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International Journal of Molecular Medical Science (online), 2025, Vol. 15, No. 5 ISSN 1927-6656 http://medscipublisher.com/index.php/ijmms © 2025 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Research Progress on Biomarkers for Early Screening ofAlzheimer’s Disease MinLi International Journal of Molecular Medical Science, 2025, Vol. 15, No. 5, 205-213 Using Regenerative Dressings in Chronic Wound Care, Molecular View of Healing Jianmin Liu International Journal of Molecular Medical Science, 2025, Vol. 15, No. 5, 214-223 Survival Benefit Analysis of PD-1/PD-L1 Inhibitors Combined with Chemotherapy in Non-Small Cell Lung Cancer Liting Wang International Journal of Molecular Medical Science, 2025, Vol. 15, No. 5, 224-234 The Renal Protective Effects ofACEI/ARB Drugs in Elderly Patients with Hypertension YanLou International Journal of Molecular Medical Science, 2025, Vol. 15, No. 5, 235-243 Therapeutic Targeting of the SIRT3-FOXO3a-SOD2 Network in Sepsis: Current Evidence and Future Prospects Tiantian Li, Jie Zhang International Journal of Molecular Medical Science, 2025, Vol. 15, No. 5, 244-252
International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 205-213 http://medscipublisher.com/index.php/ijmms 205 Systematic Review Open Access Research Progress on Biomarkers for Early Screening of Alzheimer’s Disease MinLi The First Affiliated Hospital, Zhejian Guniversity School of Medncine, Hangzhou, 310009, Zhejiang, China Corresponding email: limin@qq.com International Journal of Molecular Medical Science, 2025, Vol.15, No.5 doi: 10.5376/ijmms.2025.15.0021 Received: 03 Jul., 2025 Accepted: 10 Aug., 2025 Published: 12 Sep., 2025 Copyright © 2025 Li, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Li M., 2025, Research progress on biomarkers for early screening of alzheimer’s disease, International Journal of Molecular Medical Science, 15(5): 205-213 (doi: 10.5376/ijmms.2025.15.0021) Abstract This study explored biomarkers for the early screening of Alzheimer's disease (AD). Alzheimer's disease is the most common cause of dementia worldwide. The pathological changes of Alzheimer's disease can occur 15 to 20 years before the appearance of clinical symptoms, so early detection is very important. At present, Aβ42, total tau protein (t-tau), and phosphorylated tau protein (p-tau) in cerebrospinal fluid (CSF) are regarded as the gold standard for early diagnosis, but these tests require invasive procedures. Emerging markers such as exosome micrornas (miRNAs) and speech analysis have demonstrated potential for application. It is recommended to use multiple biomarkers together and integrate various information (such as body fluids, images, genes, etc.) with artificial intelligence. This can help improve the accuracy of early disease detection and disease monitoring. There are still some problems at present, such as the lack of a unified testing method, high testing costs, and the judgment results may be affected by different groups of people. In the future, efforts should be made to develop low-cost technologies that do not require invasive operations, and promote precise intervention and personalized management. Biomarkers have made significant progress in the early detection of Alzheimer's disease, but to further promote their application in clinical practice and thereby improve the prognosis of patients, existing problems still need to be addressed. Keywords Alzheimer’s disease (AD); Early screening biomarkers; β-amyloid (Aβ); Tau protein; Multi-modal integration 1 Introdution Alzheimer's disease (AD) is the leading cause of dementia and a very common neurodegenerative disorder worldwide. With the increase in the elderly population, its prevalence is expected to rise significantly (Klyucherev et al., 2022). This disease is mainly manifested as continuous decline in cognitive ability, memory loss and functional impairment, which usually result from the gradual degeneration and death of neurons. When AD is clinically diagnosed, significant and irreversible neuronal loss often occurs, thereby limiting the effectiveness of existing treatment methods. Therefore, early screening and diagnosis are of great significance, which helps to take timely intervention measures, possibly delaying the progression of the disease and maintaining the patient's cognitive ability for a longer period of time (Marquez and Yassa, 2019). Biomarkers are measurable biological indicators that can show possible pathological changes in Alzheimer's disease several years or even decades before the onset of clinical symptoms (Marquez and Yassa, 2019). Important biomarkers, such as Aβ and tau proteins in cerebrospinal fluid (CSF), or changes observed through advanced neuroimaging techniques, reflect the key pathological characteristics of AD and provide an objective basis for early diagnosis (Ossenkoppele et al., 2022). In recent years, scientists have been able to detect these markers and other related indicators in samples such as blood, saliva and eye tissue, providing a more convenient and less invasive method for large-scale screening. The use of biomarkers not only helps in early detection and differential diagnosis, but also helps identify high-risk populations, monitor disease development and evaluate treatment effects (Blennow and Zetterberg, 2018). This study will explore the latest research on biomarkers related to the early screening of Alzheimer's disease in terms of confirmation and validation, including the development of fluid, imaging, and new non-invasive methods. This study will also explore the difficulties and future trends faced by these biomarkers in practical medical applications, aiming to increase the early detection rate and assist in individualized treatment, thereby alleviating the health stress brought by Alzheimer's disease on a global scale.
