ischemic stroke case study nursing

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This case study presents a 68-year old “right-handed” African-American man named Randall Swanson. He has a history of hypertension, hyperlipidemia and a history of smoking one pack per day for the last 20 years. He is prescribed Atenolol for his HTN, and Simvastatin for Hyperlipidemia (but he has a history of not always taking his meds). His father had a history of hypertension and passed away from cancer 10 years ago. His mother has a history of diabetes and is still alive.

Randall was gardening with his wife on a relaxing Sunday afternoon. Out of nowhere, Randall fell to the ground. When his wife rushed to his side and asked how he was doing, he answered with garbled and incoherent speech. It was then that his wife noticed his face was drooping on the right side. His wife immediately called 911 and paramedics arrived within 6 minutes. Upon initial assessment, the paramedics reported that Randall appeared to be experiencing a stroke as he presented with right-sided facial droop and weakness and numbness on the right side of his body. Fortunately, Randall lived nearby a stroke center so he was transported to St. John’s Regional Medical Center within 17 minutes of paramedics arriving to his home.

Initial Managment

Upon arrival to the Emergency Department, the healthcare team was ready to work together to diagnose Randall. He was placed in bed with the HOB elevated to 30 degrees to decrease intracranial pressure and reduce any risks for aspiration. Randall’s wife remained at his side and provided the care team with his brief medical history which as previously mentioned, consists of hypertension, hyperlipidemia and smoking one pack per day for the last 20 years. He had no recent head trauma, never had a stroke, no prior surgeries, and no use of anticoagulation medications.

Physical Assessment

Upon first impression, Nurse Laura recognized that Randall was calm but looked apprehensive. When asked to state his name and date of birth, his speech sounded garbled at times and was very slow, but he could still be understood. He could not recall the month he was born in but he was alert and oriented to person, time, and situation. When asked to state where he was, he could not recall the word hospital. He simply pointed around the room while repeating “here.”

Further assessment revealed that his pupils were equal and reactive to light and that he presented with right-sided facial paralysis. Randall was able to follow commands but when asked to move his extremities, he could not lift his right arm and leg. He also reported that he could not feel the nurse touch his right arm and leg. Nurse Laura gathered the initial vital signs as follows: BP: 176/82, HR: 93, RR: 20, T:99.4, O2: 92% RA and a headache with pain of 3/10.

Doctor’s Orders

The doctor orders were quickly noted and included:

-2L O2 (to keep O2 >93%)

– 500 mL Bolus NS

– VS Q2h for the first 8 hrs.

-Draw labs for: CBC, INR, PT/INR, PTT, and Troponin

-Get an EKG

-Chest X ray

-Glucose check

-Obtain patient weight

-Perform a National Institute of Health Stroke Scale (also known as NIHSS) Q12h for the first 24 hours, then Q24h until he is discharged

-Notify pharmacy of potential t-PA preparation.

Nursing Actions

Nurse Laura started an 18 gauge IV in Randall’s left AC and started him on a bolus of 500 mL of NS. A blood sample was collected and quickly sent to the lab. Nurse Laura called the Emergency Department Tech to obtain a 12 lead EKG.

Pertinent Lab Results for Randall

The physician and the nurse review the labs:

WBC 7.3 x 10^9/L

RBC 4.6 x 10^12/L

Plt 200 x 10^9/L

LDL 179 mg/dL

HDL 43 mg/dL

Troponin <0.01 ng/mL

EKG and Chest X Ray Results

The EKG results and monitor revealed Randall was in normal sinus rhythm; CXR was negative for pulmonary or cardiac pathology

CT Scan and NIHSS Results 

The NIH Stroke Scale was completed and demonstrated that Randall had significant neurological deficits with a score of 13. Within 20 minutes of arrival to the hospital, Randall had a CT-scan completed. Within 40 minutes of arrival to the hospital, the radiologist notified the ED physician that the CT-scan was negative for any active bleeding, ruling our hemorrhagic stroke.

