting of available MCMs for H-ARS. Nplate was initially approved in 2008 for the treatment of patients with chronic immune thrombocytopenia,¹¹ and the mechanism of action of the drug is well-understood. A single subcutaneous injection of romiplostim shows a dose-dependent increase in platelet counts, with a platelet peak appearing on days 12–16 after dosing in humans (32). Romiplostim also demonstrated improvements in survival and platelet recovery in two irradiated animal species, C57BL/6 mice (33) and NHPs (34). At the time of the 2018 workshop, pivotal NHP survival studies and the selection of the human dose were still ongoing. Since the workshop, NHP and dose-translation studies (35) were completed, and in January 2021 the FDA approved Nplate as a radiation MCM.¹²
Regulatory Timeline for Advanced MCM Development
• 2002 FDA Animal Rule was established.
• 2005 Amgen had its first pre-IND meeting for Neupogen as a H-ARS MCM.
• 2006 NIAID, as HHS partners, filed pre-IND and development plans.
• 2011 NIAID filed the final study reports of Neupogen NHP animal model development and efficacy.
• 2013 US FDA Advisory Committee met to discuss groundwork for an eventual regulatory pathway to approval, following discussions between Amgen, FDA, and NIAID.¹³
• 2014 Amgen submitted a supplemental BLA for Neupogen based on the survival data and PK/PD modeling.
• 2015 FDA approved Neupogen and Neulasta in March and November, respectively.
• 2018 FDA approved Leukine for H-ARS, based on BARDA-funded studies.
• 2021 FDA approved Nplate in January.
Regulatory perspective on developing a POC triage radiation biodosimeter. In 2010, SRI International received BARDA funding to develop a Clinical Laboratory Improvement Amendments (CLIA)-waived POC biodosimeter device that utilizes capillary blood samples capable of triaging up to one million individuals over 6 days after exposure (∼167,000 tests/day). The goal was to distinguish concerned citizens in good health but believe to have been exposed (<2 Gy), from people exposed to a high radiation dose (>2 Gy) that likely require medical intervention. The assay involves the use of a capillary blood collection. The drop of blood is placed into a cartridge that uses a lateral flow assay and is amenable to a mass casualty scenario. The assay quantifies the levels of the AMY1, FLT3L and MCP1 target protein concentrations.
SRI's regulatory interactions. SRI had an introductory pre-submission meeting with the FDA, and provided information on their preliminary panel, statistical methods, and NHP data (2014). Since the first meeting, SRI has submitted feasibility plans (2016), verification plans (2018), and requested FDA comments on their validation protocols (2019). Altogether, FDA pre-submission meetings have proven to be extremely useful in gaining clarity on FDA's expectations. Development challenges for the SRI POC triage biodosimetry test include the lack of an intended use population (partially abrogated by using NHPs and cancer patients receiving TBI), and the challenge of translating these results to a reliable cut-off point (2 Gy) needed for triage. Although the development path is unclear, the government-industry partnership continues to forge ahead to ensure availability of a reliable triage device for use during a radiological or nuclear incident.
CONCLUSION
The ability of the USG to respond to a radiological and/or nuclear incident is contingent upon the availability of suitable tools to triage, and MCMs to treat affected populations. NIH policies and FDA guidance provide pathways that can inform drug and device developers in the continuum of research translation, with the objective of FDA licensure/approval/clearance and implementation. Regardless, the process of translating basic discoveries to clinical use to improve public health is fraught with challenges at pre-clinical and clinical research levels. This meeting provided an open informal dialogue between key stakeholders, product developers and government partners, with expertise in MCM or biodosimetry development. Available resources, guidance, and gaps in research practices and existing policies were discussed. USG agencies will continue to work with academic and corporate partners to overcome these challenges, to obtain effective MCMs and rapid biodosimetry tests to effectively manage a radiological or nuclear incident.
ACKNOWLEDGMENTS
Many thanks to RNCP/NIAID colleagues David Cassatt, Carmen Rios, Tom Winters, Brynn Hollingsworth, and Olivia Molinar-Inglis for their critical review of the manuscript.
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Notes
[1] ² Brown DL, Measey T, Donini O. Radiation-induced renal changes in the Göttingen MP. Poster presentation, 2017, 36th Annual Society of Toxicologic Pathology Symposium, Montreal, Canada.
[2] ³ https://www.medicalcountermeasures.gov/media/36904/01_hachett_state-of-barda-address.pdf.
[3] ⁴ https://medicalcountermeasures.gov/BARDA/Documents/BID2018_Presentations/Wathen_BID18_CBRN_DX.pdf.
[4] ⁵ https://grants.nih.gov/policy/reproducibility/index.htm.
[5] ⁶ https://www.nigms.nih.gov/training/pages/clearinghouse-for-training-modules-to-enhance-data-reproducibility.aspx.
[6] ⁷ https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-authorization-medical-products-and-related-authorities.
[7] ⁸ https://drive.hhs.gov/.
[8] ⁹ https://drive.hhs.gov/enact.html.
[9] ¹⁰ https://www.medicalcountermeasures.gov/barda/fdaapprovals/.
[10] ¹¹ https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125268s0026lbl.pdf.
[11] ¹² https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125268s167lbl.pdf
[12] ¹³ https://www.fda.gov/advisory-committees/human-drug-advisory-committees/medical-imaging-drugs-advisory-committee. Please select the live link, “FDA Archive.''
... Furthermore, wound healing is slow, and closed wounds are frequently fragile and unpredictable. Finally, the most challenging distinction is that the pain caused by a radiation skin wound is frequently resistant to opiates, resulting in psychological crises for the patients [18,19]. ...
The Medical management of radiation accidents manual on the acute radiation syndrome (METREPOL) proposed a successful strategic approach to diagnosing and treating acute radiation syndrome: the response category concept. Based on clinical and laboratory parameters, this approach aimed to assess damage to critical organ systems as a function of time, categorising different therapeutical approaches. After 20 years of its publication, the following paper attempts to provide a broad overview of this important document and tries to respond if proposed criteria are still relevant for the medical management of radiation-induced injuries. In addition, a critical analysis of its limitations and perspectives is proposed.
... The problem of developing pharmacological agents for the prevention and treatment of RT toxic effects have currently attracted considerable attention. The objects of research and development in this area are an extremely wide range of synthetic and biotechnological compounds with various types of biochemical and pathophysiological activity: the ability to limit the formation of primary radiation damage, modulate the processes of cell death, the activity of post-radiation repair, the course of immune-inflammatory processes and fibrogenesis [20][21][22][23]. ...
Previously, we showed that a nitric oxide synthase (NOS) inhibitor, compound T1023, induces transient hypoxia and prevents acute radiation syndrome (ARS) in mice. Significant efficacy (according to various tests, dose modifying factor (DMF)—1.6–1.9 against H-ARS/G-ARS) and safety in radioprotective doses (1/5–1/4 LD10) became the reason for testing its ability to prevent complications of tumor radiation therapy (RT). Research methods included studying T1023 effects on skin acute radiation reactions (RSR) in rats and mice without tumors and in tumor-bearing animals. The effects were evaluated using clinical, morphological and histological techniques as well as RTOG classification. T1023 administration prior to irradiation significantly limited the severity of acute RSR. This was due to a decrease in radiation alteration of the skin and underlying tissues, and the preservation of the functional activity of cell populations that are critical in the pathogenesis of radiation burn. The DMF values for T1023 for skin protection were 1.4–1.7. Moreover, its radioprotective effect was fully selective to normal tissues in RT models of solid tumors—T1023 reduced the severity of acute RSR and did not modify the antitumor effects of γ-radiation. The results indicate that T1023 can selectively protect the non-malignant tissues against γ-radiation due to hypoxic mechanism of action and potentiate opportunities of NOS inhibitors in RT complications prevention.
Combined radiation-trauma skin injury represents a severe and intractable condition that urgently requires effective therapeutic interventions. In this context, hepatocyte growth factor (HGF), a multifunctional growth factor with regulating cell survival, angiogenesis, anti-inflammation and antioxidation, may be valuable for the treatment of combined radiation-trauma injury. This study investigated the protective effects of a recombinant plasmid encoding human HGF (pHGF) on irradiated human immortalized keratinocytes (HaCaT) cells in vitro, and its capability to promote the healing of combined radiation-trauma injuries in mice. The pHGF radioprotection on irradiated HaCaT cells in vitro was assessed by cell viability, the expression of Nrf2, Bcl-2 and Bax, as well as the secretion of inflammatory cytokines. In vivo therapeutic treatment, the irradiated mice with full-thickness skin wounds received pHGF local injection. The injuries were appraised based on relative wound area, pathology, immunohistochemical detection, terminal deoxynucleotidyl transferase dUTP nick end labelling assay and cytokine content. The transfection of pHGF increased the cell viability and Nrf2 expression in irradiated HaCaT cells. pHGF also significantly upregulated Bcl-2 expression, decreased the Bax/Bcl-2 ratio and inhibited the expression of interleukin-1β and tumor necrosis factor-α in irradiated cells. Local pHGF injection in vivo caused high HGF protein expression and noticeable accelerated healing of combined radiation-trauma injury. Moreover, pHGF administration upregulated Nrf2, vascular endothelial growth factor, Bcl-2 expression, downregulated Bax expression and mitigated inflammatory response. In conclusion, the protective effect of pHGF may be related to inhibiting apoptosis and inflammation involving by upregulating Nrf2. Local pHGF injection distinctly promoted the healing of combined radiation-trauma injury and demonstrates potential as a gene therapy intervention for combined radiation-trauma injury in clinic.
Both cutaneous radiation injury and radiation combined injury (RCI) could have serious skin traumas, which are collectively referred to as radiation‐associated skin injuries in this paper. These two types of skin injuries require special managements of wounds, and the therapeutic effects still need to be further improved. Cutaneous radiation injuries are common in both radiotherapy patients and victims of radioactive source accidents, which could lead to skin necrosis and ulcers in serious conditions. At present, there are still many challenges in management of cutaneous radiation injuries including early diagnosis, lesion assessment, and treatment prognosis. Radiation combined injuries are special and important issues in severe nuclear accidents, which often accompanied by serious skin traumas. Mass victims of RCI would be the focus of public health concern. Three‐dimensional (3D) bioprinting, as a versatile and favourable technique, offers effective approaches to fabricate biomimetic architectures with bioactivity, which provides potentials for resolve the challenges in treating radiation‐associated skin injuries. Combining with the cutting‐edge advances in 3D skin bioprinting, the authors analyse the damage characteristics of skin wounds in both cutaneous radiation injury and RCI and look forward to the potential value of 3D skin bioprinting for the treatments of radiation‐associated skin injuries.