International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 205-213 http://medscipublisher.com/index.php/ijmms 206 2 The Pathological Basis of Alzheimer's Disease 2.1 Core pathological features One of the main features of Alzheimer's disease (AD) is the appearance of extracellular β -amyloid protein (Aβ) plaques and intracellular aggregation of neurofibrillary tangles formed by hyperphosphorylated tau protein. Aβ peptides aggregate in the brain parenchyma to form plaques, while tau proteins undergo abnormal hyperphosphorylation, generating tangling structures that impair the normal function and structural integrity of neurons (McGrowder et al., 2021). These two protein abnormalities are at the core of the pathogenesis of AD and are closely related to synaptic dysfunction, nerve cell death, and gradual cognitive decline (Zhang et al., 2021). The relationship between Aβ and tau is complex and mutually reinforcing. Studies have shown that the deposition of Aβ accelerates the hyperphosphorylation and aggregation of tau. The pathological changes of tau cause Aβ to have a toxic effect on nerve cells, making neuronal damage more severe (Hong et al., 2025; Lou and Xu, 2025). This combined effect not only promotes the progress of AD, but also provides a scientific basis for the development of corresponding biomarkers and treatment methods (Ossenkoppele et al., 2022). 2.2 Pathological changes begin several years before cognitive impairment The pathological changes of AD, including Aβ deposition and tau protein hyperphosphorylation, begin many years (or even decades) before the appearance of clinical symptoms (Uchida et al., 2025). Long-term follow-up studies have shown that accumulation of Aβ can be detected 15-20 years before cognitive decline, followed by tau pathology and neurodegeneration. During this preclinical stage, molecular and structural changes in the brain gradually develop in silence, and these changes can be captured by highly sensitive biomarkers in cerebrospinal fluid, blood and neuroimaging (McGrowder et al., 2021). The initial stage of the pathological process is the golden period for intervention, which also indicates that early screening is very necessary. Identifying these abnormalities before the appearance of clinical symptoms can help delay or prevent diseases, demonstrating the important role of biomarkers in screening high-risk populations (Uchida et al., 2025). 2.3 Pathological stage determines the expression patterns and detection Windows of biomarkers The pathological development of Alzheimer's disease is sequential, and different stages will affect the content of biomarkers and the difficulty of detection. In the early stage of the disease, biomarkers related to Aβ (such as decreased cerebrospinal fluid Aβ42 levels or increased amyloid PET signaling) will first show abnormalities, and then the levels of phosphorylated tau (p-tau) and markers reflecting neurodegeneration will rise (Uchida et al., 2025). For instance, p-tau231 and p-tau217 in the blood are highly sensitive to early Aβ changes, among which p-tau217 is significantly associated with disease progression and long-term cognitive decline (Ashton et al., 2022). As the disease progresses to different stages, the types and degrees of changes in biomarkers will also change accordingly. Early markers are most suitable for preclinical identification, while other markers such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are more obvious in the later stage of the disease, reflecting persistent neuronal damage and inflammatory responses (Smirnov et al., 2022; Guo, 2025; Heneka et al., 2025). The timing and sequence of the appearance of these biomarkers are of great significance for the accurate staging, prognosis judgment and disease monitoring of AD, and are conducive to achieving more targeted early diagnosis and intervention strategies. 3 Research Progress on Biomarkers of Alzheimer's Disease 3.1 Cerebrospinal fluid (CSF) biomarkers Biomarkers in cerebrospinal fluid, especially Aβ42, total tau (t-tau) and phosphorylated tau (p-tau), are regarded by many as an important basis for the early detection of Alzheimer's disease (AD). These indicators directly reflect pathological changes such as Aβ deposition and tau hyperphosphorylation, which can effectively distinguish AD from other types of dementia and accurately predict the risk of progressing from mild cognitive impairment to AD (Papaliagkas et al., 2023; Barthsamlemy et al., 2023). Because cerebrospinal fluid is in direct
