Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Bioartificial liver support systems for acute liver failure: A systematic review and meta-analysis of the clinical and preclinical literature

BACKGROUND Acute liver failure(ALF) has a high mortality varying from 80% to 85% with rapid progress in multi-organ system failure. Bioartificial liver(BAL) support systems have the potential to provide temporary support to bridge patients with ALF to liver transplantation or spontaneous recovery. In the past decades, several BAL support systems have been conducted in clinical trials. More recently,concerns have been raised on the renovation of high-quality cell sources and configuration of BAL support systems to provide more benefits to ALF models in preclinical experiments.AIM To investigate the characteristics of studies about BAL support systems for ALF,and to evaluate their effects on mortality.METHODS Eligible clinical trials and preclinical experiments on large animals were identified on Cochrane Library, PubMed, and EMbase up to March 6, 2019. Two reviewers independently extracted the necessary information, including key BAL indicators, survival and indicating outcomes, and adverse events during treatment. Descriptive analysis was used to identify the characteristics of the included studies, and a meta-analysis including only randomized controlled trial (RCT) studies was done to calculate the overall effect of BAL on mortality among humans and large animals, respectively.RESULTS Of the 30 selected studies, 18 were clinical trials and 12 were preclinical experiments. The meta-analysis result suggested that BAL might reduce mortality in ALF in large animals, probably due to the recent improvement of BAL, including the type, cell source, cell mass, and bioreactor, but seemed ineffective for humans (BAL vs control: relative risk(95% confidence interval),0.27(0.12-0.62) for animals and 0.72(0.48-1.08) for humans)Liver and renal functions, hematologic and coagulative parameters, encephalopathy index, and neurological indicators seemed to improve after BAL, with neither meaningful adverse events nor porcine endogenous retrovirus infection.CONCLUSION BAL may reduce the mortality of ALF by bridging the gap between preclinical experiments and clinical trials. Clinical trials using improved BAL must be designed scientifically and conducted in the future to provide evidence for transformation.

Hepatic encephalopathy:Lessons from preclinical studies

Hepatic encephalopathy(HE) is a major complication that is closely related to the progression of end-stage liver disease.Metabolic changes in advanced liver failure can promote cognition impairment,attention deficits and motor dysfunction that may result in coma and death.HE can be subdivided according to the type of hepatic injury,namely,type A,which results from acute liver failure,type B,which is associated with a portosystemic shunting without intrinsic liver disease,and type C,which is due to chronic liver disease.Several studies have investigated the pathogenesis of the disease,and most of the mechanisms have been explored using animal models.This article aimed to review the use of preclinical models to investigate HE.The most used animal species are rats and mice.Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications,whereas models of types B and C HE are generally surgically induced lesions in liver tissue,which evolve to hepatic cirrhosis.Preclinical models have allowed the comprehension of the pathways related to HE.

Preclinical animal studies in ischemic stroke:Challenges and some solutions

Despite the impressive efficacies demonstrated in preclinical research,hundreds of potentially neuroprotective drugs have failed to provide effective neuroprotec-tion for ischemic stroke in human clinical trials.Lack of a powerful animal model for human ischemic stroke could be a major reason for the failure to develop successful neuroprotective drugs for ischemic stroke.This review recapitulates the available cerebral ischemia animal models,provides an anatomical comparison of the circle of Willis of each species,and describes the functional assessment tests used in these ischemic stroke models.The distinct differences between human ischemic stroke and experimental stroke in available animal models is explored.Innovative animal models more closely resembling human strokes,better techniques in functional out-come assessment and better experimental designs generating clearer and stronger evidence may help realise the development of truly neuroprotective drugs that will benefit human ischemic stroke patients.This may involve use of newer molecules or revisiting earlier studies with new experimental designs.Translation of any resultant successes may then be tested in human clinical trials with greater confidence and optimism.