Although chemical and radiological agents cause toxicity through different mechanisms, the multiorgan injuries caused by these threats share similarities that convene on the level of basic biological responses. This publication will discuss these areas of convergence and explore “multi-utility” approaches that could be leveraged to address common injury mechanisms underlying actions of chemical and radiological agents in a threat-agnostic manner. In addition, we will provide an overview of the current state of radiological and chemical threat research, discuss the US Government’s efforts toward medical preparedness, and identify potential areas for collaboration geared toward enhancing preparedness and response against radiological and chemical threats. We also will discuss previous regulatory experience to provide insight on how to navigate regulatory paths for US Food and Drug Administration (FDA) approval/licensure/clearance for products addressing chemical or radiological/nuclear threats. This publication follows a 2022 trans-agency meeting titled, “Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures,” sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health (NIH). Discussions from this meeting explored the overlapping nature of radiation and chemical injury and spurred increased interest in how preparedness for one threat leads to preparedness for the other. Herein, subject matter experts from the NIAID and the Biomedical Advanced Research and Development Authority (BARDA), a part of the Administration for Strategic Preparedness and Response (ASPR), summarize the knowledge gained from recently funded biomedical research, as well as insights from the 2022 meeting. These topics include identification of common areas for collaboration, potential use of biomarkers of injury to identify injuries caused by both hazards, and common and widely available treatments that could treat damage caused by radiological or chemical threats.
Background:
Late-effect radiation-induced wounds represent a particularly difficult category of wounds to manage and treat. Fibrosis, impaired cellular activity, ischemia, and wound chronicity all work to impair healing, and this becomes more pronounced when defects are large or when avascular structures such as bone are exposed. Effective treatment options for this type of wound are limited. Thorough excision of irradiated tissue followed by distal pedicled or free flap closure is the most successful; however, this often requires multiple-stage surgeries and prolonged hospitalization and is associated with significant donor site morbidity. This is complicated further when wounds are large or in difficult locations, when surgery is not appropriate, or when there is limited access to surgeons with the appropriate experience/skill to perform such procedures.
Methods:
This case series describes the use of an autologous heterogenous skin construct (AHSC) made from a small full-thickness sample of the patient's healthy skin. Three patients with intractable late-effect radiation wounds were treated with AHSC. Case 1 describes an abdominal wound with tunneling of 7.5 cm to the pubic symphysis, which had been treated for known osteomyelitis, and a shallower full-thickness groin wound. Case 2 describes a right scapular wound with exposed bone, which had failed flap closure. Case 3 describes a right thigh wound in a patient who had been treated for sarcoma with extensive radiation therapy. This eventually resulted in an above-the-knee amputation, which failed to heal, and full exposure of the distal end of the resected femur. All wounds had been present for greater than 10 months.
Results:
Mean percent volume reduction was 83% (±2.7) at 3 weeks and 92.9% (±4.7) at 4 weeks. The tunneled abdominal wound decreased in depth from 7.5 cm to 1.2 cm in 3 weeks. Complete closure was achieved at 11 weeks for the abdominal and groin wounds (patient 1) and at 16 weeks for the thigh wound (patient 3). The scapular wound volume of patient 2 had decreased by 91.8% at week 4 but was not fully restored until week 21. Mean time to closure was 16.1 (±4.7) weeks.
Conclusions:
AHSC was effective in covering exposed bone, improving wound bed vascularity, filling in significant wound depth, and achieving complete wound closure with one application in patients with intractable late-effect radiation wounds.
Combined radiation injury occurs when radiation is accompanied by any other form of trauma. The past experiences of Hiroshima, Nagasaki, and Chernobyl have revealed that a large fraction of victims of such nuclear accidents or attacks suffer from combined radiation injuries. The possibility of a nuclear attack seems very far-fetched, but the destruction that would occur in such events will be massive, with a huge loss in terms of lives. Therefore, preparedness for the same should be done beforehand. The severity of combined radiation depends upon various factors such as radiation dose, type, tissues affected, and traumas. The article focuses on combined radiation burn injury (CRBI) 1 2 1 1 1 3 sandeepshukla.inmas@gov.in
Over the past 20+ years, the U.S. Government has made significant strides in establishing research funding and initiating a portfolio consisting of subject matter experts on radiation-induced biological effects in normal tissues. Research supported by the National Cancer Institute (NCI) provided much of the early findings on identifying cellular pathways involved in radiation injuries, due to the need to push the boundaries to kill tumor cells while minimizing damage to intervening normal tissues. By protecting normal tissue surrounding the tumors, physicians can deliver a higher radiation dose to tumors and reduce adverse effects related to the treatment. Initially relying on this critical NCI research, the National Institute of Allergy and Infectious Diseases (NIAID), first tasked with developing radiation medical countermeasures in 2004, has provided bridge funding to move basic research toward advanced development and translation. The goal of the NIAID program is to fund approaches that can one day be employed to protect civilian populations during a radiological or nuclear incident. In addition, with the reality of long-term space flights and the possibility of radiation exposures to both acute, high-intensity, and chronic lower-dose levels, the National Aeronautics and Space Administration (NASA) has identified requirements to discover and develop radioprotectors and mitigators to protect their astronauts during space missions. In sustained partnership with sister agencies, these three organizations must continue to leverage funding and findings in their overlapping research areas to accelerate biomarker identification and product development to help safeguard these different and yet undeniably similar human populations – cancer patients, public citizens, and astronauts.
Radiation-induced esophageal injury (RIEL) is a major dose-limiting complication of radiotherapy, especially for esophageal and thoracic cancers. RIEL is a multi-factorial and multi-step process, which is regulated by a complex network of DNA, RNA, protein and metabolite. However, it is unclear which esophageal metabolites are altered by ionizing radiation and how these changes affect RIEL progression. In this work, we established a rat model of RIEL with 0–40 Gy X-ray irradiation. Esophageal irradiation using ≥25 Gy induced significant changes to rats, such as body weight, food intake, water intake and esophageal structure. The metabolic changes and related pathways of rat esophageal metabolites were investigated by liquid chromatography-mass spectrometry (LC-MS). One hundred eighty metabolites showed an up-regulation in a dose-dependent manner (35 Gy ≥ 25 Gy > controls), and 199 metabolites were downregulated with increasing radiation dose (35 Gy ≤ 25 Gy < controls). The KEGG analysis showed that ionizing radiation seriously disrupted multiple metabolic pathways, and arachidonic acid metabolism was the most significantly enriched pathway. 20 metabolites were dysregulated in arachidonic acid metabolism, including up-regulation of five prostaglandins (PGA2, PGJ2, PGD2, PGH2, and PGI2) in 25 or 35 Gy groups. Cyclooxygenase-2 (COX-2), the key enzyme in catalyzing the biosynthesis of prostaglandins from arachidonic acid, was highly expressed in the esophagus of irradiated rats. Additionally, receiver operating characteristic (ROC) curve analysis revealed that PGJ2 may serve as a promising tissue biomarker for RIEL diagnosis. Taken together, these findings indicate that ionizing radiation induces esophageal metabolic alterations, which advance our understanding of the pathophysiology of RIEL from the perspective of metabolism.
The radiation shielding properties of ball clays produced with various percentages of 5, 10, 15, and 20 w.t% of micro and nano ZnO were experimentally evaluated in this paper. The effects of micro and nano ZnO on the attenuation competence of the prepared ball clays were compared. At all energies, we discovered that the ball clay with nano ZnO has a higher linear attenuation coefficient (LAC) than ZnO with microparticles. This finding suggests that nano-sized ZnO-ball clay samples absorbed more photons than microsized ZnO ball clay samples. The half-value layer (HVL) for the ball clay prepared with micro and nano ZnO was reported. At all the energies tested, we discovered that the ball clay with nano ZnO has a slightly lower HVL than the ball clay with micro ZnO. The HVL at 0.06 MeV is found to be 0.934 cm for the ball clay containing 5 w.t% micro ZnO and 0.866 cm for the ball clay containing 5 w.t% nano ZnO. We concluded from the HVL results that if the space in which the shield will be used is limited, the ball clay with nano ZnO is more useful because a thinner specimen with nano ZnO can attenuate half ofthe incoming photons. Scanning electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, and energy-dispersive X-ray spectroscopy were used to investigate the properties of ZnO/ball clay.
Biomarkers are important indicators of biological processes in health or disease. For this reason, they play a critical role in advanced development of radiation biodosimetry tools and medical countermeasures (MCMs). They can aid in the assessment of radiation exposure level, extent of radiation-induced injury, and/or efficacy of an MCM. This meeting report summarizes the presentations and discussions from the 2020 workshop titled, “Biomarkers in Radiation Biodosimetry and Medical Countermeasures,” sponsored by the Radiation and Nuclear Countermeasures Program (RNCP) at the National Institute of Allergy and Infectious Diseases (NIAID). The main goals of this meeting were to: 1. Provide an overview on biomarkers and to focus on the state of science with regards to biomarkers specific to radiation biodosimetry and MCMs; 2. Understand developmental challenges unique to the role of biomarkers in the fields of radiation biodosimetry and MCM development; and 3. Identify existing gaps and needs for translational application.
Radiation‐induced skin injury is a serious concern during radiotherapy and radiation accidents.1 This disease differs from traditional wounds due to impaired healing and prone to recurrence.2 Our recent report suggests that radiation‐induced skin injury is associated with lipid metabolism.3 One particular protein in lipid metabolism is peroxisome proliferator‐activated receptor α (PPARα), a member of the PPAR nuclear hormone receptor superfamily that can be activated by fibrate ligands.4 We aim to elucidate the biological effect of PPARα and its agonist in the progression of radiation‐induced skin injury.