International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 205-213 http://medscipublisher.com/index.php/ijmms 207 contact with the extracellular environment of brain tissue and is less affected by other factors of the body, the detection of such proteins is considered a reliable basis for early diagnosis (Sur et al., 2025). In recent years, the detection accuracy of cerebrospinal fluid markers has continued to improve. The newly discovered phosphorylated tau types (such as p-tau217 and p-tau205) may have stronger recognition ability and specificity for amyloid protein and tau pathology. However, lumbar puncture is an invasive procedure and has specific requirements for the laboratory environment. These conditions limit the promotion and application of cerebrospinal fluid biomarkers in routine screening (Leuzy et al., 2021). 3.2 Blood biomarkers: research hotspots Blood biomarkers have become a current research hotspot due to their convenient sampling and suitability for large-scale screening. It mainly includes phosphorylated tau (such as p-tau217 and p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), etc. (Leuzy et al., 2021). Plasma p-tau217 and p-tau181 can well distinguish AD from other neurodegenerative diseases and can be used to predict the trend of cognitive decline (Hansson et al., 2023; Chae et al., 2025). NfL reflects the degree of neurodegeneration, while GFAP has a suggesting effect on early amyloid pathology and cognitive decline (Gao et al., 2023; Yang et al., 2023). Analyzing these blood markers together can have a better predictive effect. Its main advantage is that the sampling is simple and no invasive procedures are required. It is very suitable for large-scale screening and long-term disease monitoring (Grande et al., 2025). The current focus of research is to improve the detection steps, with the aim of making its accuracy similar to that of cerebrospinal fluid and imaging methods (Arslan et al., 2024; Sur et al., 2025). 3.3 Emerging biomarkers Some emerging biomarkers, such as exosome micrornas (miRNAs), metabolic markers, as well as digital features like speech analysis and electroencephalogram, have shown potential for early AD identification. Exosomal mirnas in the blood are abnormally expressed in AD patients and can serve as non-invasive and easily accessible markers to help distinguish early AD patients from healthy individuals (Figure 1) (Siedlecki-Wullich et al., 2021; Petracci et al., 2025). Markers based on blood exosomes (including Aβ42, p-tau and various mirnas) can detect pathological changes several years before the onset of clinical symptoms, and their sensitivity is similar to that of cerebrospinal fluid markers (Chen et al., 2022). Metabolic markers, speech patterns, and digital features such as electroencephalograms are also regarded as potential non-invasive screening tools, but their application still needs to be further verified in more people (Klyucherev et al., 2022). These new methods are expected to work better in combination with traditional markers, thereby increasing the technical approaches for the early diagnosis of Alzheimer's disease. 4 Comprehensive Application of Biomarkers for Alzheimer's Disease 4.1 Variability in sensitivity, specificity and accessibility Different biomarkers for Alzheimer's disease (AD) have their own characteristics in terms of sensitivity, specificity and accessibility. For instance, tau protein and beta-amyloid protein markers related to cerebrospinal fluid (CSF) and positron emission tomography (PET) have high diagnostic accuracy. However, due to the invasive nature, high cost and limited popularity of the operation, they are difficult to be promoted in routine clinical practice (Ossenkoppele et al., 2022; Hansson et al., 2023). In contrast, blood biomarkers - such as plasma phosphorylated tau (p-tau), filament light chain (NfL), and glial fibrillary acidic protein (GFAP) - are more accessible and less costly, but their sensitivity and specificity may vary with the disease stage and the type of biomarker used (Figure 2) (Leuzy et al., 2021; Dhauria et al., 2024). Therefore, the selection of which biomarker to choose should be comprehensively considered in combination with the clinical scenario, resource conditions and specific goals (screening, diagnosis or follow-up). 4.2 Combine multiple biomarkers to improve the early detection rate The combined use of multiple biomarkers can effectively improve the accuracy of early Alzheimer's disease (AD)
International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 205-213 http://medscipublisher.com/index.php/ijmms 208 identification. The platform capable of measuring multiple indicators can simultaneously detect various markers such as Aβ42, t-tau, p-tau, NfL, and GFAP, thereby more comprehensively judging the pathological state of AD (Kim et al., 2020). Studies have found that the combination of blood markers with genetic information, demographic data, or imaging data can lead to better classification results, which is particularly important in the early stage of disease or preclinical stage (Ghazi et al., 2024). For instance, multimodal blood tests designed based on gene expression, proteins and clinical features, combined with machine learning methods, have been proven to have a high diagnostic accuracy, capable of identifying susceptible populations before symptoms appear (Gunes et al., 2022; AlMansoori et al., 2024). This combined approach helps address the heterogeneity