Anodal transcranial direct current stimulation alleviates cognitive impairment in an APP/PS1 model of Alzheimer’s disease in the preclinical stage

Anodal transcranial direct current stimulation(AtDCS)has been shown to alleviate cognitive impairment in an APP/PS1 model of Alzheimer’s disease in the preclinical stage.However,this enhancement was only observed immediately after AtDCS,and the long-term effect of AtDCS remains unknown.In this study,we treated 26-week-old mouse models of Alzheimer’s disease in the preclinical stage with 10 AtDCS sessions or sham stimulation.The Morris water maze,novel object recognition task,and novel object location test were implemented to evaluate spatial learning memory and recognition memory of mice.Western blotting was used to detect the relevant protein content.Morphological changes were observed using immunohistochemistry and immunofluorescence staining.Six weeks after treatment,the mice subjected to AtDCS sessions had a shorter escape latency,a shorter path length,more platform area crossings,and spent more time in the target quadrant than sham-stimulated mice.The mice subjected to AtDCS sessions also performed better in the novel object recognition and novel object location tests than sham-stimulated mice.Furthermore,AtDCS reduced the levels of amyloid-β42 and glial fibrillary acidic protein,a marker of astrocyte activation,and increased the level of neuronal marker NeuN in hippocampal tissue.These findings suggest that AtDCS can improve the spatial learning and memory abilities and pathological state of an APP/PS1 mouse model of Alzheimer’s disease in the preclinical stage,with improvements that last for at least 6 weeks.

Pancreatic cancer organotypics: High throughput, preclinical models for pharmacological agent evaluation

Pancreatic cancer carries a terrible prognosis,as the fourth most common cause of cancer death in the Western world.There is clearly a need for new therapies to treat this disease.One of the reasons no effective treatment has been developed in the past decade may in part,be explained by the diverse influences exerted by the tumour microenvironment.The tumour stroma cross-talk in pancreatic cancer can influence chemotherapy delivery and response rate.Thus,appropriate preclinical in vitro models which can bridge simple 2D in vitro cell based assays and complex in vivo models are required to understand the biology of pancreatic cancer.Here we discuss the evolution of 3D organotypic models,which recapitulare the morphological and functional features of pancreatic ductal adenocarcinoma(PDAC).Organotypic cultures are a valid high throughput preclinical in vitro model that maybe a useful tool to help establish new therapies for PDAC.A huge advantage of the organotypic model system is that any component of the model can be easily modulated in a short timeframe.This allows new therapies that can target the cancer,the stromal compartment or both to be tested in a model that mirrors the in vivo situation.A major challenge for the future is to expand the cellular composition of the organotypic model to further develop a system that mimics the PDAC environment more precisely.We discuss how this challenge is being met to increase our understanding of this terrible disease and develop novel therapies that can improve the prognosis for patients.

Towards reperfusion-centric preclinical stroke research:outside the box of “reperfusion injury”

Stroke is a major health issue of increasing significance for any society with an aging population. Globally, stroke is the second-leading cause of death with approximately 5.9 million fatal events in 2010, equivalent to 11.1% of all deaths. Yet, despite years of preclinical research on neuroprotection and a multitude of clinical trials, tissue plas- minogen activator （tPA）-mediated recanalization remains the mainstay of acute ischemic stroke therapy, whereas tPA thrombolysis rarely provides benefits in the mechanical occlusion-based stroke models. This split between the bench and bedside raised the concern over the clinical ap- plicability of neuroprotection in acute ischemic stroke. In this perspective commentary, we call for attention to the differences between mechanical-occlusion and thrombo- embolic stroke models in cerebral hemodynamics （Figure 1A, B）, the implications of these differences in view of progressive pathobiology of ischemic stroke （Figure 1C）, and the need and strategies towards reperfusion-centric preclinical stroke research.

Preclinical transplantation and safety of HS/PCs expanded from human umbilical cord blood