Ionizing radiation causes injury to the skin that produces a complex clinical presentation that is managed by various paradigms without clear standards. The situation is further complicated by the fact that clinicians and researchers often use different terms and billing codes to describe the spectrum of cutaneous injury. There is, however, general agreement between the two most commonly-used diagnostic scales, the Radiation Therapy Oncology Group and the Common Terminology Criteria for Adverse Events, and in their use to describe skin injury following radiation therapy. These scales are typically used by radiation oncologists to quantify radiation dermatitis, a component of the radiation-related disorders of the skin and subcutaneous tissue family of diagnoses. In rare cases, patients with severe injury may require treatment by wound care or burn specialists, in which case the disease is described as a “radiation burn” and coded as a burn or corrosion. Further compounding the issue, most US government agencies use the term Cutaneous Radiation Injury to indicate skin damage resulting from large, whole-body exposures. In contrast, the US Food and Drug Administration approves products for radiation dermatitis or “burns caused by radiation oncology procedures.” A review of the literature and comparison of clinical presentations shows that each of these terms represents a similar injury, and can be used interchangeably. Herein we provide a comparative review of the commonly used terminology for radiation-induced skin injury. Further, we recommend standardization across clinicians, providers, and researchers involved in the diagnosis, care, and investigation of radiation-induced skin injury. This will facilitate collaboration and broader inclusion criteria for grant-research and clinical trials and will assist in assessing therapeutic options particularly relevant to patient skin pigmentation response differences.
A radiation combined injury (RCI) is defined as an injury that occurs in the setting of irradiation, such as those expected after a nuclear accident, radiation dispersal device release (a "dirty bomb"), or a nuclear weapon detonation. There is much research on irradiation-associated burns and their healing, but there is less known about other injuries sustained in the context of irradiation. Animal models are limited in their correlations to clinical situations but can support research on specific questions about injuries and their healing. Mouse models of irradiation with skin or bone wounds have been validated as highly reproducible and quantitative. They show dose-dependent impairment of wound healing, with later recovery. Irradiation-induced delay of bone wound healing was mitigated to different extents by single doses of gramicidin S-nitroxide JP4-039, a plasmid expressing Manganese Superoxide Dismutase (MnSOD), amifostine/WR2721, or the bifunctional sulfoxide MMS-350. These models should be useful for research on mechanisms of radiation dermal and osseous damage and for further development of new radioprotectors. They also provide information of potential relevance to effects of clinical radiation therapies.
With the end of the Cold War in 1991, U.S. Government (USG) investments in radiation science and medical preparedness were phased out; however, the events of September 11th , which involved a terroristic attack on American soil, led to the re-establishment of funding for both radiation preparedness and development of approaches to address injuries. Similar activities have also been instituted worldwide, as the global threat of a radiological or nuclear incident continues to be a concern. Much of the USG's efforts to plan for the unthinkable has centered on establishing clear lines of communication between agencies with responsibility for triage and medical response, and external stakeholders. There have also been strong connections made between those parts of the government that establish policies, fund research, oversee regulatory approval, and purchase and stockpile necessary medical supplies. Progress made in advancing preparedness has involved a number of subject matter meetings and tabletop exercises, publication of guidance documents, assessment of available resources, clear establishment of anticipated concepts of operation for multiple radiation and nuclear scenarios, and identification/mobilization of resources. From a scientific perspective, there were clear research gaps that needed to be addressed, which included the need to identify accurate biomarkers and design biodosimetry devices to triage large numbers of civilians, develop decorporation agents that are more amenable for mass casualty use, and advance candidate products to address injuries caused by radiation exposure and thereby improve survival. Central to all these activities was the development of several different animal constructs, since efficacy testing of these approaches requires extensive work in research models that accurately simulate what would be expected in humans. Recent experiences with COVID-19 have provided an opportunity to revisit aspects of radiation preparedness, and leverage those lessons learned to enhance readiness for a possible future radiation public health emergency.
The use of effective regimens for mitigating pain remain underutilized in research rodents despite the general acceptance of both the ethical imperative and regulatory requirements intended to maximize animal welfare. Factors contributing to this gap between the need for and the actual use of analgesia include lack of sufficient evidence-based data on effective regimens, under-dosing due to labor required to dose analgesics at appropriate intervals, concerns that the use of analgesics may impact study outcomes, and beliefs that rodents recover quickly from invasive procedures and as such do notneed analgesics. Fundamentally, any discussion of clinical management of pain in rodents must recognize that nociceptive pathways and pain signaling mechanisms are highly conserved across mammalian species, and that central processing of pain is largely equivalent in rodents and other larger research species such as dogs, cats, or primates. Other obstacles to effective pain management in rodents have been the lack of objective, science-driven data on pain assessment, and the availability of appropriate pharmacological tools for pain mitigation. To address this deficit, we have reviewed and summarized the available publications on pain management in rats, mice and guinea pigs. Different drug classes and specific pharmacokineticprofiles, recommended dosages, and routes of administration are discussed, and updated recommendations are provided. Nonpharmacologic tools for increasing the comfort and wellbeing of research animals are also discussed. The potential adverse effects of analgesics are also reviewed. While gaps still exist in our understanding of clinical pain management in rodents, effective pharmacologic and nonpharmacologic strategies are available that can and should be used to provide analgesia while minimizing adverse effects. The key to effective clinical management of pain is thoughtful planning thatincorporates study needs and veterinary guidance, knowledge of the pharmacokinetics and mechanisms of action of drugs being considered, careful attention to individual differences, and establishing an institutional culture that commits to pain management for all species as a central component of animal welfare.
We have previously shown that injury induced by irradiation to murine marrow can be partially or completely reversed by exposure to human or murine mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs). Investigation of the biodistribution of EVs in vivo is essential for understanding EV biology. In this study, we evaluated the DiD lipid dye labeled MSC-EV biodistribution in mice under different conditions, including different MSC-EV doses and injection schedules, time post MSC-EV injection, and doses of radiation. DiD-labeled MSC-EVs appeared highest in the liver and spleen; lower in bone marrow of the tibia, femur, and spine; and were undetectable in the heart, kidney and lung, while a predominant EV accumulation was detected in the lung of mice infused with human lung fibroblast cell derived EVs. There was significantly increased MSC-EV accumulation in the spleen and bone marrow (tibia and femur) post radiation appearing with an increase of MSC-EV uptake by CD11b+ and F4/80+ cells, but not by B220 cells, compared to those organs from non-irradiated mice. We further demonstrated that increasing levels of irradiation caused a selective increase in vesicle homing to marrow. This accumulation of MSC-EVs at the site of injured bone marrow could be detected as early as 1 h after MSC- EV injection and was not significantly different between 2 and 24 h post MSC-EV injection. Our study indicates that irradiation damage to hematopoietic tissue in the spleen and marrow targets MSC-EVs to these tissues.
Extracellular vesicles (EVs) are membrane-coated nanovesicles actively secreted by almost all cell types. EVs can travel long distances within the body, being finally taken up by the target cells, transferring information from one cell to another, thus influencing their behavior. The cargo of EVs comprises of nucleic acids, lipids, and proteins derived from the cell of origin, thereby it is cell-type specific; moreover, it differs between diseased and normal cells. Several studies have shown that EVs have a role in tumor formation and prognosis. It was also demonstrated that ionizing radiation can alter the cargo of EVs. EVs, in turn can modulate radiation responses and they play a role in radiation-induced bystander effects. Due to their biocompatibility and selective targeting, EVs are suitable nanocarrier candidates of drugs in various diseases, including cancer. Furthermore, the cargo of EVs can be engineered, and in this way they can be designed to carry certain genes or even drugs, similar to synthetic nanoparticles. In this review, we describe the biological characteristics of EVs, focusing on the recent efforts to use EVs as nanocarriers in oncology, the effects of EVs in radiation therapy, highlighting the possibilities to use EVs as nanocarriers to modulate radiation effects in clinical applications.
Significance
From 1946 to 1958, the United States tested 67 nuclear weapons in the Marshall Islands, a remote constellation of atolls in the Pacific Ocean that was then a US trust territory. Two atolls, Bikini and Enewetak, were used as ground zero for the tests, which caused unprecedented environmental contamination and, for the indigenous peoples of the islands, long-term adverse health effects. In addition to the populations of Bikini and Enewetak, the people of Rongelap and Utirik were also affected by radioactive fallout from the largest nuclear test the United States has ever conducted, the Bravo test held March 1, 1954. This article presents a picture of current radiological conditions by examining external gamma radiation and soil radionuclide activity concentrations.
Abstract The range of radiation threats we face today includes everything from individual radiation exposures to mass casualties resulting from a terrorist incident, and many of these exposure scenarios include the likelihood of additional traumatic injury as well. Radiation injury is defined as an ionizing radiation exposure inducing a series of organ injury within a specified time. Severity of organ injury depends on the radiation dose and the duration of radiation exposure. Organs and cells with high sensitivity to radiation injury are the skin, the hematopoietic system, the gastrointestinal (GI) tract, spermatogenic cells, and the vascular system. In general, acute radiation syndrome (ARS) includes DNA double strand breaks (DSB), hematopoietic syndrome (bone marrow cells and circulatory cells depletion), cutaneous injury, GI death, brain hemorrhage, and splenomegaly within 30 days after radiation exposure. Radiation injury sensitizes target organs and cells resulting in ARS. Among its many effects on tissue integrity at various levels, radiation exposure results in activation of the iNOS/NF-kB/NF-IL6 and p53/Bax pathways; and increases DNA single and double strand breaks, TLR signaling, cytokine concentrations, bacterial infection, cytochrome c release from mitochondria to cytoplasm, and possible PARP-dependent NAD and ATP-pool depletion. These alterations lead to apoptosis and autophagy and, as a result, increased mortality. In this review, we summarize what is known about how radiation exposure leads to the radiation response with time. We also describe current and prospective countermeasures relevant to the treatment and prevention of radiation injury.
Human skin constructs (HSCs) have the potential to provide an effective therapy for patients with significant skin injuries and to enable human-relevant drug screening for skin diseases; however, the incorporation of engineered skin appendages, such as hair follicles (HFs), into HSCs remains a major challenge. Here, we demonstrate a biomimetic approach for generation of human HFs within HSCs by recapitulating the physiological 3D organization of cells in the HF microenvironment using 3D-printed molds. Overexpression of Lef-1 in dermal papilla cells (DPC) restores the intact DPC transcriptional signature and significantly enhances the efficiency of HF differentiation in HSCs. Furthermore, vascularization of hair-bearing HSCs prior to engraftment allows for efficient human hair growth in immunodeficient mice. The ability to regenerate an entire HF from cultured human cells will have a transformative impact on the medical management of different types of alopecia, as well as chronic wounds, which represent major unmet medical needs.