of AD and also provides assistance for more personalized and precise diagnosis (Bhalala et al., 2024; Dhauria et al., 2024; Zu et al., 2024). Figure 1 Main stages and features of Alzheimer’s disease (Adopted from Siedlecki-Wullich et al., 2021) Image caption: Pathological changes and cognitive symptoms are represented as blue and brown lines, respectively. Pathological hallmarks currently used as biomarkers (Aβ and tau) are shown in blue rectangles, while key global pathological changes are indicated with arrows. Cognitive symptoms are summarized as MCI (mild cognitive impairment) and dementia stages. miRNA-based signatures for potential diagnosis of MCI and AD stages are indicated as references (Adopted from Siedlecki-Wullich et al., 2021) 4.3 Multi-mode integration facilitates early diagnosis and dynamic monitoring Combining biomarkers from different sources, such as those related to body fluids, imaging and genetics, can help achieve early detection and long-term follow-up of the disease course of Alzheimer's disease. The multimodal analysis framework integrates advanced neuroimaging techniques, blood and cerebrospinal fluid markers, and computational models to clarify the pathophysiological mechanism of AD more accurately, thereby promoting disease staging, prognosis determination, and follow-up after treatment (Jamal et al., 2025). Incorporating machine learning and artificial intelligence technologies can further enhance the predictive ability of this integrated model, supporting the judgment of risks based on individual circumstances and real-time disease monitoring (Gunes et al., 2022; Lou and Xu, 2025). Nowadays, in both scientific research and clinical
International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 205-213 http://medscipublisher.com/index.php/ijmms 209 applications, multimodal approaches have been widely recognized as key methods for improving clinical trial design, screening subjects, and evaluating intervention effects (Ossenkoppele et al., 2022; Jiao et al., 2024). Figure 2 Most promising plasma-based biomarkers across the clinical continuum of AD (Adopted from Leuzy et al., 2021) 5 Challenges in Alzheimer's Disease Research 5.1 The detection methods did not uniformly limit the reproducibility of the study At present, a consistent operating procedure has not been established, resulting in significant differences in biomarker measurements among different laboratories and institutions. Variables such as sample processing methods, reagent sources and detection platforms may introduce errors, affect the credibility of the results, make the data difficult to compare directly, and also hinder the establishment of a unified clinical judgment standard. Even minor deviations during the detection process can significantly weaken the clinical judgment value of biomarkers, especially when the variation range is small, such as the plasma Aβ42/40 ratio (Altomare et al., 2023). Because there is no cross-center validation and standardized operating procedures-which are necessary for applying research results to clinical practice-it is more difficult to repeat the research. The test results vary at different times or in different laboratories, and it is necessary to establish reference ranges suitable for different populations. All these indicate the need for unified norms to ensure consistent and accurate interpretation of biomarkers. 5.2 Cost, equipment and ethical factors limit clinical translation Advanced diagnostic methods such as PET imaging and cerebrospinal fluid testing are costly and have limited popularity, which restricts their wide application in primary care and resource-poor areas (Ossenkoppele et al., 2022). Although blood biomarkers offer better cost-effectiveness and are easier to promote, to achieve accurate detection and result interpretation, corresponding resources still need to be invested in equipment configuration, personnel training and infrastructure. When informing biomarker results, especially among people with normal cognition, there are ethical issues, such as the uncertainty of whether the disease will progress, which may cause psychological stress. In addition, there are still disputes over how to correctly use biomarker data to assist clinical judgment, inform and consent to patients, and handle cases of unexpected detections. All these issues require clear guiding rules and a patient-centered communication approach (Arslan et al., 2024). 5.3 Population heterogeneity affects the universality and accuracy of biomarker results The expression and interpretation of biomarkers for Alzheimer's disease are susceptible to population differences, including race, age, comorbidiasis and socioeconomic status, etc. Most existing biomarker studies are based on strictly screened subject populations, which may not fully reflect the diversity of the real clinical population, leading to a decline in the effectiveness of the conclusions when widely applied, and even misjudgment (Ossenkoppele et al., 2022).
