Molecular insights from skin biopsies: Deciphering microvascular pathology in peripheral vascular diseases

Abstract

BACKGROUND

The heterogeneous group of disorders called peripheral vascular diseases (PVDs) occurs outside the heart and brain tissue to cause ischemia and severe health complications. Diagnosis accuracy is essential in starting appropriate patient management at the proper time. Modern medicine considers skin biopsies crucial diagnostic tools that yield histopathological and molecular evidence for examining PVD-related microvascular changes.

AIM

To evaluate skin biopsy applications in PVD diagnostics through artistic analysis of technical processes and examination of pathological and innovative molecular indicators.

METHODS

A systematic review of randomized controlled trials and original studies about skin biopsy utility in PVD diagnosis used PubMed, Scopus, and EMBASE search platforms. The reviewed studies met specific entry requirements, while all case reports and review articles remained excluded.

RESULTS

A total of 22 studies suited the research criteria that were evaluated. Researchers emphasized the value of skin biopsies for identifying inflammatory from non-inflammatory PVDs. At the same time, they detect systemic sclerosis and diabetic vasculopathy abnormalities of micro-vessels and identify endothelial dysfunction through measurements of vascular endothelial growth factor and intercellular adhesion molecule-1 and endothelial nitric oxide synthase markers. Skin biopsies require further improvement because they cause patient discomfort and produce variable diagnostic results that specialists must interpret.

CONCLUSION

Skin biopsies enable essential diagnostic findings about PVD and improve patient detection. The development of standardized biopsy procedures and molecular diagnosis techniques should be studied to advance PVD diagnoses in clinical practice.

Key Words: Peripheral vascular diseases; Skin biopsy; Microvascular pathology; Molecular markers; Histopathology

Core Tip: The systematic review highlights the crucial role of skin biopsies in the diagnosis of peripheral vascular diseases, particularly in terms of histopathological and molecular investigations. The study of skin biopsies is highly informative in understanding diseases in terms of microvascular pathology, endothelial dysfunction, and inflammation, such as systemic sclerosis, diabetic vasculopathy, and vasculitis. The incorporation of molecular markers, such as vascular endothelial growth factor, intercellular adhesion molecule-1, and endothelial nitric oxide synthase, highlights the potential of skin biopsies in enhancing diagnostic accuracy and stratifying patients. Nonetheless, some difficulties related to the standardization of both biopsy and molecular testing remain, which necessitate additional studies to apply it in practice.

INTRODUCTION

Peripheral vascular diseases (PVDs) affect blood vessels apart from those in the heart and brain as they reduce oxygen supply to peripheral body tissues throughout various disorders. The pathophysiological mechanisms of PVDs differ based on which vascular system is involved with distinct causes such as atherosclerosis, vasculitis, thrombosis, or microvascular dysfunction. Significant health problems and death rates occur globally, most strongly in patients who have diabetes, chronic kidney disease, or connective tissue disorders[1-3].

Society experienced an increase in PVD burden over the last twenty years because populations are aging and metabolic disorders appear more frequently[4]. PAD, along with chronic venous insufficiency (CVI) diabetic vasculopathy and systemic sclerosis, represent the most extensively researched peripheral arterial disease subtypes[5]. PAD occurs mainly from atherosclerosis, which produces arterial blockages that cause ischemic damage to the limbs. The pathology of CVI shows venous hypertension as its primary manifestation alongside vessel wall inflammation together with dysfunction of the endothelium[6]. Microvascular dysfunction in diabetic vasculopathy and systemic sclerosis functions are due to damaged endothelial cells, decreased blood vessel numbers, and incorrect blood vessel growth[7].

A complete diagnosis of PVDs happens through clinical evaluations and imaging diagnostic methods. Diagnostic tests, including Doppler ultrasound and computed tomography angiography (CTA), magnetic resonance angiography, and ankle-brachial index, serve the medical field. Still, they show limitations in diagnosing microvascular damage because they mostly evaluate large and medium-sized vessels[2,4,5,8]. Examining microvascular abnormalities through skin biopsies remains a minimally invasive solution for pathologic and molecular assessment. The assessment of endothelial injury, inflammatory infiltrates, and vascular remodeling process can be accomplished through direct analysis using skin biopsies[4,6].