AIM: To expand hematopoietic/progenitor stem cells (HS/PCs) from umbilical cord blood (UCB) and prepare the HS/PC product, and analyze preclinical transplantation and safety of HS/PC product. METHODS: Human bone marrow-derived mesenchymal stem cells (MSCs) were used as feeder cells to expand HS/PCs from UCB in a serum-free culture system. The proliferation potential of HS/PCs was analyzed. The expanded HS/PCs were suspended in the L-15 medium to prepare the HS/PC product. The contamination of bacteria, fungi and mycoplasmas, the infection of exogenous virus, the concentration of bacterial endotoxin, and the SCF residual in HS/PC product were determined. Finally, cells from the HS/PC product with or without bone marrow-derived mesenchymal stem cells (BM-MSCs) were transplanted into the irradiated NOD/SCID mice to determine the in vivo engraftment potential. RESULTS: After co-culture for 10 d, the total nuclear cells (TNCs) increased 125-fold, and CD34 + cells increased 43-fold. The granulocyte-macrophage colonyforming cells (GM-CFCs) and erythroid colony-forming cells (E-CFCs) increased 3.3and 4.7-fold respectively. The expanded cells were collected and prepared as the expanded product of HS/PCs by re-suspending cells in L-15 medium. For preclinical safety, the HS/PC product was analysed for contamination by bacteria, fungi and mycoplasmas, the bacterial endotoxin concentration and the SCF content. The results showed that the HS/PC product contained no bacteria, fungi or mycoplasmas. The bacterial endotoxin concentration was less than the detection limit of 6 EU/mL, and residual SCF was 75 pg/mL. Based on clinical safety, the HS/PC product was qualified for clinical transplantation. Finally, the HS/PC product was transplanted the irradiated mice where it resulted in rapid engraftment of hematopoietic cells. CONCLUSION: HSPC product prepared from UCB in the serum-free culture system with hMSCs as feeder cells should be clinically safe and effective for clinical transplantation.

Comparison of gene expression in cynomolgus monkeys with preclinical type Ⅱ diabetes induced by different high energy diets

Background : Cynomolgus disease models that are similar to the preclinical stage of human type 2 diabetes mellitus(T2 DM) were established by feeding middle-aged cynomolgus monkeys different high energy diets to study the differential expression of diabetes-related genes. Methods : A total of 36 male monkeys were randomly divided into four groups and fed human diets with high sugar, high fat, double high sugar and fat, and a normal diet. The preclinical diabetes phase was determined by monitoring the metabolic characteristic indices and the results of oral glucose tolerance tests( OGTT). The mRNA expression of 45 diabetes-related genes in peripheral blood leukocytes was analyzed using real-time PCR. Results : A total of 22, 25, and 21 genes were significantly up-regulated( P < 0.05) and 5, 7, and 5 genes were significantly down-regulated( P < 0.05) in the above three induced groups, respectively, compared with the control group. Of the 45 tested genes, the expression profiles of 21 genes were consistent. Most of the expression levels in the double high sugar-and-fat individuals were slightly lower than those in the high glucose and high fat groups, although the expression patterns of the three groups were essentially similar. Conclusion : The different high energy diets all induced diabetes and shared some phenotypic properties with human T2 DM. Most of the expression patterns of the related genes were identical. The gene expression profiles could be used as references for the study of early diagnostic indicators and T2 DM pathogenesis.

Preclinical stem cell therapy in Chagas Disease: Perspectives for future research

Chagas cardiomyopathy still remains a challenging problem that is responsible for high morbidity and mortality in Central and Latin America. Chagas disease disrupts blood microcirculation via various autoimmune mechanisms, causing loss of cardiomyocytes and severe impairment of heart function. Different cell types and delivery approaches in Chagas Disease have been studied in both preclinical models and clinical trials. The main objective of this article is to clarify the reasons why the benefits that have been seen with cell therapy in preclinical models fail to translate to the clinical setting. This can be explained by crucial differences between the cellular types and pathophysiological mechanisms of the disease, as well as the differences between human patients and animal models. We discuss examples that demonstrate how the results from preclinical trials might have overestimated the efficacy of myocardial regeneration therapies. Future research should focus, not only on studying the best cell type to use but, very importantly, understanding the levels of safety and cellular interaction that can elicit efficient therapeutic effects in human tissue. Addressing the challenges associated with future research may ensure the success of stem cell therapy in improving preclinical models and the treatment of Chagas disease.