International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 205-213 http://medscipublisher.com/index.php/ijmms 210 Non-AD factors, such as other chronic diseases, the use of drugs or different sample treatments, may also cause changes in biomarker levels, thereby affecting its credibility as a standalone diagnostic tool. Therefore, large-scale validation trials need to be conducted among different community populations to establish reliable judgment thresholds and ensure the accuracy and accessibility of diagnosis (Bouteloup et al., 2024). 6 Prospects for the Future of Alzheimer's Disease Screening 6.1 Develop low-cost and non-invasive detection technologies to enhance clinical accessibility Current research is leading detection methods towards a direction that does not invade the body and is cost-effective. For instance, biomarkers from blood, saliva, urine, and eyes, as well as digital features recorded by voice and wearable devices, are used to address the issues of high harm and cost associated with traditional diagnostic tools. These technologies are suitable for use in primary care and communities, enabling early AD screening to reach a wider population, including residents in areas with insufficient medical resources (Dave et al., 2025). In recent years, digital biomarkers such as voice analysis and eye-tracking have been evolving, providing more low-cost and non-invasive options for the early identification of AD. These methods alleviate patients' discomfort and risks, can be incorporated into routine health check-ups, and help enhance their clinical application (Gunes et al., 2022). 6.2 Combine multimodal data with artificial intelligence to enhance screening accuracy Integrating blood markers, neuroimaging, genetic information and digital health data, and leveraging artificial intelligence and machine learning technologies, can effectively enhance the accuracy and reliability of early AD screening (Kale et al., 2024; Hechkel and Helali, 2024). Models based on artificial intelligence can handle complex large-scale data, identify subtle change patterns from it, and thereby predict disease risks or disease progression more accurately (Gaubert et al., 2021). At present, artificial intelligent-assisted tools have been used to interpret neuroimages, analyze speech and cognitive test results, and integrate multiple types of biomarker information, providing support for personalized risk assessment and dynamic disease monitoring (Gunes et al., 2022; Kale et al., 2024). 6.3 Move from early identification to precise intervention and personalized management The focus of future AD diagnosis and treatment is shifting from early detection to precision medicine, that is, individualized biomarker-guided management strategies are formulated based on the unique biological and clinical characteristics of each patient (Kale et al., 2024). This includes using multimodal biomarker data for risk classification, selecting targeted treatment plans, and real-time tracking of efficacy changes (Chang et al., 2021; Jamal et al., 2025). To achieve the goal of precise intervention, it is necessary to verify more deeply the credibility and applicability of biomarkers in different populations and clinical situations, to ensure that the new tools are both fair and useful, and can also meet personalized needs. The update of this medical model is expected to improve the prognosis of patients and make the allocation of medical resources for Alzheimer's disease more reasonable (Arafah et al., 2023; Jamal et al., 2025). 7 Concluding Remarks In recent years, significant progress has been made in the discovery and validation of biomarkers in the field of early screening for Alzheimer's disease (AD). Sensitive detection techniques for tau protein, Aβ and neurodegenerative related markers in cerebrospinal fluid and blood, combined with imaging methods, make it possible to more accurately identify AD pathology before the appearance of clinical symptoms or in the early stage of the disease. Especially the development of blood biomarkers, with their characteristics of convenience, economy and easy promotion, is gradually changing the landscape of screening and diagnosis, and has demonstrated good diagnostic performance in both research and clinical scenarios.
International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 205-213 http://medscipublisher.com/index.php/ijmms 211 The lack of a unified detection standard, coupled with the poor results of repeated research, remain the main problems that prevent the widespread use of AD biomarkers in clinical practice. Factors such as the methods of sample processing, the detection techniques used, and the different populations may all affect the accuracy and stability of marker measurements. Therefore, it is necessary to set uniform technical rules in different practical scenarios and conduct sufficient verification. At the same time, it is also necessary to address core challenges such as cost, availability of equipment, and related ethical issues (such as the notification and communication of test results) to ensure that this technology can be used fairly and effectively in clinical practice. Combining biomarker information from multiple aspects such as body fluids, imaging, genetics and digital health with artificial intelligence and machine learning technologies is expected to further enhance the accuracy of AD screening and management. Such integrated methods help achieve more comprehensive risk stratification, early identification and dynamic disease monitoring, thereby laying the foundation for individualized prevention and precise intervention, and ultimately improving the treatment effect of patients and rationally allocating AD medical resources. Acknowledgments The author extends sincere thanks to Dr Luo for his feedback on the manuscript. Conflict of Interest Disclosure The author affirms that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References AlMansoori M., Jemimah S., Abuhantash F., and AlShehhi A., 2024, Predicting early Alzheimer’s with blood biomarkers and clinical features, Scientific Reports, 14(1): 6039. https://doi.org/10.1038/s41598-024-56489-1 Altomare D., Stampacchia S., Ribaldi F., Tomczyk S., Chevalier C., Poulain G., Asadi S., Bancila B., Marizzoni M., Martins M., Lathuilière A., Scheffler M., Ashton N., Zetterberg H., Blennow K., Kern I., Frias M., Garibotto V., and Frisoni G., 2023, Plasma biomarkers for Alzheimer’s disease: a field-test in a memory clinic, Journal of Neurology Neurosurgery and Psychiatry, 94: 420-427. https://doi.org/10.1136/jnnp-2022-330619 Arafah A., Khatoon S., Rasool I., Khan A., Rather M., Abujabal