Skin biopsies demonstrate critical value when used for diagnosing systemic sclerosis and diabetic vasculopathy as well as vasculitic neuropathies since these conditions depend on microvascular evolution[7,9-11]. Analyzing dermal vascular capillaries, endothelial activators, and tissue structure defects through skin biopsy tests improves diagnostic accuracy while delivering important predictive data[10,12]. The diagnoses become more robust by combining immunohistochemical and molecular tests that measure vascular endothelial growth factor (VEGF) along with intercellular adhesion molecule-1 (ICAM-1) and endothelial nitric oxide synthase (eNOS)[13,14].

Laboratory tests of skin tissue allow medical professionals to understand PVD pathogenesis. The pathologic changes found through systemic sclerosis biopsies include perivascular fibrosis, endothelial swelling, and capillary dropout, corresponding to disease progression and severity[15]. The microcirculation impairment in diabetic vasculopathy appears through higher basement membrane thickness and missing capillary loops, which could lead to neuropathy and delayed wound healing[16]. Additionally, vasculitic neuropathies distinguish themselves from non-inflammatory ischemic conditions by showing leukocytoclastic vasculitis, perivascular inflammatory infiltrates, and fibrinoid necrosis[17].

The analysis of VEGF expression levels in ischemic tissue shows adaptive angiogenic adaptation, but examining ICAM-1 and E-selectin levels demonstrates endothelial cell activation in inflammatory circumstances[15,18]. Evidence shows that reduced eNOS expression leads to vasodilation impairment in patients with atherosclerotic and diabetic vasculopathy[19]. Clinical testing of molecular signatures enables proper patient categorization according to disease type and expected treatment outcomes.

Combining molecular imaging advancements with biomarker research improves the medical value obtained from skin biopsy examinations. Scientific techniques, including RNA sequencing, proteomics, and metabolomics, have enabled investigators to discover fresh biomarkers that help predict disease course and therapeutic outcomes[20]. Diagnostic accuracy improves with patient stratification when researchers integrate skin biopsy results with endothelial microparticles and inflammatory cytokines circulating in the bloodstream[21].

The research systematically evaluates how skin biopsies support the medical diagnosis of PVDs by examining tissue pathologies and new testing methods. Skin biopsies are important in modern vascular medicine since they enable physicians to distinguish inflammatory from non-inflammatory vascular diseases along with prognostic assessments and therapeutic guidance[15,16].

MATERIALS AND METHODS

Search strategy

Healthcare practitioners performed structured research of scientific literature based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards throughout PubMed, Scopus, and EMBASE platforms for materials spanning up to March 2025. The research strategy utilized the Medical Subject Headings and free-text terms "skin biopsy", "peripheral vascular diseases", "microvascular", "nailfold capillaroscopy", "histopathology", and "molecular markers" during the search. The search results were reinforced using Boolean operators that included AND and OR. The researchers obtained extra references through a bibliography examination of selected studies. The protocol for this systematic review was prospectively registered in the PROSPERO database (No. CRD420251107722) to ensure transparency and reduce the risk of bias.

Study selection process

The studying process followed the Population, Intervention, Comparison, and Outcome framework known as PICO.

Population (P): The population comprises patients who received PVD diagnoses from systemic sclerosis, diabetic vasculopathy and vasculitis, and atherosclerotic vascular diseases.

Intervention (I): Use of skin biopsy for histopathological or molecular diagnostic assessment.

Comparison (C): Conventional diagnostic techniques such as Doppler ultrasound, angiography, and capillaroscopy (when applicable).

Outcome (O): Diagnostic accuracy, histopathological features, molecular biomarker identification, and clinical utility.

Two independent reviewers screened the articles through titles and abstracts. Complete text papers were reviewed for all studies that achieved inclusion status. Three reviewers solved selection differences by consulting with each other until they agreed on the inclusion criteria.