The doctors consulted and diagnosed Randall with a thrombotic ischemic stroke and determined that that plan would include administering t-PA. Since Randall’s CT scan was negative for a bleed and since he met all of the inclusion criteria he was a candidate for t-PA. ( Some of the inclusion criteria includes that the last time the patient is seen normal must be within 3 hours, the CT scan has to be negative for bleeding, the patient must be 18 years or older, the doctor must make the diagnosis of an acute ischemic stroke, and the patient must continue to present with neurological deficits.)

Since the neurologist has recommended IV t-PA, the physicians went into Randall’s room and discussed what they found with him and his wife. Nurse Laura answered and addressed any remaining concerns or questions.

Administration

Randall and his wife decided to proceed with t-PA therapy as ordered, therefore Nurse Laura initiated the hospital’s t-PA protocol. A bolus of 6.73 mg of tPA was administered for 1 minute followed by an infusion of 60.59 mg over the course of 1 hour. ( This was determined by his weight of 74.8 kg).  After the infusion was complete, Randall was transferred to the ICU for close observation. Upon reassessment of the patient, Randall still appeared to be displaying neurological deficits and his right-sided paralysis had not improved. His vital signs were assessed and noted as follows: BP: 149/79 HR: 90 RR: 18 T:98.9 O2: 97% 2L NC Pain: 2/10.

Randall’s wife was crying and he appeared very scared, so Nurse John tried to provide as much emotional support to them as possible. Nurse John paid close attention to Randall’s blood pressure since he could be at risk for hemorrhaging due to the medication. Randall was also continually assessed for any changes in neurological status and allergic reactions to the t-PA. Nurse John made sure that Stroke Core Measures were followed in order to enhance Randall’s outcome.

In the ICU, Randall’s neurological status improved greatly. Nurse Jan noted that while he still garbled speech and right-sided facial droop, he was now able to recall information such as his birthday and he could identify objects when asked. Randall was able to move his right arm and leg off the bed but he reported that he was still experiencing decreased sensation, right-sided weakness and he demonstrated drift in both extremities.

The nurse monitored Randall’s blood pressure and noted that it was higher than normal at 151/83. She realized this was an expected finding for a patient during a stroke but systolic pressure should be maintained at less than 185 to lower the risk of hemorrhage. His vitals remained stable and his NIHSS score decreased to an 8. Labs were drawn and were WNL with the exception of his LDL and HDL levels. His vital signs were noted as follows: BP 151/80 HR 92 RR 18 T 98.8 O2 97% RA Pain 0/10

The Doctor ordered Physical, Speech, and Occupational therapy, as well as a swallow test.

Swallowing Screen

Randall remained NPO since his arrival due to the risks associated with swallowing after a stroke. Nurse Jan performed a swallow test by giving Randall 3 ounces of water. On the first sip, Randall coughed and subsequently did not pass. Nurse Jan kept him NPO until the speech pathologist arrived to further evaluate Randall. Ultimately, the speech  pathologist determined that with due caution, Randall could be put on a dysphagia diet that featured thickened liquids

Physical Therapy & Occupational Therapy

A physical therapist worked with Randall and helped him to carry out passive range of motion exercises. An occupational therapist also worked with Randall to evaluate how well he could perform tasks such as writing, getting dressed and bathing. It was important for these therapy measures to begin as soon as possible to increase the functional outcomes for Randall. Rehabilitation is an ongoing process that begins in the acute setting.

Day 3- third person 

During Day 3, Randall’s last day in the ICU, Nurse Jessica performed his assessment. His vital signs remained stable and WNL as follows: BP: 135/79 HR: 90 RR: 18 T: 98.9 O2: 97% on RA, and Pain 0/10. His NIHSS dramatically decreased to a 2. Randall began showing signs of improved neurological status; he was able to follow commands appropriately and was alert and oriented x 4. The strength  in his right arm and leg markedly improved. he was able to lift both his right arm and leg well and while he still reported feeling a little weakness and sensory loss, the drift in both extremities was absent.

Rehabilitation Therapies

Physical, speech, and occupational therapists continued to work with Randall. He was able to call for assistance and ambulate with a walker to the bathroom and back. He was able to clean his face with a washcloth, dress with minimal assistance, brush his teeth, and more. Randall continued to talk with slurred speech but he was able to enunciate with effort.