Diffusion tensor imaging as a tool to detect presymptomatic axonal degeneration in a preclinical spinal cord model of amyotrophic lateral sclerosis

The G93A-SOD1 mice model and MRI diffusion as a preclinical tool to study amyotrophic lateral sclerosis （ALS）： ALS is a progressive neurological disease characterized primarily by the development of limb paralysis, which eventually leads to lack of control on muscles under voluntary control and death within 3–5 years. Genetic heterogeneity and environmental factors play a critical role in the rate of disease progression and patients display faster declines once the symptoms have manifested. Since its original discovery, ALS has been associated with pathological alterations in motor neurons located in the spinal cord （SC）, where neuronal loss by a mutation in the protein superoxide dismutase in parenthesis （mSOD1） and impairment in axonal connectivity, have been linked to early functional impairments. In addition,mechanisms of neuroinflammation, apoptosis, necroptosis and autophagy have been also implicated in the development of this disease. Among different animal models developed to study ALS, the transgenic G93A-SOD1 mouse has become recognized as a benchmark model for preclinical screening of ALS therapies. Furthermore, the progressive alterations in the locomotor phenotype expressed in this model closely resemble the progressive lower limb dysfunction of ALS patients. Among other imaging tools, MR diffusion tensor imaging （DTI） has emerged as a crucial, noninvasive and real time neuroimaging tool to gather information in ALS. One of the current concerns with the use of DTI is the lack of biological validation of the microstructural information given by this technique. Although clinical studies using DTI can provide a remarkable insight on the targets of neurodegeneration and disease course,they lack histological correlations. To address these shortcomings, preclinical models can be designed to validate the microstructural information unveiled by this particular MRI technique. Thus, the scope of this review is to describe how MRI diffusion and optical microscopy evaluate axonal structural changes at early stages of the disease in a preclinical model of ALS.

Importance of microenvironment in preclinical models of breast and prostate cancer

he majority of cancer drugs entering clinical trials fail to reach the market due to poor efficacy. Preclinical efficacy has been traditionally tested using subcutaneous xenograft models that are cheap, fast and easy to perform. However, these models lack the correct tumor microenvironment, leading to poor clinical predictivity. Selecting compounds for clinical trials based on efficacy results obtained from subcutaneous xenograft models may therefore be one important reason for the high failure rates. In this review we concentrate in describing the role and importance of the tumor microenvironment in progression of breast and prostate cancer, and describe some breast and prostate cancer cell lines that are widely used in preclinical studies. We go through different preclinical efficacy models that incorporate the tissue microenvironment and should therefore be clinically more predictive than subcutaneous xenografts. These include three-dimensional cell culture models, orthotopic and metastasis models, humanized and transgenic mouse models, and patient-derived xenografts. Different endpoint measurements and applicable imaging techniques are also discussed. We conclude that models that incorporate the tissue microenvironment should be increasingly used in preclinical efficacy studies to reduce the current high attrition rates of cancer drugs in clinical trials.

Non-human primate pluripotent stem cells for the preclinical testing of regenerative therapies

Non-human primates play a key role in the preclinical validation of pluripotent stem cell-based cell replacement therapies.Pluripotent stem cells used as advanced therapy medical products boost the possibility to regenerate tissues and organs affected by degenerative diseases.Therefore,the methods to derive human induced pluripotent stem cell and embryonic stem cell lines following clinical standards have quickly developed in the last 15 years.For the preclinical validation of cell replacement therapies in non-human primates,it is necessary to generate non-human primate pluripotent stem cell with a homologous quality to their human counterparts.However,pluripotent stem cell technologies have developed at a slower pace in non-human primates in comparison with human cell systems.In recent years,however,relevant progress has also been made with non-human primate pluripotent stem cells.This review provides a systematic overview of the progress and remaining challenges for the generation of non-human primate induced pluripotent stem cells/embryonic stem cells for the preclinical testing and validation of cell replacement therapies.We focus on the critical domains of(1)reprogramming and embryonic stem cell line derivation,(2)cell line maintenance and characterization and,(3)application of non-human primate pluripotent stem cells in the context of selected preclinical studies to treat cardiovascular and neurodegenerative disorders performed in non-human primates.

Establishment of various biliary tract carcinoma cell lines and xenograft models for appropriate preclinical studies

We recently reported several driver genes of biliary tract carcinoma(BTC) that are known to play important roles in oncogenesis and disease progression. Although the need for developing novel therapeutic strategies is increasing, there are very few BTC cell lines and xenograft models currently available for conducting preclinical studies. Using a total of 88 surgical BTC specimens and 536 immunodeficient mice, 28 xenograft models and 13 new BTC cell lines, including subtypes, were established. Some of our cell lines were found to be resistant to gemcitabine, which is currently the first choice of treatment, thereby allowing highly practical preclinical studies to be conducted. Using the aforementioned cell lines and xenograft models and a clinical pathological database of patients undergoing BTC resection, we can establish a preclinical study system and appropriate parameters for drug efficacy studies to explore new biomarkers for practical applications in the future studies.