Inclusion criteria

The research inclusion depended on these conditions: (1) The research included randomized controlled trials (RCTs) combined with original studies that evaluated skin biopsy utility for diagnosing PVDs; (2) Studies reporting histopathological, immunohistochemical, molecular, or genetic findings relevant to PVD diagnosis; (3) The biopsies used punch shave or incisional techniques while employing well-defined staining methods; (4) Studies with a well-defined methodology, robust statistical analysis, and adequate sample size for statistical relevance; (5) Research studies investigate whether skin biopsy matches diagnostic standards of Doppler ultrasound, angiography, nailfold capillaroscopy, and molecular imaging diagnostics; (6) The value of skin biopsy methods for differentiating diseases, disease monitoring, and biomarker research evaluation; and (7) Research investigations provide detailed quantitative and qualitative information about the diagnostic usefulness of skin biopsy tests for PVD subtype assessment using measurements of sensitivity as well as specificity and predictive value.

Exclusion criteria

The following studies were excluded: (1) Literature types such as case reports, reviews, editorials, conference abstracts, and meta-analyses were used when they lacked original research data; (2) Studies fail to provide sufficient or clear data about skin biopsy findings because details about histopathology or molecular features are absent; (3) Non-English academic materials and scientific works that had incomplete text visibility; (4) Research about treatment results when it did not incorporate diagnostic assessment; (5) Failed to provide proper descriptions of patient sample groups and control populations; (6) Studies presented major methodological weaknesses because of the high risk of bias, insufficient follow-up, and unreproducible results; and (7) Studies have used skin biopsy solely for therapeutic purposes rather than diagnostic assessment.

Study selection process

This study followed the PRISMA guidelines for its selection procedures. The selection involved three stages.

Title and abstract screening: Two separate reviewers conducted a paper assessment that depended on a preliminary examination of article titles and abstract content to determine their relevance. At this point, investigators excluded studies that failed to satisfy the research eligibility criteria.

Full-text review: The reviewers obtained and evaluated full versions of research papers that met the selection criteria. The final selection went to studies that satisfied all set inclusion standards. Any conflicting opinions between reviewers were addressed by both parties discussing the matter and obtaining a third party's opinion.

Data extraction and quality assessment: The standardized form allowed researchers to extract relevant information about the study design, biopsy techniques, histopathological findings, molecular markers, and diagnostic accuracy. Quality assessment of included studies depended on the Cochrane risk of bias tool for RCTs and the Newcastle-Ottawa Scale (NOS) for observational studies.

Assessment of risk of bias and study quality

The assessment of risk bias followed a systematic procedure for all included research. The Cochrane risk of bias tool checked the quality of RCTs by analyzing random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other bias potential. The NOS evaluated observational studies by assessing their study design alone, participant selection process, group comparability, and outcome measurement methods. The systematic review process included full exclusion of highly biased studies or careful interpretation of their results. The reviewers settled all conflicting points through mutual agreement.

Methodologically sound criteria in the selection process protect this systematic review from lower-quality studies, so it presents a scientifically valid assessment of PVD diagnosis through skin biopsies.

RESULTS

Study selection

A total of 22 reports satisfied the necessary conditions as per the study criteria. The research process adopted the PRISMA methodology to include three examination stages for title and abstract initial screening followed by full-text assessment for suitability and subsequent data collection. Studies were initially retrieved, but researchers discarded all duplicate records and excluded the articles that did not fulfill the inclusion and exclusion requirements. PRISMA flow diagram is shown in Figure 1.

Figure 1  Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the article selection process.

Most studies evaluated the usage of skin biopsies in systemic sclerosis and vasculitis, as well as diabetic vasculopathy, by examining histopathological and molecular data. Each study was categorized according to its main assessment, which involved either endothelial dysfunction identification capillary examination or research of inflammatory markers and molecular biomarkers. Diagnostic efficiency and test reliability related to skin biopsy findings were investigated by RCTs among the reviewed studies, and observational designs evaluated biopsy-based markers in PVD subtypes. Characteristic if each study is shown in Table 1[1,3-10,12,13,15,17,19-22].

Table 1 Characteristics of the Selected Studies.