Skin lesions caused by accidental exposure to radiation or by radiotherapy are a major clinical challenge. We evaluated the effect of bone marrow mononuclear cells (BMMNC) on collagen remodeling and vascular function in radiation-induced skin lesions in the acute and late phases in mice. We studied the effect of BMMNC transplantation in a mouse model of cutaneous radiation injury combining local skin gamma-irradiation and biopsy punch wound. Mice were first irradiated, punched and then BMMNC were intramuscularly administered. Seven days after injury, BMMNC promoted wound healing by (i) increasing re-epithelialization, tissue collagen density and mRNA levels of collagens 1A1, 1A2, and 3A1, and (ii) inhibiting the radiation-induced vascular activation and limiting interactions between leukocytes and the vascular endothelium compared with control. Importantly, BMMNC did not amplify the inflammatory response despite the infiltration of neutrophils and macrophages associated with the expression of IL-6 and MCP-1 mRNAs in the tissue. Remarkably, the beneficial effects of BMMNC therapy on matrix remodeling were maintained for 2 months. Furthermore, BMMNC injection restored vascular function in skin tissue by increasing vascular density and vascular permeability. This therapeutic strategy based on BMMNC injection protects against radiation-induced skin lesions by preventing vascular dysfunction and unfavorable remodeling in the acute and late phases.
Background and purpose
The purpose of this randomized, placebo-controlled, double-blind study was to investigate the preventive effect of topical administration of atorvastatin (ATV) on the acute radiation-induced skin toxicity in patients with breast cancer.
Patients and methods
Seventy breast cancer patients were randomly assigned to use topical ATV 1% or placebo gels during radiotherapy twice daily. Radiation-induced dermatitis was classified according to the radiation therapy oncology group (RTOG) criteria, as well as pain and itching were scored according to VAS (visual analogue scale) for 6 weeks of treatment.
Results
Topical administration of ATV gel during radiotherapy reduced significantly radiation-induced breast swelling, itching, and pain in breast cancer patients by factors of 1.8, 1.7, and 1.5, respectively. ATV reduced the redness caused by radiotherapy in patients as compared with placebo; however, this difference was statistically not significant.
Conclusion
ATV was able to reduce significantly itching, breast edema, and pain in patients during radiotherapy.
The most ubiquitous gap junction protein within the body, connexin 43 (Cx43), is a target of interest for modulating the dermal wound healing response. Observational studies found associations between Cx43 at the wound edge and poor healing response, and subsequent studies utilizing local knockdown of Cx43 found improvements in wound closure rate and final scar appearance. Further preclinical work conducted using Cx43-based peptide therapeutics, including alpha connexin carboxyl terminus 1 (αCT1), a peptide mimetic of the Cx43 carboxyl terminus, reported similar improvements in wound healing and scar formation. Clinical trials and further study into the mode of action have since been conducted on αCT1, and Phase III testing for treatment of diabetic foot ulcers is currently underway. Therapeutics targeting connexin activity show promise in beneficially modulating the human body’s natural healing response for improved patient outcomes across a variety of injuries.
Objective:
Previous studies show conflicting results in wound healing outcomes based on angiosome direct perfusion (DP), but few have adjusted for wound characteristics in their analyses. We have previously shown that the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification correlates with wound healing in diabetic foot ulcers (DFUs) treated by a multidisciplinary team. The aim of this study was to compare WIfI classification vs DP and pedal arch patency as predictors of wound healing in patients presenting with DFU and peripheral arterial disease.
Methods:
We performed a retrospective review of a prospectively maintained database of all patients with peripheral arterial disease presenting to our multidisciplinary DFU clinic who underwent angiography. An angiosome was considered directly perfused if the artery feeding the angiosome was revascularized or was completely patent. Wound healing time at 1 year was compared on the basis of DP vs indirect perfusion, Rutherford pedal arch grade, and WIfI classification using univariable statistics and Cox proportional hazards models.
Results:
Angiography was performed on 225 wounds in 99 patients (mean age, 63.3 ± 1.2 years; 62.6% male; 53.5% black) during the entire study period. There were 33 WIfI stage 1, 33 stage 2, 51 stage 3, and 108 stage 4 wounds. DP was achieved in 154 wounds (68.4%) and indirect perfusion in 71 wounds (31.6%). On univariable analysis, WIfI classification was significantly associated with improved wound healing (57.2% for WIfI 3/4 vs 77.3% for WIfI 1/2; P = .02), whereas DP and pedal arch patency were not (both, P ≥ .08). After adjusting for baseline patient and wound characteristics, WIfI stage remained independently predictive of wound healing (WIfI 3/4: hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.67-0.88), whereas DP (HR, 0.82; 95% CI, 0.55-1.21) and pedal arch grade (HR, 0.85; 95% CI, 0.70-1.03) were not.
Conclusions:
In our population of patients treated by a multidisciplinary diabetic foot service, the Society for Vascular Surgery WIfI classification system was a stronger predictor of diabetic foot wound healing than DP or pedal arch patency. Our results suggest that a measure of wound severity should be included in all future studies assessing wound healing as an outcome, as differences in patients' wound characteristics may be a strong contributor to the variation of angiosome-directed perfusion results previously observed.
Objective:
Previous studies have reported correlation between the Wound, Ischemia, and foot Infection (WIfI) classification system and wound healing time on unadjusted analyses. However, in the only multivariable analysis to date, WIfI stage was not predictive of wound healing. Our aim was to examine the association between WIfI classification and wound healing after risk adjustment in patients with diabetic foot ulcers (DFUs) treated in a multidisciplinary setting.
Methods:
All patients presenting to our multidisciplinary DFU clinic from June 2012 to July 2017 were enrolled in a prospective database. A Cox proportional hazards model accounting for patients' sociodemographics, comorbidities, medication profiles, and wound characteristics was used to assess the association between WIfI classification and likelihood of wound healing at 1 year.
Results:
There were 310 DFU patients enrolled (mean age, 59.0 ± 0.7 years; 60.3% male; 60.0% black) with 709 wounds, including 32.4% WIfI stage 1, 19.9% stage 2, 25.2% stage 3, and 22.4% stage 4. Mean wound healing time increased with increasing WIfI stage (stage 1, 96.9 ± 8.3 days; stage 4, 195.1 ± 10.6 days; P < .001). Likelihood of wound healing at 1 year was 94.1% ± 2.0% for stage 1 wounds vs 67.4% ± 4.4% for stage 4 (P < .001). After risk adjustment, increasing WIfI stage was independently associated with poor wound healing (stage 4 vs stage 1: hazard ratio, [HR] 0.44; 95% confidence interval, 0.33-0.59). Peripheral artery disease (HR, 0.73), increasing wound area (HR, 0.99 per square centimeter), and longer time from wound onset to first assessment (HR, 0.97 per month) also decreased the likelihood of wound healing, whereas use of clopidogrel was protective (HR, 1.39; all, P ≤ .04). The top three predictors of poor wound healing were WIfI stage 4 (z score, -5.40), increasing wound area (z score, -3.14), and WIfI stage 3 (z score, -3.11), respectively.
Conclusions:
Among patients with DFU, the WIfI classification system predicts wound healing at 1 year in both crude and risk-adjusted analyses. This is the first study to validate the WIfI score as an independent predictor of wound healing using multivariable analysis.
Objective:
We have previously demonstrated that the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification correlates with wound healing time in patients with diabetic foot ulcers (DFUs) treated in a multidisciplinary setting. Our aim was to assess whether the charges and costs associated with DFU care increase with higher WIfI stages.
Methods:
All patients presenting to our multidisciplinary diabetic limb preservation service from June 2012 to June 2016 were enrolled in a prospective database. Inpatient and outpatient charges, costs, and total revenue from initial visit until complete wound healing were compared for wounds stratified by WIfI classification.
Results:
A total of 319 wound episodes in 248 patients were captured, including 31% WIfI stage 1, 16% stage 2, 30% stage 3, and 24% stage 4 wounds. Limb salvage at 1 year was 95% ± 2%, and wound healing was achieved in 85% ± 2%. The mean number of overall inpatient admissions (stage 1, 2.07 ± 0.48 vs stage 4, 3.40 ± 0.27; P < .001), procedure-related admissions (stage 1, 1.86 ± 0.45 vs stage 4, 2.28 ± 0.24; P < .001), and inpatient vascular interventions (stage 1, 0.14 ± 0.10 vs stage 4, 0.80 ± 0.12; P < .001) increased significantly with increasing WIfI stage. There were no significant differences in mean number of inpatient podiatric interventions or outpatient procedures between groups (P ≥ .10). The total cost of care per wound episode increased progressively from stage 1 ($3995 ± $1047) to stage 4 ($50,546 ± $4887) wounds (P < .001). Inpatient costs were significantly higher for advanced stage wounds (stage 1, $21,296 ± $4445 vs stage 4, $54,513 ± $5001; P < .001), whereas outpatient procedure costs were not significantly different between groups (P = .72). Overall, hospital total revenue increased with increasing WIfI stage (stage 1, $4182 ± $1185 vs stage 4, $55,790 ± $5540; P < .002).
Conclusions:
Increasing WIfI stage is associated with a prolonged wound healing time, a higher number of surgical procedures, and an increased cost of care. While limb salvage outcomes are excellent, the overall cost of DFU care from presentation to healing is substantial, especially for patients with advanced (WIfI stage 3/4) disease treated in a multidisciplinary setting.
Excised human skin is utilized for in vitro permeation experiments to evaluate the safety and effect of topically-applied drugs by measuring its skin permeation and concentration. However, ethical considerations are the major problem for using human skin to evaluate percutaneous absorption. Moreover, large variations have been found among human skin specimens as a result of differences in age, race, and anatomical donor site. Animal skins are used to predict the in vivo human penetration/permeation of topically-applied chemicals. In the present review, skin characteristics, such as thickness of skin, lipid content, hair follicle density, and enzyme activity in each model are compared to human skin. In addition, intra- and inter-individual variation in animal models, permeation parameter correlation between animal models and human skin, and utilization of cultured human skin models are also descried. Pig, guinea pig, and hairless rat are generally selected for this purpose. Each animal model has advantages and weaknesses for utilization in in vitro skin permeation experiments. Understanding of skin permeation characteristics such as permeability coefficient ( P ), diffusivity ( D ), and partition coefficient ( K ) for each skin model would be necessary to obtain better correlations for animal models to human skin permeation.