K., Faqih Y., Rashid H., Rashid S., Ahmad S., Alexiou A., and Rehman M., 2023, The future of precision medicine in the cure of Alzheimer’s disease, Biomedicines, 11(2): 335. https://doi.org/10.3390/biomedicines11020335 Arslan B., Zetterberg H., and Ashton N., 2024, Blood-based biomarkers in Alzheimer’s disease-moving towards a new era of diagnostics, Clinical Chemistry and Laboratory Medicine, 62: 1063-1069. https://doi.org/10.1515/cclm-2023-1434 Ashton N., Janelidze S., Mattsson-Carlgren N., Binette A., Strandberg O., Brum W., Karikari T., González-Ortiz F., Di Molfetta G., Meda F., Jonaitis E., Koscik R., Cody K., Betthauser T., Li Y., Vanmechelen E., Palmqvist S., Stomrud E., Bateman R., Zetterberg H., Johnson S., Blennow K., and Hansson O., 2022, Differential roles of Aβ42/40 p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring, Nature Medicine, 28: 2555-2562. https://doi.org/10.1038/s41591-022-02074-w Bhalala O., Watson R., and Yassi N., 2024, Multi-omic blood biomarkers as dynamic risk predictors in late-onset Alzheimer’s disease, International Journal of Molecular Sciences, 25(2): 1231. https://doi.org/10.3390/ijms25021231 Blennow K., and Zetterberg H., 2018, Biomarkers for Alzheimer's disease: current status and prospects for the future, Journal of Internal Medicine, 284 643-663. https://doi.org/10.1111/joim.12816 Bouteloup V., Pellegrin I., Dubois B., Chêne G., Planche V., and Dufouil C., 2024, Explaining the variability of Alzheimer disease fluid biomarker concentrations in memory clinic patients without dementia, Neurology, 102(8): e209219. https://doi.org/10.1212/wnl.0000000000209219 Chae H., Kim H., Kim Y., Ji H., Oh E., and Yang D., 2025, Diagnostic performance of eight blood-based biomarkers in a well-characterized Korean cohort of preclinical Alzheimer’s disease, Annals of Laboratory Medicine, 45: 428-436. https://doi.org/10.3343/alm.2024.0498 Chang C., Lin C., and Lane H., 2021, Machine learning and novel biomarkers for the diagnosis of Alzheimer’s disease, International Journal of Molecular Sciences, 22(5): 2761. https://doi.org/10.3390/ijms22052761
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International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 214-223 http://medscipublisher.com/index.php/ijmms 214 Research Insight Open Access Using Regenerative Dressings in Chronic Wound Care, Molecular View of Healing Jianmin Liu Sinovac Biotech Co., Ltd., Haidian, 100193, Beijing, China Corresponding email: Jianminliu@sinovac.com International Journal of Molecular Medical Science, 2025, Vol.15, No.5 doi: 10.5376/ijmms.2025.15.0022 Received: 15 Jul., 2025 Accepted: 20 Aug., 2025 Published: 23 Sep., 2025 Copyright © 2025 Liu, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Liu J.M., 2025, Using regenerative dressings in chronic wound care, molecular view of healing, International Journal of Molecular Medical Science, 15(5): 214-223 (doi: 10.5376/ijmms.2025.15.0022) Abstract This study explored the role and molecular mechanism of regenerative dressings in chronic wound healing. Chronic wounds are difficult to heal due to persistent inflammation, oxidative stress and angiogenic disorders. Regenerated dressings are composed of natural, artificial or intelligent biomaterials, which accelerate tissue repair by regulating molecular signals, promoting cell growth and activating growth factors such as VEGF and TGF-β. The exosomes and micrornas released by these dressings can regulate intercellular communication and promote tissue regeneration. Experimental and clinical results show that this type of dressing can significantly accelerate healing and reduce inflammation. The combination of nanotechnology, stem cell therapy and precision medicine is expected to drive the development of regenerative dressings towards individualized and scar-free repair. Keywords Chronic wounds; Regenerative dressings; Molecular healing; Angiogenesis; Biomaterials 1 Introduction Chronic wounds usually refer to wounds that do not recover on time during the normal repair stage and persist for more than 4 to 6 weeks even with appropriate treatment. Such wounds include diabetic foot ulcers, lower extremity venous ulcers and pressure sores. The common characteristics are prolonged inflammation, weak cellular response and disruption of the local repair environment (Raziyeva et al., 2021; Raju et al., 2022). The incidence of chronic wounds is not low worldwide. Estimates show that approximately 2.21 out of every 1,000 people are affected by mixed-cause wounds, while the rate for chronic lower limb ulcers is about 1.51. With the aging of the population and the increase of diseases such as diabetes and obesity, their incidence and economic burden are still rising. Chronic wounds not only significantly reduce the quality of life of patients, but also bring heavy economic pressure to the global healthcare system. Effective wound healing is of great significance for restoring skin integrity, preventing infection and maintaining overall health. However, chronic wounds are often characterized by slow healing, high risk of infection, intense pain, limited mobility, and significant psychological and economic burdens (Han and Ceilley, 2017). Its formation mechanism is very complex, involving persistent inflammation, microbial membrane formation, insufficient vascular growth and abnormal immune system (Raziyeva et al., 2021; Cavallo et al., 2024). Due to the diverse types of wounds, numerous complications and the lack of unified treatment standards, there are great challenges in clinical management (Harding, 2022). Although there have been many research achievements in molecular and cellular mechanisms, many chronic wounds are still difficult to cure with traditional methods, which indicates the need to explore new treatment approaches (Mamun et al., 2024). This study will explore the role and principle of regenerative dressings in the treatment of chronic wounds. With the continuous progress of molecular biology, materials science and tissue engineering, the treatment directions for chronic wounds are also constantly being updated. Regenerated dressings can provide a moist and active environment and release drugs such as growth factors, stem cells or antibacterial substances to improve the wound environment and promote tissue repair. The emergence of this new type of dressing aims to address issues such as long-term inflammation, infection and low cell activity. Basic research and clinical results show that wound management is moving towards individualization and mechanism-oriented directions, which will help increase the healing speed and alleviate the global health burden caused by chronic wounds.