On day 4, Randall was transferred to the med-surg floor to continue progression. He continued to work with physical and occupational therapy and was able to perform most of his ADLs with little assistance. Randall could also ambulate 20 feet down the hall with the use of a walker.

Long-Term Rehabilitation and Ongoing Care

On day 5, Randall was discharged to a rehabilitation facility and continued to display daily improvement. The dysphagia that he previously was experiencing resolved and he was discharged home 1.5 weeks later. Luckily for Randall, his wife was there to witness his last known well time and she was able to notify first responders. They arrived quickly and he was able to receive t-PA in a timely manner. With the help of the interdisciplinary team consisting of nurses, therapists, doctors, and other personnel, Randall was put on the path to not only recover from the stroke but also to quickly regain function and quality of life very near to pre-stroke levels. It is now important that Randall continues to follow up with his primary doctor and his neurologist and that he adheres to his medication and physical therapy regimen.

Case Management

During Randall’s stay, Mary the case manager played a crucial role in Randall’s path to recovery. She determined that primary areas of concern included his history of medical noncompliance and unhealthy lifestyle. The case manager consulted with Dietary and requested that they provide Randall with education on a healthy diet regimen. She also provided him with smoking cessation information. Since Randall has been noncompliant with his medications, Mary determined that social services should consult with him to figure out what the reasons were behind his noncompliance. Social Services reported back to Mary that Randall stated that he didn’t really understand why he needed to take the medication. It was apparent that he had not been properly educated. Mary also needed to work with Randall’s insurance to ensure that he could go to the rehab facility as she knew this would greatly impact his ultimate outcome. Lastly, throughout his stay, the case manager provided Randall and his wife with resources on stroke educational materials. With the collaboration of nurses, education on the benefits of smoking cessation, medication adherence, lifestyle modifications, and stroke recognition was reiterated to the couple. After discharge, the case manager also checked up with Randall to make sure that he complied with his follow up appointments with the neurologist and physical and speech therapists,

• What risk factors contributed to Randall’s stroke?
• What types of contraindications could have prevented Randall from receiving t-PA?
• What factors attributed to Randall’s overall favorable outcome?

Nursing Case Studies by and for Student Nurses Copyright © by jaimehannans is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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Stroke Case Study (45 min)

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Mrs. Blossom is a 57-year-old female who presented to the Emergency Room with new onset Atrial Fibrillation with Rapid Ventricular Response (RVR). She is admitted to the cardiac telemetry unit after being converted to normal sinus rhythm with a calcium channel blocker (diltiazem). When you enter the room to assess Mrs. Blossom, her daughter looks at you concerned and says “mom’s acting kinda funny.”

What nursing assessments should be completed at this time?

• Full set of vital signs (Temp, HR, BP, RR, SpO2)
• Should probably get a 12-lead EKG
• Assess symptoms using PQRST or OLDCARTS

You assess Mrs. Blossom to find she has a left sided facial droop, slurred speech, and is unable to hold her left arm up for more than 3 seconds.

What is/are your priority nursing action(s) at this time?

• Call a Code Stroke (or whatever the equivalent is at your facility) to initiate response of the neurologist or Stroke team.
• Notify the charge nurse to help you obtain emergency equipment if you don’t already have it at the bedside to be prepared in case of emergency

What may be occurring in Mrs. Blossom?

• She may be having a stroke

You call a Code Stroke and notify the charge nurse for help. You obtain suction to have at bedside just in case. The neurologist arrives at bedside within 7 minutes to assess Mrs. Blossom. He notes her NIH Stroke Scale score is 32. He orders a STAT CT scan, which shows there is no obvious bleed in the brain.

What are the possible interventions for Mrs. Blossom at this time?

• Since there is no bleed evident on scan, Mrs. Blossom would qualify for a thrombolytic like tPA (alteplase) or for surgical intervention, as long as there are no contraindications

What are the contraindications for thrombolytics like tPA (alteplase)?

• Recent surgery, current or recent GI bleed within the last 3 months, excessive hypertension, evidence of cerebral hemorrhage

You administer tPA per protocol, initiate q15min vital signs and neuro checks. You stay with the patient to continue to monitor her symptoms.