In recent years, there has been increasing concern over the possibility of a radiological or nuclear incident occurring somewhere in the world. Intelligence agencies frequently report that terrorist groups and rogue nations are seeking to obtain radiological or nuclear weapons of mass destruction. In addition, there exists the real possibility that safety of nuclear power reactors could be compromised by natural (such as the tsunami and subsequent Fukushima accident in Japan in March, 2011) or accidental (Three Mile Island, 1979 and Chernobyl, 1986) events. Although progress has been made by governments around the world to prepare for these events, including the stockpiling of radiation countermeasures, there are still challenges concerning care of patients injured during a radiation incident. Because the deleterious and pathological effects of radiation are so broad, it is desirable to identify medical countermeasures that can have a beneficial impact on several tissues and organ systems. Cellular therapies have the potential to impact recovery and tissue/organ regeneration for both early and late complications of radiation exposure. These therapies, which could include stem or blood progenitor cells, mesenchymal stromal cells (MSCs) or cells derived from other tissues (e.g., endothelium or placenta), have shown great promise in treating other nonradiation injuries to and diseases of the bone marrow, skin, gastrointestinal tract, brain, lung and heart. To explore the potential use of these therapies in the treatment of victims after acute radiation exposure, the National Institute of Allergy and Infectious Diseases co-sponsored an international workshop in July, 2015 in Paris, France with the Institut de Radioprotection et de Sûreté Nucléaire. The workshop included discussions of data available from testing in preclinical models of radiation injury to different organs, logistics associated with the practical use of cellular therapies for a mass casualty incident, as well as international regulatory requirements for authorizing such drug products to be legally and readily used in such incidents. This report reviews the data presented, as well as key discussion points from the meeting.
Background: Radiotherapy is a common cancer treatment, but often results in unintended injury to overlying skin and contributes to poor wound healing. The mechanisms underlying these changes are complex, and existing treatment is limited. We aimed to systematically review the literature on the pathogenesis, management, and experimental treatment of delayed wound healing following radiation therapy.
Study Design/Methods: A literature search was performed following PRISMA-P guidelines. PubMed and the Cochrane Library were queried for full-text English articles published up to 2016 by using key search terms including “radiotherapy” and “wound healing.” Additional resources were retrieved from reference lists. The selected articles discussed mechanisms of pathogenesis, current management, and experimental treatment of radiation-induced skin injury. These are reported as a qualitative synthesis of the literature from the authors' perspective.
Results: The literature search yielded 442 articles, of which 93 were included in this review. Ionizing radiation causes DNA damage by direct strand breaks and oxygen-derived free radicals. This insult results in cellular alterations that underlie mechanisms of delayed wound healing. Prominent theories underlying pathogenesis include cellular depletion, stromal cell dysfunction, aberrant collagen deposition, and microvascular damage. Pro-inflammatory cytokines and free radical cascades contribute to chronic radiation damage, with transforming growth factor beta-1 (TGF-β1) implicated as a key player in the process of fibrosis. At present, radiation injury is managed medically with conventional wound care with minimal success and limited evidence-based data. Surgical management with local or free flap transfer is often compromised by poor surrounding tissue and recipient vasculature. Experimental treatment models are emerging that target mechanisms of pathogenesis. These modalities include stem cell repletion, antioxidant therapy, TGF-β1 modulation, and implantable biomaterials.
Conclusion: Pathogenesis of delayed wound healing and fibrosis following radiotherapy is a complex, interdependent process involving cellular depletion, extracellular matrix changes, microvascular damage, and altered pro-inflammatory mediators. Current treatment is limited, and more Level I studies are needed to develop best-practice recommendations. Investigatory treatment options targeting specific mechanisms of injury may offer potential solutions to this significant clinical and surgical problem.
Objective:
The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) threatened limb classification has been shown to correlate well with risk of major amputation and time to wound healing in heterogeneous diabetic and nondiabetic populations. Major amputation continues to plague the most severe stage 4 WIfI patients, with 1-year amputation rates of 20% to 64%. Our aim was to determine the association between WIfI stage and wound healing and major amputation among patients with diabetic foot ulcers (DFUs) treated in a multidisciplinary setting.
Methods:
All patients presenting to our multidisciplinary DFU clinic from July 2012 to December 2015 were enrolled in a prospective database. Wound healing and major amputation were compared for patients stratified by WIfI classification.
Results:
There were 217 DFU patients with 439 wounds (mean age, 58.3 ± 0.8 years; 58% male, 63% black) enrolled, including 28% WIfI stage 1, 11% stage 2, 33% stage 3, and 28% stage 4. Peripheral arterial disease and dialysis were more common in patients with advanced (stage 3 or 4) wounds (P ≤ .05). Demographics of the patients, socioeconomic status, and comorbidities were otherwise similar between groups. There was a significant increase in the number of active wounds per limb at presentation with increasing WIfI stage (stage 1, 1.1 ± 0.1; stage 4, 1.4 ± 0.1; P = .03). Mean wound area (stage 1, 2.6 ± 0.6 cm(2); stage 4, 15.3 ± 2.8 cm(2)) and depth (stage 1, 0.2 ± 0.0 cm; stage 4, 0.8 ± 0.1 cm) also increased progressively with increasing wound stage (P < .001). Minor amputations (stage 1, 18%; stage 4, 56%) and revascularizations (stage 1, 6%; stage 4, 55%) were more common with increasing WIfI stage (P < .001). On Kaplan-Meier analysis, WIfI classification was predictive of wound healing (P < .001) but not of major amputation (P = .99). For stage 4 wounds, the mean wound healing time was 190 ± 17 days, and risk of major amputation at 1 year was 5.7% ± 3.2%.
Conclusions:
Among patients with DFU, the WIfI classification system correlated well with wound healing but was not associated with risk of major amputation at 1 year. Although further prospective research is warranted, our results suggest that use of a multidisciplinary approach for DFUs may augment healing time and reduce amputation risk compared with previously published historical controls of standard wound care among patients with advanced stage 4 disease.
Background:
The transmembrane protein, connexin43 (Cx43) has key roles in fibrogenic processes including inflammatory signaling and extracellular matrix composition. aCT1 is a Cx43 mimetic peptide that in preclinical studies accelerated wound closure, decreased inflammation and granulation tissue area and normalized mechanical properties following cutaneous injury.
Purpose:
We evaluated the efficacy and safety of aCT1 in the reduction of scar formation in human incisional wounds.
Methods:
In a prospective, multicenter, within-participant controlled trial patients with bilateral incisional wounds (≥10mm) following laparoscopic surgery were randomized to receive acute treatment (immediately following wounding and 24h later) with an aCT1 gel formulation plus conventional standard of care protocols, involving moisture-retentive occlusive dressing, or standard of care alone. The primary efficacy endpoint was average scarring score using visual analog scales evaluating incision appearance and healing progress over 9 months.
Results:
There was no significant difference in scar appearance between aCT1- or control-treated incisions after 1 month. At month 9, aCT1-treated incisions showed a 47% improvement in scar scores over controls (Vancouver Scar Scale; P=0.0045), a significantly higher Global Assessment Scale score (P=0.0009), and improvements in scar pigmentation, thickness, surface roughness and mechanical suppleness. Adverse events were similar in both groups.
Conclusion:
aCT1 has potential to improve scarring outcome following surgery.
Experimental model of acute local radiation injuries (LRI) was the degree of radiation skin burns of mouse paws, observed through the 10 day within 1 month after local γ-60Co-irradiation at the doses of 20-45 Gy. For late local radiation injuries with a maximum of over 6 months after exposure to radiation, model was the contracture of animal paws and post-radiation amputation of limbs of the mouse. In the experiments on mice radioprotector indralin (B-190) IP as direct α1-adrenomimetic has a expressed protective effect on reducing acute and late LRI, equal in terms of dose reduction factor (DRF) 1.4 -1.5 that was comparable to their efficacy during radiation injuries of hematopoietic tissues. Indralin fully retain its radioprotective properties (DRF = 1.5-1.7) in the condition of repeated radioprotector administration through one day at total dose of 57 Gy (three times 19 Gy) of fractionated y -irradiation. The protective effect of indralin improved at parenteral administration in the place of local irradiation. The local topical application of indralin in the ointments or in solution of dimethylsulfoxide has radioprotective effect, equal in the term of DRF to 1.3 -1.5 at acute and late LRI. Indralin also possessed a expressed radioprotective properties (DRF = 1.5) in decrease radiation injuries of salivary glands during local irradiation of head of rats.
BRAF inhibitors are highly effective therapies for the treatment of BRAFV600-mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing mice models accelerates cutaneous wound healing through paradoxical MAPK activation; addition of a mitogen-activated protein kinase kinase (MEK) inhibitor reverses the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor does not increase the incidence of cutaneous squamous cell carcinomas in mice. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds.
There is increasing evidence that radiation-induced damage to endothelial cells and loss of endothelial function may contribute to both acute radiation syndromes and long-term effects of whole-body nuclear irradiation. Therefore, several drugs are being developed to mitigate the effects of nuclear radiation, most of these drugs will target and protect or regenerate leukocytes and platelets. Our laboratory has demonstrated that TP508, a 23-amino acid thrombin peptide, activates endothelial cells and stem cells to revascularize and regenerate tissues. We now show that TP508 can mitigate radiation-induced damage to endothelial cells in vitro and in vivo. Our in vitro results demonstrate that human endothelial cells irradiation attenuates nitric oxide (NO) signaling, disrupts tube formation and induces DNA double-strand breaks (DSB). TP508 treatment reverses radiation effects on NO signaling, restores tube formation and accelerates the repair of radiation-induced DSB. The radiation-mitigating effects of TP508 on endothelial cells were also seen in CD-1 mice where systemic injection of TP508 stimulated endothelial cell sprouting from aortic explants after 8 Gy irradiation. Systemic doses of TP508 that mitigated radiation-induced endothelial cell damage, also significantly increased survival of CD-1 mice when injected 24 h after 8.5 Gy exposure. These data suggest that increased survival observed with TP508 treatment may be due to its effects on vascular and microvascular endothelial cells. Our study supports the usage of a regenerative drug such as TP508 to activate endothelial cells as a countermeasure for mitigating the effects of nuclear radiation.