International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 214-223 http://medscipublisher.com/index.php/ijmms 215 2 Pathological and Molecular Basis of Chronic Wound Formation 2.1 Mechanisms of chronic inflammation and immune imbalance The main characteristic of chronic wounds is that the inflammatory response lasts for a long time and is abnormally regulated, which can disrupt the normal healing process. The inflammation of acute wounds can be controlled in time and is easy to repair, while chronic wounds remain in a state of severe inflammation all year round. Specifically, it is manifested as an increase in cytokines promoting inflammation (such as TNF-α and IL-1β), a higher activity of matrix metalloproteinases, and an excessive amount of reactive oxygen species (ROS) (Sousa et al., 2022). In addition, chronic wounds often have bacterial biofilms that constantly stimulate the immune system, prolonging the duration of inflammation and affecting healing (Raziyeva et al., 2021; Versey et al., 2021). Problems with the immune system caused by chronic wounds are often related to the inability of macrophages to function normally. Under normal circumstances, macrophages change from the pro-inflammatory M1 type to the restorative M2 type, helping to repair tissues. However, in wounds that have not healed for a long time, this transformation cannot be achieved. M1-type macrophages remain very active, thereby triggering persistent inflammation (Li et al., 2021). Meanwhile, immune cells such as neutrophils and mast cells either decrease in number or weaken in function, which further slows down wound healing (Raziyeva et al., 2021; Jabbari et al., 2025). This immune imbalance disrupts the microenvironment around the wound, causing immune cells to keep gathering and the tissue to be damaged, eventually slowing down the repair rate (Sousa et al., 2022). 2.2 Impaired cell function and delayed tissue repair Impaired cell function is an important pathological feature of chronic wounds, which affects various cells involved in repair. In chronic wounds, fibroblasts change from the type that helps with healing to the type with low activity, and their abilities to proliferate, move and secrete extracellular matrix (ECM) all weaken. The reduction in the number of keratinocytes, the slowdown in their movement speed and the increase in their death rate all slow down the process of re-epithelialization. Reduced numbers and impaired functions of endothelial cells and lymphocytes can also affect angiogenesis and nutrient delivery (Jabbari et al., 2025). Cellular aging, especially in the context of diabetes and aging, can amplify the above problems. Senescent cells gather on the wound surface, release pro-inflammatory molecules, resist apoptosis and inhibit regeneration, thereby maintaining inflammation. This kind of cellular imbalance caused by aging disrupts the wound environment, leading to reduced angiogenesis, limited ECM remodeling and delayed healing. Abnormal interactions among various cells form chronic cycles that are difficult to break, making traditional treatments ineffective (Yang et al., 2024). 2.3 The role of oxidative stress and microcirculation injury Oxidative stress is an important cause of chronic trauma. An appropriate amount of reactive oxygen species is beneficial for immune defense and signal transduction, but too much can harm cellular components, causing persistent inflammation and tissue damage (Hunt et al., 2024). Chronic wounds are generally accompanied by elevated levels of oxidative stress, weakened mitochondrial function and reduced protective heat shock proteins, which will cause more severe cell damage and slow down the healing process (Jabbari et al., 2025). Problems such as diabetes, obesity and aging can also make oxidative stress more severe, make it difficult for the body to control oxidative responses, prolong inflammation and affect tissue repair (Ukaegbu et al., 2025). Abnormal microcirculation function also plays an important role. Insufficient angiogenesis and microvascular damage can restrict the delivery of oxygen and nutrients, causing local hypoxia, which in turn triggers more severe oxidative stress and hinders wound healing. Oxidative stress, immune disorder and microvascular injury interact with each other and constitute the key mechanism of chronic wound occurrence, forming a vicious cycle of tissue damage and difficult repair (Hunt et al., 2024). Therefore, intervention methods targeting oxidative stress and microcirculation are of great value for the recovery and regeneration of chronic wounds (Wang, 2025).