What are possible complications of tPA administration? What should you monitor for?

• Bleeding, especially into the brain or a GI bleed
• She may bruise easily or bleed from IV sites or her gums
• Monitor for s/s bleeding or worsening stroke symptoms, which may indicate a hemorrhagic stroke has developed.

After 2 hours, Mrs. Blossom is showing signs of improvement. She is able to speak more clearly, though with a slight slur. She is still slightly weak on the left side, but is able to hold her arm up for 10 seconds now. Her NIHSS is now 6. Mrs. Blossom’s daughter asks you why this happened.

What would you explain has happened to Mrs. Blossom physiologically?

• Because of her new onset atrial fibrillation, the blood was likely pooling in her atria because they were just quivering and not contracting. When blood pools, it clots. When she was converted back into a normal rhythm and her atria began contracting again, that likely dislodged a clot, which went to her brain.
• The clot in her brain caused brain tissue to die → ischemic stroke.

Two days later, Mrs. Blossom has recovered fully. She will be discharged today on Clopidogrel and Aspirin, plus a calcium channel blocker,  with a follow up appointment in 1 week to see the neurologist.

What education topics should be included in the discharge teaching for Mrs. Blossom and her family?

• Anticoagulant therapy is imperative to prevent further clots from forming within Mrs. Blossom’s atria if she stays in Atrial Fibrillation.
• They should be taught the signs of a stroke (FAST) and call 911 if they notice them.
• They should be taught signs of Atrial Fibrillation with RVR and be sure to go to the hospital if this occurs – the patient is at higher risk for stroke.
• Medication instructions for calcium channel blockers and anticoagulants.

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Chapter 7:  10 Real Cases on Transient Ischemic Attack and Stroke: Diagnosis, Management, and Follow-Up

Jeirym Miranda; Fareeha S. Alavi; Muhammad Saad

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Case 1: Management of Acute Thrombotic Cerebrovascular Accident Post Recombinant Tissue Plasminogen Activator Therapy

A 59-year-old Hispanic man presented with right upper and lower extremity weakness, associated with facial drop and slurred speech starting 2 hours before the presentation. He denied visual disturbance, headache, chest pain, palpitations, dyspnea, dysphagia, fever, dizziness, loss of consciousness, bowel or urinary incontinence, or trauma. His medical history was significant for uncontrolled type 2 diabetes mellitus, hypertension, hyperlipidemia, and benign prostatic hypertrophy. Social history included cigarette smoking (1 pack per day for 20 years) and alcohol intake of 3 to 4 beers daily. Family history was not significant, and he did not remember his medications. In the emergency department, his vital signs were stable. His physical examination was remarkable for right-sided facial droop, dysarthria, and right-sided hemiplegia. The rest of the examination findings were insignificant. His National Institutes of Health Stroke Scale (NIHSS) score was calculated as 7. Initial CT angiogram of head and neck reported no acute intracranial findings. The neurology team was consulted, and intravenous recombinant tissue plasminogen activator (t-PA) was administered along with high-intensity statin therapy. The patient was admitted to the intensive care unit where his hemodynamics were monitored for 24 hours and later transferred to the telemetry unit. MRI of the head revealed an acute 1.7-cm infarct of the left periventricular white matter and posterior left basal ganglia. How would you manage this case?

This case scenario presents a patient with acute ischemic cerebrovascular accident (CVA) requiring intravenous t-PA. Diagnosis was based on clinical neurologic symptoms and an NIHSS score of 7 and was later confirmed by neuroimaging. He had multiple comorbidities, including hypertension, diabetes, dyslipidemia, and smoking history, which put him at a higher risk for developing cardiovascular disease. Because his symptoms started within 4.5 hours of presentation, he was deemed to be a candidate for thrombolytics. The eligibility time line is estimated either by self-report or last witness of baseline status.

Ischemic strokes are caused by an obstruction of a blood vessel, which irrigates the brain mainly secondary to the development of atherosclerotic changes, leading to cerebral thrombosis and embolism. Diagnosis is made based on presenting symptoms and CT/MRI of the head, and the treatment is focused on cerebral reperfusion based on eligibility criteria and timing of presentation.