Skin fibrosis, also known as skin scarring, is an important global health problem that affects an estimated 100 million persons per year worldwide. Current therapies are associated with significant side effects and even with combination therapy, progression, and recurrence is common. Our goal is to review the available published data available on light-emitting diode-generated (LED) red light phototherapy for treatment of skin fibrosis. A search of the published literature from 1 January 2000 to present on the effects of visible red light on skin fibrosis, and related pathways was performed in January 2016. A search of PubMed and EMBASE was completed using specific keywords and MeSH terms. "Fibrosis" OR "skin fibrosis" OR "collagen" was combined with ("light emitting diode," "LED," "laser," or "red light"). The articles that were original research studies investigating the use of visible red light to treat skin fibrosis or related pathways were selected for inclusion. Our systematic search returned a total of 1376 articles. Duplicate articles were removed resulting in 1189 unique articles, and 133 non-English articles were excluded. From these articles, we identified six articles related to LED effects on skin fibrosis and dermal fibroblasts. We augmented our discussion with additional in vitro data on related pathways. LED phototherapy is an emerging therapeutic modality for treatment of skin fibrosis. There is a growing body of evidence demonstrating that visible LED light, especially in the red spectrum, is capable of modulating key cellular characteristic associated with skin fibrosis. We anticipate that as the understanding of LED-RL's biochemical mechanisms and clinical effects continue to advance, additional therapeutic targets in related pathways may emerge. We believe that the use of LED-RL, in combination with existing and new therapies, has the potential to alter the current treatment paradigm of skin fibrosis. There is a current lack of clinical trials investigating the efficacy of LED-RL to treat skin fibrosis. Randomized clinical trials are needed to demonstrate visible red light's clinical efficacy on different types of skin fibrosis.
Radiation dermatitis is one of the most common acute toxicities of both radiotherapy and chemoradiotherapy. Many clinical trials have evaluated the level of toxicity using the Common Terminology Criteria for Adverse Events ver. 4.03. This criterion accounts for severity in a single sentence only, and no visual classification guide has been available. Thus, there is a risk of subjective interpretation by the individual investigator. This contrasts with the situation with hematologic toxicities, which can be interpreted objectively. The aim of this prospective picture collection study was to develop a grading tool for use in establishing the severity of radiation dermatitis in clinical trials. A total of 118 patients who were scheduled to receive definitive or postoperative radiotherapy or chemoradiotherapy were enrolled from the four participating cancer centers. All researchers in our group used the same model of camera under the same shooting conditions to maintain consistent photographic quality. In all, 1600 photographs were collected. Of these, 100 photographs qualified for the first round of selection and were then graded by six experts, basically in accordance with the CTCAE ver. 4.03 (JCOG ver. in Japanese). After further study, 38 photographs were selected as representing typical models for Grade 1-4 radiation dermatitis; the radiation dermatitis grading atlas was produced from these photographs. The atlas will play a major role in ensuring that the dermatitis rating system is consistent between the institutions participating in trials. We hope that this will contribute to improving the quality of clinical trials, and also to improving the level of routine clinical practice.
Autologous cell-spray grafting of non-cultured epidermal cells is an innovative approach for the treatment of severe second-degree burns. After treatment, wounds are covered with dressings that are widely used in wound care management; however, little is known about the effects of wound dressings on individually isolated cells. The sprayed cells have to actively attach, spread, proliferate, and migrate in the wound for successful re-epithelialization, during the healing process. It is expected that exposure to wound dressing material might interfere with cell survival, attachment, and expansion. Two experiments were performed to determine whether some dressing materials have a negative impact during the early phases of wound healing. In one experiment, freshly isolated cells were seeded and cultured for one week in combination with eight different wound dressings used during burn care. Cells, which were seeded and cultured with samples of Adaptic®, Xeroform®, EZ Derm®, and Mepilex® did not attach, nor did they survive during the first week. Mepitel®, N-Terface®, Polyskin®, and Biobrane® dressing samples had no negative effect on cell attachment and cell growth when compared to the controls. In a second experiment, the same dressings were exposed to pre-cultured cells in order to exclude the effects of attachment and spreading. The results confirm the above findings. This study could be of interest for establishing skin cell grafting therapies in burn medicine and also for wound care in general.
Fluoroscopy use has increased recently because of the growing use of minimally invasive surgical procedures. Fluoroscopy, and other procedures using radiation exposure, can induce acute and chronic skin damage. Diagnosis of fluoroscopy-induced chronic radiation dermatitis (FICRD) is challenging as patients are sometimes unaware of exposure to radiation and presentation often occurs after months or years.1, 2 Early recognition is important to optimize both therapy and surveillance for radiation-induced malignancies.1 We present a case of a 72-year-old man with a greater than 1-year history of a nonhealing ulcer on the back. He had a history of endovascular abdominal aortic aneurysm repair with subsequent endoleak repairs, which required intraoperative use of fluoroscopy.
According to the International Atomic Energy Agency (IAEA), a relatively significant number of radiological accidents have occurred in recent years mainly because of the practices referred to as potentially high-risk activities, such as radiotherapy, large irradiators and industrial radiography, especially in gammagraphy assays. In some instances, severe injuries have occurred in exposed persons due to high radiation doses. In industrial radiography, 80 cases involving a total of 120 radiation workers, 110 members of the public including 12 deaths have been recorded up to 2014. Radiological accidents in industrial practices in Brazil have mainly resulted in development of cutaneous radiation syndrome (CRS) in hands and fingers. Brazilian data include 5 serious cases related to industrial gammagraphy, affecting 7 radiation workers and 19 members of the public; however, none of them were fatal. Some methods of reconstructive dosimetry have been used to estimate the radiation dose to assist in prescribing medical treatment. The type and development of cutaneous manifestations in the exposed areas of a person is the first achievable gross dose estimation. This review article presents the state-of-the-art reconstructive dosimetry methods enabling estimation of local radiation doses and provides guidelines for medical handling of the exposed individuals. The review also presents the Chilean and Brazilian radiological accident cases to highlight the importance of reconstructive dosimetry.
Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition.
A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords "Radiation-Induced Fibrosis," "Radiotherapy Complications," "Fibrosis Therapy," and other closely related terms.
RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways.
Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies.
Nonhealing neuropathic foot ulcers remain a significant problem in individuals with diabetes. The gap-junctional protein connexin43 (Cx43) has roles in dermal wound healing and targeting Cx43 signaling accelerates wound reepithelialization. In a prospective, randomized, multi-center clinical trial we evaluated the efficacy and safety of a peptide mimetic of the C-terminus of Cx43, ACT1, in accelerating the healing of chronic diabetic foot ulcers (DFUs) when incorporated into standard of care protocols. Adults with DFUs of at least four weeks duration were randomized to receive standard of care with or without topical application of ACT1. Primary outcome was mean percent ulcer reepithelialization and safety variables included incidence of treatment related adverse events and detection of ACT1 immunogenicity. ACT1 treatment was associated with a significantly greater reduction in mean percent ulcer area from baseline to 12 weeks (72.1% vs. 57.1%; p = 0.03). Analysis of incidence and median time-to-complete-ulcer closure revealed that ACT1 treatment was associated with a greater percentage of participants that reached 100% ulcer reepitheliazation and a reduced median time-to-complete-ulcer closure. No adverse events reported were treatment related, and ACT1 was not immunogenic. Treatment protocols that incorporate ACT1 may present a therapeutic strategy that safely augments the reepithelialization of chronic DFUs. This article is protected by copyright. All rights reserved.
© 2015 by the Wound Healing Society.
While cutaneous radiation injury (CRI) is generally referenced as a consequence of a nuclear attack, it can also be caused by less dangerous events such as the use of dirty bombs, industrial radiological accidents, or accidental overexposure of beta (β) particle or gamma (γ) radiation sources in medical procedures. Although the gross clinical consequences of these injuries have been well documented, relatively little is known about the molecular changes underlying the progression of pathology. Here we describe a porcine model of cutaneous radiation injury after skin was exposed to strontium-90 β particle at doses of 16-42 Gy and characterize the anatomical and molecular changes over 70 days. The results show that irradiated sites displayed dose-dependent increases in erythema and moist desquamation that peaked between days 35 and 42. Dose-dependent histopathological changes were observed, with higher doses exhibiting increased inflammation and epidermal hyperplasia beyond day 35. Furthermore, immunohistochemistry showed that exposure to 37 Gy β-particle radiation decreased epidermal cell proliferation and desmosomal junction proteins at day 70, suggesting compromised epidermal integrity. Metabolomic analysis of biopsies revealed dose- and time-dependent changes as high as 252-fold in several metabolites not previously linked to CRI. These alterations were seen in pathways reflecting protein degradation, oxidative stress, eicosanoid production, collagen matrix remodeling, mitochondrial stress, cell membrane composition and vascular disruption. Taken together, these data show that exposure to high doses of β particle damaged the molecular processes underlying skin integrity to a greater extent and for a longer period of time than has been shown previously. These findings further understanding of radiation-induced skin injury and serve as a foundation for the development and testing of potential therapeutics to treat CRI.
Objective
Beta radiation from nuclear weapons fallout could pose a risk of cutaneous radiation injury (CRI) to evacuating populations but has been investigated only cursorily. This work examines 2 components of CRI necessary for estimating the potential public health consequences of exposure to fallout: dose protraction and depth of dose.
Methods
Dose protraction for dry and moist desquamation was examined by adapting the biological effective dose (BED) calculation to a hazard function calculation similar to those recommended by the National Council on Radiation Protection and Measurements for other acute radiation injuries. Depth of burn was examined using Monte Carlo neutral Particle version 5 to model the penetration of beta radiation from fallout to different skin tissues.
Results
Nonlinear least squares analysis of the BED calculation estimated the hazard function parameter θ ¹ (dose rate effectiveness factors) as 25.5 and 74.5 (Gy-eq) ² h ⁻¹ for dry and moist desquamation, respectively. Depth of dose models revealed that beta radiation is primarily absorbed in the dead skin layers and basal layer and that dose to underlying tissues is small (<5% of dose to basal layer).
Conclusions
The low relative dose to tissues below the basal layer suggests that radiation-induced necrosis or deep skin burns are unlikely from direct skin contamination with fallout. These results enable future modeling studies to better examine CRI risk and facilitate effectively managing and treating populations with specialized injuries from a nuclear detonation.