International Journal of Molecular Medical Science, 2025, Vol.15, No.5, 214-223 http://medscipublisher.com/index.php/ijmms 216 3 Molecular Regulation of Wound Healing 3.1 Cytokines and immune regulation in the inflammatory phase The inflammatory stage of wound healing is regulated by multiple cytokines and immune cells together. After injury, pro-inflammatory factors such as IL-1β, IL-6, TNF-α, as well as various chemokines, will be released rapidly, attracting neutrophils and monocytes to the wound site to clear necrotic tissue and resist infection (Cioce et al, 2024). These factors can not only initiate the immune response, but also promote the production of growth factors, laying the foundation for the subsequent repair process (Wong et al., 2025). The intensity and duration of these inflammatory signals need to be appropriately adjusted. If the inflammatory response is too intense or lasts for too long, it will interfere with the normal healing process and subsequently form chronic wounds (Raziyeva et al., 2021; Zhu, 2025). As the inflammatory phase progresses, anti-inflammatory factors such as IL-10 and IL-4 gradually gain the upper hand, helping to calm the inflammation and guide tissue repair (Allen, 2022). Macrophages are particularly crucial among them. They will change from pro-inflammatory type (M1) to repair type (M2) and secrete anti-inflammatory and pro-regeneration molecules (Cioce et al., 2024). When this conversion is blocked, for example, when m1 type is chronically active or the anti-inflammatory signal is insufficient, the wound is prone to be difficult to heal (Raziyeva et al., 2021; Sousa et al., 2022). Therefore, precisely regulating the immune response is the prerequisite for effective healing and also the core direction of regenerative therapy. 3.2 Proliferative angiogenesis and extracellular matrix remodeling During the proliferative phase, the key to tissue repair lies in the formation of new blood vessels and the reconstruction of the extracellular matrix (ECM). Angiogenesis can form new blood vessels to supply oxygen to tissues and is controlled by various growth factors such as VEGF, FGF, and TGF-β (Shi et al., 2023). Endothelial cells help form the capillary network through division and movement, while fibroblasts and keratinocytes promote granulation tissue growth and epidermal repair (Dikici et al., 2021). The interaction between inflammatory cells and pro-angiogenic signals helps the wound smoothly enter the tissue reconstruction stage from this period (Shi et al., 2023). The renewal of ECM relies on the generation and degradation of matrices such as collagen to provide scaffold support for new tissues. Fibroblasts are responsible for the production and arrangement of collagen, and matrix metalloproteinases (MMPs) and their inhibitors, together, maintain the stability of the matrix. Appropriate ECM remodeling is helpful for functional recovery, but too much or too little may cause fibrosis or slow down healing (Kim et al., 2022). Therefore, coordinating well with the processes of angiogenesis and ECM remodeling is of great significance for wound repair and the design of related dressings. 3.3 Signal pathways and tissue maturation mechanisms during the remodeling period Under the regulation of multiple signaling pathways, the main goal of the remodeling period is to make the newly formed tissues more mature and stable. At this stage, type III collagen is gradually replaced by type I collagen, tissue strength increases, and the structure also tends to be complete. Myofibroblasts and macrophages prevent excessive scar formation by secreting MMPs. MMPs are involved in ECM recombination and remove residual substances, while regulating the growth and death of excess cells (Cioce et al., 2024). The key signaling pathways include TGF-β, ERK and p38 MAPK, etc., which together regulate fibroblast function, collagen synthesis and matrix renewal. Anti-inflammatory factors such as IL-10 and TGF-β1 can help tissues grow better, completely eliminate inflammation, and also assist in the remodeling of normal scars. If these signals are unbalanced, it may cause abnormal healing, such as prolonged wound failure or excessive scar growth, which indicates that molecular regulation plays a key role in the later stage of healing (Kim et al., 2022). 4 Types and Characteristics of Recycled Dressings 4.1 Natural polymer materials Natural polymer dressings, such as those made from collagen, chitosan, hyaluronic acid, alginate and gelatin, are widely used in wound care due to their good biocompatibility, degradability and structural resemblance to human
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