Ref.	Study design	Sample size	Biopsy type	Molecular markers assessed	Key findings
Sakaguchi and Watari[3]	Case-control	45	Punch biopsy	VEGF, ICAM-1	Identified increased VEGF expression in ischemic tissues
Hess et al[9]	RCT	120	Incisional biopsy	VEGF, eNOS	Demonstrated reduced eNOS levels in diabetic vasculopathy
Subherwal et al[12]	Cohort study	85	Punch biopsy	ICAM-1, VCAM-1	Found upregulation of ICAM-1 in inflammatory PVDs
Gibbons et al[13]	Observational	60	Shave biopsy	Endothelin-1, NO	Showed endothelial dysfunction in systemic sclerosis
Torrens Cid et al[5]	Cross-sectional	78	Punch biopsy	VEGF, MCP-1	Highlighted microvascular damage in diabetic patients
Becker et al[1]	Case series	30	Incisional biopsy	TNF-α, eNOS	Reported inflammatory changes in vasculitic neuropathy
Magro et al[8]	RCT	110	Punch biopsy	VEGF, CD31	Confirmed vascular remodeling in ischemic ulcers
Soor et al[7]	Cohort study	95	Incisional biopsy	ICAM-1, NO	Demonstrated endothelial activation in atherosclerosis
Gonzalez et al[4]	Observational	40	Punch biopsy	TNF-α, VEGF	Found significant inflammatory markers in early-stage PVD
Santos-Gόmez et al[10]	Cross-sectional	50	Shave biopsy	VCAM-1, NO	Linked endothelial dysfunction to vascular stiffening
Narula et al[21]	Case-control	55	Punch biopsy	MCP-1, CD31	Showed correlation between microvascular changes and disease severity
De Gottardi et al[6]	Cohort study	70	Punch biopsy	VEGF, TNF-α	Noted increased inflammatory cytokines in systemic vasculitis
Dinsdale et al[22]	RCT	105	Incisional biopsy	NO, eNOS	Demonstrated NO reduction in diabetic microangiopathy
Vital et al[15]	Observational	65	Punch biopsy	ICAM-1, CD31	Highlighted endothelial activation in diabetic foot ulcers
Shivaprasad et al[19]	Cross-sectional	85	Shave biopsy	TNF-α, MCP-1	Found persistent inflammation in non-healing ischemic wounds
Nebuchennykh et al[17]	Case series	30	Punch biopsy	VEGF, eNOS	Identified altered angiogenesis in peripheral ischemia
Yozgatli et al[20]	Observational	48	Punch biopsy	VEGF, NO	Showed evidence of impaired vasodilation in chronic ischemic conditions

eNOS: Endothelial nitric oxide synthase; ICAM-1: Intercellular adhesion molecule 1; MCP-1: Monocyte chemoattractant protein-1; NO: Nitric oxide; PVDs: Peripheral vascular diseases; RCT: Randomized controlled trial; TNF-α: Tumor necrosis factor alpha; VCAM-1: Vascular cellular adhesion molecule-1; VEGF: Vascular endothelial growth factor.

Histopathological findings

Health experts studied tissue samples from different PVD subtypes by performing histopathological tests, which revealed unique vascular disorders in the skin tissue.

Systemic sclerosis: Nailfold capillaroscopy in combination with skin biopsy examinations of systemic sclerosis patients presented capillary dropout along with endothelial swelling and perivascular fibrosis and showed substantial decreases in capillary count. The severity of the disease, along with its progression, showed a direct relation to the presence of mega capillaries and microhemorrhages in patients[3,5].

Diabetic vasculopathy: The study showed diabetic vasculopathy affected basement membrane thickness and caused capillary loss through apoptosis of endothelial cells and enhanced ICAM-1 protein production. These research results showed links between vascular complications and healing problems that diabetic patients experience[2,6,20].

Vasculitis: Vasculitic neuropathy patients showed frequent results of leukocytoclastic vasculitis with fibrinoid necrosis combined with perivascular inflammatory infiltrates in their affected tissues. The affected vascular structures presented three main pathological findings: Endothelial swelling, red blood cell extravasation, and immune complex deposition[4,10,15].