Symptoms include alteration of sensorium, numbness, decreased motor strength, facial drop, dysarthria, ataxia, visual disturbance, dizziness, and headache.

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This presents an analysis of a case of Ischemic stroke in terms of possible etiology, pathophysiology, drug analysis and nursing care

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Ischemic stroke: A case study

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Ischemic Stroke

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Patient M is an active woman, 70 years of age, who lost consciousness and collapsed at home. Her daughter, who was visiting her at the time, did not witness the collapse but found her mother on the floor, awake, confused, and slightly short of breath. The daughter estimated that she called EMS within 5 minutes after the collapse, and EMS responded within 15 minutes. EMS evaluated Patient M, drew blood for a glucose level, and determined that she may have had a stroke. They notified the nearest designated comprehensive stroke center that they would be arriving with the patient in approximately 20 minutes. Patient M's daughter accompanied her.

The triage and transportation of an individual with suspected stroke should be similar to that for an individual with serious trauma, and treatment is recommended within 3 hours after the onset of stroke. Because of the limited time available for assessment and diagnosis before optimal treatment, the EMS dispatcher should notify EMS personnel immediately and coordinate transport of the individual to the closest emergency facility, preferably one that is a designated primary (or comprehensive) stroke care center.

On presentation in the emergency department, Patient M is immediately triaged. Because Patient M is still somewhat confused, her daughter is asked to provide information on the patient's history. The daughter reports that her mother had had an episode of sudden-onset numbness and tingling in the right limb, with slight confusion and slurred speech, 3 days previously. The episode lasted only 5 minutes, and Patient M had not called her primary care physician. Additional information provided by the daughter indicates that Patient M has been treated for hypertension for 10 years but notes that she is often not compliant with her antihypertensive medicine, a diuretic. The patient has never smoked, drinks occasionally, and is of normal weight.

Patient M has two significant risk factors for stroke; one is a long history of hypertension. More than two-thirds of individuals older than 65 years of age are hypertensive, and it is important for individuals with hypertension to have regular blood pressure screening and to maintain a blood pressure of less than 140/90 mm Hg. Antihypertension therapy has been found to reduce the incidence of stroke by 30% to 40%. Patient M's noncompliance with her antihypertension medicine likely includes her among the 65% of known hypertensive individuals in whom blood pressure is not controlled.

Patient M's previous episode of numbness, confusion, and slurred speech appears to be evidence of a TIA, another substantial risk factor for stroke. Research has shown that approximately 5% of patients will have an ischemic stroke within 7 days after a TIA. In addition, the risk of stroke within 7 days is doubled for patients with TIAs who did not seek treatment. As is the case for many individuals who have a TIA, Patient M did not seek medical attention because the clinical symptoms resolved quickly. However, research findings indicate that urgent treatment should be provided for TIAs, as early treatment for TIA and minor stroke has been shown to reduce the risk of early recurrent stroke by 80%.

On physical examination, Patient M's blood pressure is 150/95 mm Hg. She has pain in her left arm and a slight headache. There is a focal carotid bruit on the right. She is assessed with use of the NIHSS and found to have 1/5 weakness in the left upper and lower extremities and left visual/spatial neglect. The results of laboratory tests, including a complete blood count, prothrombin time, serum electrolyte levels, cardiac biomarkers, and renal function studies, are all within normal limits. CT of the head obtained about 45 minutes into her ED evaluation (1.5 to 2 hours since last well) indicates an occlusion in a branch of the right internal carotid artery with 50% narrowing due to atherosclerosis. An area of ischemia/infarction is visible in the right anterior cerebral hemisphere. There is no evidence of subarachnoid hemorrhage. Approximately 2.5 to 3 hours after Patient M collapsed at home, she is treated with IV rt-PA at a dose of 0.9 mg/kg. Twenty-four hours later, aspirin antiplatelet therapy is started at an initial dose of 325 mg, and a maintenance dose of 75 mg per day.