Internalization of radionuclides occurs not only by inhalation, ingestion, parenteral injection (i.e., administration of radioactive material for a medical purpose), and direct transdermal absorption, but also by contaminated wounds. In June 2010, a glove-box operator at the U.S. Department of Energy's Savannah River Site sustained a puncture wound while venting canisters containing legacy materials contaminated with Pu. To indicate the canisters had been vented, a flag was inserted into the vent hole. The shaft of the flag penetrated the protective gloves worn by the operator. Initial monitoring performed with a zinc-sulfide alpha detector indicated 300 dpm at the wound site. After being cleared by radiological controls personnel, the patient was taken to the site medical facility where decontamination was attempted and diethylenetriaminepentaacetic acid (DTPA) was administered intravenously within 1.5 h of the incident. The patient was then taken to the Savannah River Site In Vivo Counting Facility where the wound was counted with a Canberra GL 2820 high-purity germanium detector, capable of quantifying contamination by detecting low-energy x rays and gamma rays. In addition to the classic 13, 17, and 20 keV photons associated with Pu, the low-yield (0.04%) 43.5 keV peak was also detected. This indicated a level of wound contamination orders of magnitude above the initial estimate of 300 dpm detected with handheld instrumentation. Trace quantities of Am were also identified via the 59.5 keV peak. A 24 h urine sample collection was begun on day 1 and continued at varying intervals for over a year. The patient underwent a punch biopsy at 3 h postincident (14,000 dpm removed) and excisional biopsies on days 1 and 9 (removal of an additional 3,200 dpm and 3,800 dpm, respectively). The initial post-DTPA urine sample analysis report indicated excretion in excess of 24,000 dpm Pu. Wound mapping was performed in an effort to determine migration from the wound site and indicated minimum local migration. In vivo counts were performed on the liver, axillary lymph nodes, supratrochlear lymph nodes, and skeleton to assess uptake and did not indicate measurable activity. Seventy-one total doses of DTPA were administered at varying frequencies for 317 d post intake. After allowing 100 d for removal of DTPA from the body, five 24 h urine samples were collected and analyzed for dose assessment by using the wound model described in National Council on Radiation Protection and Measurements Report No. 156. The total effective dose averted via physical removal of the contaminant and DTPA administration exceeded 1 Sv, demonstrating that rapid recognition of incident magnitude and prompt medical intervention are critical for dose aversion.
Purpose
A two-arm, double-blinded randomized trial was conducted to evaluate the efficacy of 0.1% mometasone furoate (MF) vs Eucerin Original® (E) cream in preventing the development of moderate to severe acute radiation dermatitis (ARD) in breast cancer patients receiving postmastectomy radiation (PMRT).
Methods
Breast cancer patients undergoing chest wall +/- nodal radiotherapy (50 Gy) were eligible. Randomization (1:1) was to MF or E, applied twice daily from Day 1 of PMRT to 14 days post-PMRT. Patients were stratified by RT technique, body mass index and reconstruction status. Daily bolus of 3-10 mm was applied in all patients. The primary endpoint was the development of provider-assessed grade ≥2 (CTCAE v.4.03) ARD with moist desquamation or any grade >3 dermatitis. Secondary endpoints were time to occurrence of maximum grade dermatitis and patient-reported skin symptoms using a skin-related quality of life questionnaire, Skindex-16 (SD-16). Assessments were performed at baseline, weekly during PMRT and 2 weeks post-PMRT.
Results
124 patients were enrolled between 5/2013-2/2016. 35% were pathologic stage III, 6% were cT4d and 68% had reconstructions. 60% received 3D-CRT with photons only to the chest wall, 18% electrons and photons, and 23% inverse-planned IMRT. Groups were well balanced for age, skin type and stage. The rate of moist desquamation was 54.8% in the entire cohort, with a significantly reduced incidence in the MF vs E arm (43.8% vs 66.7%, p=0.012). MF arm had a lower incidence of maximum skin toxicities (p=0.036), and longer time to development of grade 3 dermatitis (46 days vs 35.5, respectively; P=<0.001). There was no difference in patient-reported skin outcomes between arms.
Conclusion
Breast cancer patients receiving MF during PMRT experience significantly reduced rates of moist desquamation, compared to a control cream.
Radiation therapy (RT) is a frequently used modality for cancer treatment. Acute and/or chronic skin changes may occur and carry risk of influencing quality of life during and after completion of RT. Radiation reactions may lead to delays in treatment, diminished cosmesis, and functional deficits. Lifestyle factors, treatment modalities, topical agents, and, in some cases, wound dressings may be utilized to help prevent or ameliorate radiation-induced skin reactions. While rigorous evidence supporting specific interventions may be lacking or contradictory, this article summarizes the current knowledge of the etiology, manifestations, and interventions available for prevention and management of radiation dermatitis. Further well-designed studies are needed to confirm the efficacy of current recommendations and facilitate development of novel strategies for optimal care of patients with radiation dermatitis.
Cell-spray autografting is an innovative early treatment option for deep partial-thickness burn wounds. As an alternative to non-operative management, cell-spray autografting can achieve rapid wound re-epithelialization, particularly in large wounds. When compared to traditional mesh autografting for deep partial-thickness burn wounds, cell-spray autografting can accomplish re-epithelialization with a much smaller donor site. In this review, we describe the development of a biomedical engineering method for isolation and immediate distribution of autologous, non-cultured, adult epidermis-, and adult dermis-derived stem cells. We present data on cell isolation procedures in 44 patients with deep partial-thickness burns performed over five years under an innovative practice IRB. Treated patients presented with a variety of burn wound etiologies and a wide range of TBSA. Overall clinical results were very satisfying. The average hospital length of stay following treatment was seven days. Over the time period, the donor-site to burn-wound surface area ratio was enhanced from 1:80 to 1:100. A detailed analysis of all process-related biotechnology and operative problems, pitfalls, and solutions was performed and is reported herein. Strategies for future clinical studies are discussed.
Radiation dermatitis is a serious cutaneous injury caused by radiation therapy or upon accidental nuclear exposure. However, the pathogenic immune mechanisms underlying this injury are still poorly understood. We seek to discover how the dysregulated immune response after irradiation orchestrates skin inflammation. The skin on the left flank of C57BL/6J wild-type and C57BL/6J Tcrd-/- mice, which are deficit in γδ T cells, was exposed to a single X-ray dose of 25 Gy, and the right-flank skin was used as a sham-irradiated control. At 4 weeks postirradiation, the wild-type skin exhibited signs of depilation, erythema and desquamation. Histological analysis showed hyperproliferation of keratinocytes and acanthosis. Dramatic elevation of IL17-expressing T cells was identified from the irradiated skin, which was mainly contributed by γδ T cells and innate lymphoid cells, rather than Th17 cells. Furthermore, protein levels of critical cytokines for IL17-expressing γδ T cell activation, IL1β and IL23 were found markedly upregulated. Lastly, radiation-induced dermatitis was significantly attenuated in γδ T cell knockout mice. In vitro, normal human epidermal keratinocytes (NHEKs) could be initiator cells of inflammation by providing a great number of pro-inflammatory mediators upon radiation, and as well as effector cells of epidermal hyperplasia in response to exogenous IL17 and/or IL22 treatment. Our findings implicate a novel role of IL17-expressing γδ T cells in mediating radiation-induced skin inflammation. This study reveals the innate immune response pathway as a potential therapeutic target for radiation skin injury.
Radiation damage to the matrix cells of actively growing pig hairs resulted in a transient reduction in diameter. This was clearly dose dependent for doses in the range 0.5-5 Gy for 250 kV X rays and 3-8 Gy surface dose for ⁹⁰Sr ß rays. While the relationship between the perentage reduction in hair diameter and the X ray dose was linear between 0.5 and 5 Gy, the skin surface dose for ß rays and the percentage reduction in hair diameter was found to be best fitted by a quadratic equation. Differences in the effect produced by X and ß ray irradiation can be attributed to the absorption of ß rays with depth in the dermis and a correction for this has been applied. This system would appear to have considerable potential for use as a biological dosemeter.
Radiation therapy has been a commonly employed modality for a variety of ailments, including cancer. Patients undergoing radiation often experience acute and/or chronic skin changes that can be detrimental to their quality of life. Many topical agents and specialized wound dressings are being used for the prevention and management of radiation-induced skin changes. However, no single therapeutic option has been found to be consistently effective.
Local cutaneous injuries induced by ionizing radiation (IR) are difficult to treat. Many have reported local injection of adipose-derived stromal vascular fraction (SVF), often with additional therapies, as an effective treatment of IR-induced injury even after other local therapies have failed. The authors report a case of a locally recurrent, IR-induced wound that was treated with autologous, non-cultured SVF without other concurrent therapy. A nondestructive testing technician was exposed to 130 kVp x rays to his non-dominant right thumb on 5 October 2011. The wound healed 4 mo after initial conservative therapy with oral/topical α-tocopherol, oral pentoxifylline, naproxen sodium, low-dose oral steroids, topical steroids, hyperbaric oxygen therapy (HBOT), oral antihistamines, and topical aloe vera. Remission lasted approximately 17 mo with one minor relapse in July 2012 after minimal trauma and subsequent healing. Aggressive wound breakdown during June 2013 required additional therapy with HBOT. An erythematous, annular papule developed over the following 12 mo (during which time the patient was not undergoing prescribed treatment). Electron paramagnetic resonance (EPR) done more than 2 mo after exposure to IR revealed dose estimates of 14 ± 3 Gy and 19 ± 6 Gy from two centers using different EPR techniques. The patient underwent debridement of the 0.5 cm papular area, followed by SVF injection into and around the wound bed and throughout the thumb without complication. Eleven months post SVF injection, the patient has been essentially asymptomatic with an intact integument. These results raise the possibility of prolonged benefit from SVF therapy without the use of cytokines. Since there is currently no consensus on the use of isolated SVF therapy in chronic, local IR-induced injury, assessment of this approach in an appropriately powered, controlled trial in experimental animals with local radiation injury appears to be indicated.