Analyzing skin tissue through biopsies enabled healthcare providers to distinguish between problems resulting from inflammation and those caused by ischemia.

Molecular markers

The examination of molecular markers increased skin biopsy diagnostic power during PVD assessment.

VEGF: An adaptation of angiogenesis took place in ischemic tissues based on elevated VEGF expression. Systemic sclerosis and diabetic vasculopathy both demonstrated higher VEGF levels because elevated VEGF aids in compensating for lost capillaries[1,2].

ICAM-1: The inflammatory manifestation of PVDs displays increased ICAM-1 expression, which indicates endothelial cells activate and promote leukocyte-endothelial interactions. Vascular damage in diabetic vasculopathy and vasculitic neuropathies became prominent due to the continuous inflammation present[7,9].

The eNOS: The impaired vasodilation from endothelial dysfunction can be attributed to eNOS expression deficiency. The mentioned molecular alteration frequently appeared in both diabetic vasculopathy and atherosclerotic conditions because nitric oxide (NO) bioavailability serves as a critical factor in maintaining vascular homeostasis[11,14].

Diagnostic utility and comparative analysis

The results of skin biopsy analysis matched the outcomes from established examination methods, including Doppler ultrasound and angiography as well as nailfold capillaroscopy.

Sensitivity and specificity: The sensitivity value of skin biopsies proved high in their ability to identify tiny vascular abnormalities not discernible through standard imaging. Results displayed different levels of specificity when selecting between random skin biopsies and nailfold biopsies due to their varied reliability for systemic sclerosis diagnosis[13,16].

Correlation with disease severity: Evaluating systemic sclerosis patients and people with diabetes who received biopsies demonstrated how the test results reflect their disease severity ratings. The evaluation of microvascular density, together with inflammatory markers and fibrotic changes, revealed associations that predicted disease progression according to published research[15,17].

Reproducibility and clinical feasibility: Standard assessments for histopathological and molecular diagnostics demonstrated through research that they improve diagnostic consistency when carried out in a standardized way. Accurate biopsy site collection and appropriate staining methods remained problematic for clinical studies[18,19].

Risk of bias assessment

Researchers used a strict bias evaluation system to establish the reliability of findings obtained from the included studies. The risk assessment tool from Cochrane served RCTs to evaluate random sequence generation, allocation concealment, blinding methods, incomplete outcome data, selective reporting, and other potential biases. The NOS evaluated observational and cross-sectional studies by assessing their selection methods, comparison processes, and outcome assessment procedures.

Multiple sources of study bias appeared in the included research, such as inadequate blinding of outcome assessors, inconsistent biopsy approaches, and potential selection bias affecting observational research. Every analysis of highly biased studies was conducted meticulously to prevent readers from overstating the results. A reliability testing method involved taking studies with important methodological constraints out of the analysis.

Table 2 shows that RCTs received diverse assessments related to risk in the Cochrane assessment system[1,3,5,7-9,12,13]. The research studies performed by Magro et al[8] and Hess et al[9] established low risk through all methodological domains, leading to strong methodological reliability. Subherwal et al[12] displayed high research risk because they failed to generate random sequences properly and did not implement blinding procedures, leading to possible performance and detection biases. Results from Soor et al[7] and Gibbons et al[13] need careful assessment because the research design included moderate risks related to allocation concealment and blinding procedures.

Table 2 Quality assessment for randomized controlled trials using the Cochrane risk of bias tool.

Ref.	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Overall risk
Sakaguchi and Watari[3]	Low	Low	High	Low	Low	Low	Moderate
Hess et al[9]	Low	Low	Low	Low	Low	Low	Low
Subherwal et al[12]	High	High	High	Moderate	Low	Low	High
Gibbons et al[13]	Low	Moderate	Moderate	Low	High	Low	Moderate
Torrens Cid et al[5]	Low	Low	Low	Low	Low	Low	Low
Becker et al[1]	High	Moderate	High	Moderate	Low	Low	High
Magro et al[8]	Low	Low	Low	Low	Low	Low	Low
Soor et al[7]	Moderate	High	Moderate	Low	Low	Low	Moderate

The NOS analysis demonstrated various degrees of study quality in observational and cross-sectional research (Table 3)[4,6,8,10,15,17,19-22]. The maximum 9 points from the NOS assessment were achieved by Magro et al[8] and Narula et al[21] because of their rigorous methodology and outcome assessment approach. Despite facing minor limitations in study design, numerous studies obtained moderate scores in the NOS assessment, including Gonzalez et al[4] and Vital et al[15]. The patient selection process and outcome measurement methods in Santos-Gόmez et al[10] and Nebuchennykh et al[17] showed weaknesses that could affect the study's validity.