Transcatheter mitral valve implantation using a novel system:preclinical results

Background This preclinical study in sheep sought to demonstrate the initial safety and feasibility of a novel transcatheter mitral valve system(Mi-thos valve)composed of a self-expanding frame and a bovine pericardial tissue bioprosthesis.Methods The valve was implanted in 26 sheep using a transapical approach for short-and long-term evaluation.The technical feasibility,safety,durability,and valve function were evaluated during and 6 months after the procedure using intracardiac and transthoracic echocardiography,multisliced computed tomography,histological analysis,and electron microscopy.Results The success rate of valve implantation was 100%,and the immediate survival rate after surgery was 84%.Five animals died within 90 min after the development of the prosthetic valve due to an acute left ventricular outflow tract obstruction(n=2)and sudden intraoperative ventricular fibrillation(n=3).Twelve animals died within 1 month due to acute left heart dysfunction.Mild(n=5)and moderate(n=2)paravalvular leakage occurred in seven animals,and two moderate PVL animals died of chronic heart failure within three months.Multimodality imaging studies of the remaining seven animals showed excellent function and alignment of the valves,with no coronary artery obstruction,no left ventricular outflow tract obstruction,no severe transvalvular gradients and no paravalvular leakage.Macroscopic evaluation demonstrated stable,secure positioning of the valve,with full endothelialization of the valve leaflets without injury to the ventricular or atrial walls.Histological and electron microscopic examinations at six months showed no obvious macro-or microcalcification in the leaflets.Conclusions Preclinical studies indicate that transcatheter implantation of the Mi-thos valve is technically safe and feasible.The durability,functionality,and lack of leaflet calcification were all verified in animal experiments.The information from these preclinical studies will be applied to patient selection criteria and the first-in-human studies.

A revisit of rod microglia in preclinical studies

Microglial cells（or microglia）are the mononuclear phagocytes residing in the central nervous system（CNS）.In homeostasis,they showed ramified morphology with relative small cell bodies and long processes（Figure 1A）.They detect injury signals in the CNS and get activated.

Update on the preclinical and clinical assessment of Withania somnifera: from ancient Rasayana to modern perspectives

The Rasayana plant Withania somnifera(W.somnifera)Dunal,also known as“Ashwagandha”,has been mentioned in various classical Ayurvedic texts,such as Charaka Samhita,Sushruta Samhita,and Nighantus.This Ayurvedic drug has been referred to as a tonic that renews the body,provides physical and mental vigor in weakened states,and promotes endurance and longevity.W.somnifera possesses notable biological activity in many ailments,such as diabetes,conjunctivitis,insomnia,senile dementia,Parkinson’s disease,nervous system disorders,rheumatism,and arthritis.These pharmacological activities are due to the presence of diverse active components and their derivatives.Some lead compounds are found to be effective against anxiety and other central nervous system disorders.W.somnifera has been proven to be effective and safe for a wide range of ailments from ancient to modern times.Its reported properties represent the traditional use of W.somnifera as indicated in the literature;furthermore,W.somnifera is one of the most important prescribed drugs in Ayurveda for its multimodal effects.This current review highlights the bioactive present and provides an overview of the toxicological and pharmacological studies on W.somnifera,including preclinical and clinical studies.From its earliest utilization to its current application,W.somnifera has been recognized to be effective at clinical levels for human health and welfare.Greater attention to the safety and efficacy of W.somnifera would provide more scientific evidence,promoting global acceptance of the Ayurvedic plant.