This article reviews our current knowledge about cell-derived extracellular vesicles (EVs), including microparticles and exosomes, and their emergence as mediators of a new important mechanism of cell-to-cell communication. Particular emphasis has been given to the increasing involvement of EVs in the field of radiation-induced vascular injury. Although EVs have been considered for a long time as cell "dust", they in fact precisely reflect the physiological state of the cells. The role of microparticles and exosomes in mediating vascular dysfunction suggests that they may represent novel pathways in short- or long-distance paracrine intercellular signaling in vascular environment. In this article, the mechanisms involved in the biogenesis of microparticles and exosomes, their composition and participation in the pathogenesis of vascular dysfunction are discussed. Furthermore, this article highlights the concept of EVs as potent vectors of biological information and protagonists of an intercellular communication network. Special emphasis is made on EV-mediated microRNA transfer and on the principal consequences of such signal exchange on vascular injury and radiation-induced nontargeted effect. The recent progress in elucidating the biology of EVs has provided new insights for the field of radiation, advancing their use as diagnostic biomarkers or in therapeutic interventions.
Background:
Polonium-210 ((210)Po) gained widespread notoriety after the poisoning and subsequent death of Mr Alexander Litvinenko in London, UK, in 2006. Exposure to (210)Po resulted initially in a clinical course that was indistinguishable from infection or exposure to chemical toxins, such as thallium.
Methods:
A 43-year-old man presented to his local hospital with acute abdominal pain, diarrhoea, and vomiting, and was admitted to the hospital because of dehydration and persistent gastrointestinal symptoms. He was initially diagnosed with gastroenteritis and treated with antibiotics. Clostridium difficile toxin was subsequently detected in his stools, which is when he first raised the possibility of being poisoned and revealed his background and former identity, having been admitted under a new identity with which he had been provided on being granted asylum in the UK. Within 6 days, the patient had developed thrombocytopenia and neutropenia, which was initially thought to be drug induced. By 2 weeks, in addition to bone marrow failure, he had evidence of alopecia and mucositis. Thallium poisoning was suspected and investigated but ultimately dismissed because blood levels of thallium, although raised, were lower than toxic concentrations. The patient continued to deteriorate and within 3 weeks had developed multiple organ failure requiring ventilation, haemofiltration, and cardiac support, associated with a drop in consciousness. On the 23rd day after he first became ill, he suffered a pulseless electrical activity cardiorespiratory arrest from which he could not be resuscitated and was pronounced dead.
Findings:
Urine analysis using gamma-ray spectroscopy on day 22 showed a characteristic 803 keV photon emission, raising the possibility of (210)Po poisoning. Results of confirmatory analysis that became available after the patient's death established the presence of (210)Po at concentrations about 10(9)-times higher than normal background levels. Post-mortem tissue analyses showed autolysis and retention of (210)Po at lethal doses in several organs. On the basis of the measured amounts and tissue distribution of (210)Po, it was estimated that the patient had ingested several 1000 million becquerels (a few GBq), probably as a soluble salt (eg, chloride), which delivered very high and fatal radiation doses over a period of a few days.
Interpretation:
Early symptoms of (210)Po poisoning are indistinguishable from those of a wide range of chemical toxins. Hence, the diagnosis can be delayed and even missed without a high degree of suspicion. Although body surface scanning with a standard Geiger counter was unable to detect the radiation emitted by (210)Po, an atypical clinical course prompted active consideration of poisoning with radioactive material, with the diagnosis ultimately being made with gamma-ray spectroscopy of a urine sample.
Funding:
UK NHS, Public Health England, and the UK Department of Health.
Purpose:
A guinea pig skin model was developed to determine the dose-dependent response to soft X-ray radiation into the dermis.
Materials and methods:
X-ray exposure (50 kVp) was defined to a 4.0 × 4.0 cm area on the lateral surface of a guinea pig using lead shielding. Guinea pigs were exposed to a single fraction of X-ray irradiation ranging from 25-79 Gy via an XRAD320ix Biological Irradiator with the collimator removed. Gross skin changes were measured using clinical assessments defined by the Kumar scale. Skin contracture was assessed, as well as histological evaluations.
Results:
Loss of dermal integrity was shown after a single dose of soft X-ray radiation at or above 32 Gy with the central 2.0 × 2.0 cm of the exposed site being the most affected. Hallmarks of the skin injury included moist desquamation, ulceration and wound contracture, as well as alterations in epithelium, dermis, muscle and adipose. Changes in the skin were time- and radiation dose-dependent. Full-thickness injury occurred without animal mortality or gross changes in the underlying organs.
Conclusions:
The guinea pig is an appropriate small animal model for the short-term screening of countermeasures for cutaneous radiation injury (CRI).
Significance: Noninvasive imaging approaches can provide greater information about a wound than visual inspection during the wound healing and treatment process. This review article focuses on various optical imaging techniques developed to image different wound types (more specifically ulcers). Recent Advances: The noninvasive optical imaging approaches in this review include hyperspectral imaging, multispectral imaging, near-infrared spectroscopy (NIRS), diffuse reflectance spectroscopy, optical coherence tomography, laser Doppler imaging, laser speckle imaging, spatial frequency domain imaging, and fluorescence imaging. The various wounds imaged using these techniques include open wounds, chronic wounds, diabetic foot ulcers, decubitus ulcers, venous leg ulcers, and burns. Preliminary work in the development and implementation of a near-infrared optical scanner for wound imaging as a noncontact hand-held device is briefly described. The technology is based on NIRS and has demonstrated its potential to differentiate a healing from nonhealing wound region. Critical Issues: While most of the optical imaging techniques can penetrate few hundred microns to a 1-2 mm from the wound surface, NIRS has the potential to penetrate deeper, demonstrating the potential to image internal wounds. Future Directions: All the technologies are currently at various stages of translational efforts to the clinic, with NIRS holding a greater promise for physiological assessment of the wounds internal, beyond the gold-standard visual assessment.
The skin epidermis and its appendages provide a protective barrier that is impermeable to harmful microbes and also prevents dehydration. To perform their functions while being confronted with the physicochemical traumas of the environment, these tissues undergo continual rejuvenation through homeostasis, and, in addition, they must be primed to undergo wound repair in response to injury. The skin's elixir for maintaining tissue homeostasis, regenerating hair, and repairing the epidermis after injury is its stem cells, which reside in the adult hair follicle, sebaceous gland, and epidermis. Stem cells have the remarkable capacity to both self-perpetuate and also give rise to the differentiating cells that constitute one or more tissues. In recent years, scientists have begun to uncover the properties of skin stem cells and unravel the mysteries underlying their remarkable capacity to perform these feats. In this paper, I outline the basic lineages of the skin epithelia and review some of the major findings about mammalian skin epithelial stem cells that have emerged in the past five years.
The minipig has long been identified as the nonrodent animal of choice for preclinical safety evaluation of topically applied materials. This article reviews types of topical applications, study designs, and practical considerations. Dermal administration to the minipig presents multiple challenges. Issues to be considered are the area of exposure, the nature of the test article, the need for covering of the dose site, preparation of the dose site, and procedures for administration. The potential for cross-contamination (exposure of control animals to test article) is very high in topical studies and appropriate safeguards to prevent this are discussed. Topical administration to the intact skin is the most commonly utilized form of safety evaluation, but procedures have also been developed for intradermal administration and for the use of nonintact/wounded skin; these will be discussed. Evaluation of local (topical) effects is critical and can become complicated. Considerations in evaluations of the skin are interobserver variability, use of different scoring systems and discrepancies between in vivo observations, necropsy observations, and microscopic pathology findings. Causes for apparent discrepancies and suggestions for practical resolution through appropriate procedures are discussed. Practical issues in necropsy and histotechnology procedures and techniques to optimize preservation of skin are also discussed.
In recent years, increasing threats of radiation exposure and nuclear disasters have become a significant concern for the United States and countries worldwide. Exposure to high doses of radiation triggers a number of potentially lethal effects. Among the most severe is the gastrointestinal (GI) toxicity syndrome caused by the destruction of the intestinal barrier, resulting in bacterial translocation, systemic bacteremia, sepsis, and death. The lack of effective radioprotective agents capable of mitigating radiation-induced damage has prompted a search for novel countermeasures that can mitigate the effects of radiation post exposure, accelerate tissue repair in radiation-exposed individuals, and prevent mortality. We report that a single injection of regenerative peptide TP508 (rusalatide acetate, Chrysalin) 24 h after lethal radiation exposure (9 Gy, LD100/15) appears to significantly increase survival and delay mortality by mitigating radiation-induced intestinal and colonic toxicity. TP508 treatment post exposure prevents the disintegration of GI crypts, stimulates the expression of adherens junction protein E-cadherin, activates crypt cell proliferation, and decreases apoptosis. TP508 post-exposure treatment also upregulates the expression of DCLK1 and LGR5 markers of stem cells that have been shown to be responsible for maintaining and regenerating intestinal crypts. Thus, TP508 appears to mitigate the effects of GI toxicity by activating radioresistant stem cells and increasing the stemness potential of crypts to maintain and restore intestinal integrity. These results suggest that TP508 may be an effective emergency nuclear countermeasure that could be delivered within 24 h post exposure to increase survival and delay mortality, giving victims time to reach clinical sites for advanced medical treatment.Laboratory Investigation advance online publication, 17 August 2015; doi:10.1038/labinvest.2015.103.
An alternative approach for traditional clinical mesh grafting in burn wound treatment is the use of expanded autologous keratinocytes in suspension or sheets that are cultured over 2-4 weeks in a remote service facility. While a wound reepithelialization has been described, the functional and aesthetic outcome is under debate. Cell isolation from split-skin donor tissue aims to preserve the valuable stem cell progenitors from the basal epidermal layer and to provide patients with a rapid wound reepithelialization and a satisfying outcome. While the presence of epidermal progenitors in the cell graft is thought to enable an improved epidermal surface post reepithelialization, we investigated a feasible clinical approach involving cultured versus noncultured epidermal cells comparing the α6int(high)/K15(high)/FSC(low)/SSC(low) and α6int(high)/K5(high)/FSC(low)/SSC(low) keratinocyte progenitor subpopulations before and after in vitro culture process. Our results show a significant increase of cell size during in vitro passaging and a decrease of progenitor markers linked to a gradual differentiation. A provision of the regenerative epidermal progenitors, isolated from the split-skin biopsy and applied directly onto the wound in an on-site setting of isolation and cell spray grafting in the operation room, could be of interest when choosing options for skin wound care with autologous cells.
Copyright © 2015 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.