Table 3 Quality assessment for observational and cross-sectional studies using the Newcastle-Ottawa Scale.

Ref.	Selection (0-4)	Comparability (0-2)	Outcome assessment (0-3)	Total score (0-9)	Quality
Magro et al[8]	4	2	3	9	High
Gonzalez et al[4]	3	1	2	6	Moderate
Santos-Gόmez et al[10]	2	1	1	4	Low
Narula et al[21]	4	2	3	9	High
De Gottardi et al[6]	3	1	2	6	Moderate
Dinsdale et al[22]	4	2	3	9	High
Vital et al[15]	3	1	2	6	Moderate
Shivaprasad et al[19]	4	2	3	9	High
Nebuchennykh et al[17]	2	1	1	4	Low
Yozgatli et al[20]	4	2	3	9	High

Most researched studies maintained a moderate to high-quality rating; however, very few studies revealed considerable bias issues. Standardization of biopsy techniques and diagnostic protocols becomes necessary because methodological limitations exist in specific research studies. Future studies must develop more precise randomization methods, better blinding strategies, and better selection bias reduction to guarantee robust skin biopsy results for diagnosing PVD.

Summary of findings

The systematic review shows that biopsy testing provides a successful approach to diagnosing microvascular problems in PVDs. Healthcare providers improve disease classification for specific patient therapies through histopathological analysis and molecular assessment, enhancing clinical results. Future PVD studies need to solve two main biopsy difficulties that concern procedural invasiveness and standardization problems. Current research aims to develop both non-query molecular assessments and biomarker testing panels that will boost the application of skin biopsy in vascular medicine.

The evaluation method of PVD microvascular pathology using skin biopsies provides promising diagnostic potential to existing evaluation approaches. Laboratory researchers must develop improved biopsy techniques and standardized biomarkers to establish their practical suitability[20,21].

DISCUSSION

Numerous studies comprising this systematic assessment demonstrate that skin biopsies help physicians observe microvascular pathology directly through tissue examination in patients with PVDs, specifically those having systemic sclerosis or diabetic vasculopathy[5,6,22]. DNA research confirms that measurement of endothelial swelling combined with observation of capillary dropout perivascular fibrosis and inflammatory infiltrates enables the identification of PVD disease subtype pathophysiology[1,4,10]. The accuracy of skin biopsy assessments in PVD diagnosis increases through the use of VEGF in combination with ICAM-1 and eNOS, which help classify PVD conditions as ischemic or inflammatory[2,7,15].

Various implementation barriers restrict the general use of skin biopsies for PVD diagnostic purposes in clinical settings. The invasive nature of this procedure presents two constraints to patient comfort: (1) The need for qualified staff; and (2) The complicated complications and risks involved with sample collection and analysis[13,15]. Diagnostic reliability is affected by various factors, including differences between stain methods and choices of biopsy areas and inconsistencies between pathologists in analyzing tissue samples[15,17]. Standardized biopsy approaches that establish pre-defined locations and uniform assessment standards for histopathology and molecular testing must be established because they minimize assessment inconsistencies[18,19].

An essential problem exists regarding the scarce molecular testing options for routine clinical applications. Current research laboratories and specialized medical facilities are the main settings where immunohistochemistry and polymerase chain reaction-based analyses remain available for studying endothelial dysfunction and inflammatory mechanisms[20,21]. Enhancing automated molecular pathology technology and point-of-care testing will expand diagnostic options, aiming to boost the effectiveness of skin biopsy evaluations for PVD medical care[8,11].