Preclinical models in ophthalmic oncology-a narrative review

Objective:This review serves as a comprehensive description and summary of currently available preclinical models of three tumors in ophthalmic oncology:conjunctival melanoma(CM),uveal melanoma(UM),and retinoblastoma.Background:Malignant melanomas are the most common tumors of the eye in adults,most often localized in the uvea and conjunctiva.Although the primary tumor can be successfully eliminated in many cases,nearly one in two UMs-and one in three CMs-are fatal to the patient due to metastasis.Effective therapies for metastatic uveal and CMs are unfortunately still not available,so there is an urgent need for new therapeutic strategies to improve prognosis quoad vitam and prolong the survival of melanoma patients.Another widely known tumor of the eye is retinoblastoma,which is the most common pediatric ocular malignancy,occurring in approximately 1 in 15,000-18,000 live births.Overall,it is considered well treatable,with a survival rate of approximately 90%at 3 years,although fatal if untreated.For a long time,enucleation was also considered the treatment of choice,with bilateral cases having one eye irradiated and the eye with the more advanced tumor removed.Since the 1990s,however,systemic chemotherapy has been predominantly used to preserve the quality of life and vision of young patients,although the cellular activity of the retinoblastoma often remains after treatment with chemotherapeutic agents.Prognosis of the disease is immensely depending on the stage and time of diagnosis and is varying between countries due to different developmental status of health care systems.Methods:We review recent advances in the available literature on established preclinical models in CM,UM,and retinoblastoma.In addition,we discuss the advantages and limitations of these models and provide an overview of current alternatives to animal testing in preclinical studies.Conclusions:In the case of all three diseases,further research is needed for improved therapeutic options.Animal models in particular are indispensable for cancer research in order to mimic the extremely complex processes of human carcinogenesis,physiology and progression.Certainly,animal studies do not easily translate to human diseases due to biological differences and limitations.However,they continue to serve as the primary source and link between in vitro testing and clinical studies in patients.In order to minimize animal experiments and possibly even replace them in the future,alternatives such as 3D cell cultures and in silico predictions are useful and insightful additions and require further development.Still,no currently available preclinical model can be fully translated to some of here described diseases.Nevertheless,they all provide essential insights and knowledge that should be of use in the future for better understanding and pursuit of new therapeutic strategies.

Characteristics of a primate model of focal motor cortical seizures suitable for preclinical testing of therapies like DBS

Background and objective: Generating and characterizing primate models of epileptic seizures are important for understanding pathophysiology of diseases and establishing preclinical efficacy of novel therapies like Deep Brain Stimulation. A focal motor epilepsy model is described here. Method: Seizures were obtained after intracortical penicillin injection into the motor strip through a cannula in two awake monkeys and electrocorticograms were recorded by epidural screws. Seizures were analyzed and compared for number, average duration of each seizure and total duration of ictal activity. Pharmaco-resistance for antiepileptic drug was tested by administration of Diazepam during seizures. Results: A motor status with seizures mimicking those seen in Kojevnikov’s syndrome was easily generated several minutes after penicillin injection and lasted 24 h on an average. The model thus characterized appears stable and consistent. There is no significant variation between experiments in individual primate as well as between two specimens. Diazepam though reduced the total duration of seizures, failed to abolish behavioural seizures. Conclusion: This model represents a good alternative model for preclinical research aiming at testing novel therapies because seizures are obtained on demand, last up to 24 h after a single penicillin injection, are stable and resistant to Diazepam.

X-ray photon counting detectors for preclinical and clinical applications

Photon counting detectors(PCDs) have attained w ide use in X-ray imaging for various preclinical and clinical applications in the past decade. This paper briefly review s the preclinical and clinical applications of PCDs based X-ray imaging systems.Starting with an introduction of X-ray single photon detection mechanism,the brief review first describes tw o major advantages of utilizing PCDs: photon energy resolving capability and electronic noise elimination. Compared to energy integrating detectors(EIDs),the aforementioned advantages make PCDs more favorable in X-ray imaging with profound benefits such as enhanced tissue contrast,decreased image noise,increased signal to noise ratio,decreased radiation dose to the small animals and patients,and more accurate material decomposition. The utilizations of PCDs in X-ray projection radiography and computed tomography(CT)including micro-CT,dedicated breast CT,K-edge CT,and clinical CT are then review ed for the imaging applications ranging from phantoms to small animals and humans. In addition,optimization methods aiming to improve the imaging performance using PCDs are briefly review ed. PCDs are not flaw less though,and their limitations are also discussed in this review. Nevertheless,PCDs may continuously contribute to the advancement of X-ray imaging techniques in future preclinical and clinical applications.