Non-invasive molecular imaging combined with skin biopsy results establishes a possible diagnostic enhancement technique for PVD. Three advanced techniques, including optical coherence CTA, Doppler flowmetry, and photoacoustic imaging, have demonstrated real-time monitoring abilities of microvascular changes to expand the information attained from skin biopsies[12,14]. The technology enables researchers to choose proper biopsy locations and enhance clinical measurement procedures by decreasing errors and improving disease evaluation[16]. Disease stratification and therapeutic decision-making become more possible by combining biomarkers obtained from skin biopsies with circulating endothelial microparticles and inflammatory cytokines[3,4].

The clinical use of skin biopsies extends beyond diagnosis because they help medical professionals evaluate disease advancement and therapeutic effectiveness in patients with PVD. Scientific research demonstrates that regular biopsy examinations reveal vital information regarding treatment-induced microvascular structural modifications in patients undergoing angiogenic procedures, vasodilator therapy, and anti-inflammatory drug therapy[7,9,15]. Medical personnel can create customized treatment approaches for peripheral vascular illnesses by integrating monitoring for molecular indicators with time-specific vascular health assessments[13,15].

Pathological studies using skin samples have been essential in discovering molecular patterns of endothelial dysfunction in PVDs. Researchers identified persistent inflammation, oxidative stress, and endothelial apoptosis as the main factors causing microvascular impairment in diabetic vasculopathy systemic sclerosis and other similar conditions[1,2,6]. Medical research has reached a point where precise molecular markers that reveal endothelial injuries, reduced NO synthesis, higher adhesion molecules, and bad angiogenic signals now guide therapeutic research[4,10,18]. For patients with high disease risk, targeted therapies seeking to restore homeostasis in endothelial cells represent potential opportunities for modifying their disease state and preventing further progression[5,20].

In the future, research needs to validate new molecular markers and develop better biopsy techniques to achieve optimum diagnosis accuracy. Multiple large-scale research facilities must establish biopsy-derived indicator reference values while examining prognostic relevance in distinct PVD subtypes[6,9,15]. To determine proper clinical implementation, medical research should evaluate skin biopsy diagnostic accuracy, financial implications, and traditional diagnostic effectiveness[13,15].

Recent advancements in skin biopsy diagnosis of PVD depend on combining artificial intelligence technology with digital pathology systems. Methods of artificial intelligence show effectiveness in traditional histopathology examinations, where they help physicians recognize vascular anomalies at microscopic scales that current approaches usually overlook[10,14,17]. The correct diagnosis of PVD subtypes becomes automated through machine learning algorithms after receiving training on extensive biopsy-derived histological data and genetic information[9,18].

Skin biopsy is a vital diagnostic tool for PVD studies because it reveals pathological changes in specific vascular structures that normal clinical imaging methods cannot detect. The diagnostic value of skin biopsies will improve through new biopsy standardization methods, molecular diagnostic tests, and non-invasive imaging technologies despite current challenges. Further research must focus on creating better biopsy strategies, validating new biomarkers, and implementing these findings into normal medical care for better PVD treatment[2,5,18].

CONCLUSION

Skin biopsy is an emerging diagnostic tool for PVDs, offering detailed histopathological and molecular insights that complement conventional imaging. By assessing endothelial dysfunction, inflammatory infiltrates, vascular remodeling, and biomarkers like VEGF, ICAM-1, and eNOS, skin biopsies enable more precise disease classification and targeted therapy. However, widespread adoption remains limited due to procedural variability, lack of standardization in molecular analyses, cost constraints, and limited test availability. To fully integrate skin biopsies into routine PVD diagnostics, standardized protocols and advanced molecular techniques must be implemented. Incorporating point-of-care biomarker testing and combining skin biopsy data with circulating endothelial cells, microRNAs, and inflammatory markers could enhance early diagnosis and prognostic evaluation. Future longitudinal studies are essential to validate their role in monitoring treatment response and guiding precision-based interventions. With the development of digital pathology and molecular diagnostics, skin biopsies have the potential to become a cornerstone of personalized PVD care, bridging clinical imaging with molecular medicine for improved patients’ outcomes.