Many of the patient's symptoms, including her loss of consciousness, shortness of breath, pain, and headache, are nontraditional symptoms of stroke. Studies have demonstrated that nontraditional symptoms are more prevalent among women, often leading to a delay in the evaluation for stroke. EMS personnel and clinicians should be aware of the potential for nontraditional symptoms in women and carry out a diagnostic evaluation addressing a suspicion of stroke.

Patient M is eligible for thrombolytic therapy with rt-PA according to evidence-based guidelines developed by the AHA/ASA: her blood pressure is lower than 185/110 mm Hg, the onset of symptoms is less than 3 hours prior to the start of treatment, and the laboratory values are within normal limits. Antiplatelet therapy with aspirin 325 mg daily (versus anticoagulant therapy with warfarin) is recommended for treatment of patients with stroke or TIA due to intracranial atherosclerosis with 50% to 99% occlusion. Antiplatelet therapy is not recommended as an adjunctive therapy within 24 hours of thrombolytic therapy.

When Patient M's condition is stabilized, her primary care physician and consultant neurologist provide a referral for stroke rehabilitation, and a multidisciplinary rehabilitation team is formed to assess her rehabilitative needs, recommend the proper rehabilitation setting, and develop a treatment strategy tailored to her specific needs that includes daily antiplatelet therapy. Patient M is again assessed with the NIHSS, and the score is 12. The patient's cognitive and communication skills are intact on evaluation with the FIM, with the exception of the previously documented left visual/spatial neglect. The assessment also includes evaluation of the patient's risk for complications. Because of her spatial neglect, she is screened with the Berg Balance Scale and the Stops Walking When Talking test. The score on the Berg Balance Scale is 43, and Patient M does stop walking to engage in conversation. Psychosocial assessment includes screening with the Center for Epidemiologic Studies Depression (CES-D) Scale, as well as review of the medical history and conversations with the patient and her children; no signs of depression are present.

Patient M's score of 12 on the NIHSS falls within the range (6 to 15) that indicates she is likely to benefit from rehabilitation. Evaluating a stroke survivor's risk of complications is an important component of the overall assessment, and among the most common complications are falls, deep vein thrombosis, pressure ulcers, swallowing dysfunction, bladder and bowel dysfunction, and depressive symptoms. In assessing the risk of complications, the Berg Balance Scale appears to be the most appropriate screen for patients who are likely to fall, and a score of less than 45 is associated with a likelihood of falling. The risk of a fall is also increased when a patient stops walking to talk, as Patient M did, during the Stops Talking When Walking test.

Screening for signs of depression is also essential, as depression affects approximately 33% of stroke survivors. Signs of depression are subtle and may be vague. Several screening tools are available, but there is no universally accepted tool for use in the post-stroke setting. The CES-D was chosen in this case because it is easy to administer, is useful in older individuals, and has been found to be effective for screening in the stroke population, except for individuals who have aphasia. The diagnosis of depression in stroke survivors should be based on sources in addition to a formal screening tool, such as a medical evaluation, patient self-report, observation of patient behavior, patient history, and staff reports of changes in behavior and motivation.

The rehabilitation team discusses the results of the assessment with Patient M's daughter and son, both of whom live about 45 minutes away from the patient. Together, the team and the family members explore options to determine the best approach to rehabilitation. A decision is made to transfer Patient M to an inpatient stroke unit, and a rehabilitation program is developed. The nurse on the team discusses the program with Patient M and her children and explains the course of rehabilitation and the expectations. Rehabilitation will focus on an exercise program consisting of aerobic exercise, strength training, stretching, and coordination and balance activities.

Early initiation of rehabilitation is a particularly strong predictor of improved outcome, and rehabilitation in a stroke unit has been associated with improved quality of life, survival, and functional status at 5 years compared with a general healthcare facility. No studies have demonstrated the superiority of one rehabilitation setting over another, and the inpatient setting was chosen primarily to ensure consistent care, given how far away Patient M's children live, and the limited support she otherwise has for healthcare needs. Decisions about the setting and program for rehabilitation should be shared with family members, and family and other caregivers should be provided with educational resources about the rehabilitation process.

The exercise program developed for Patient M is designed to help her regain the ability to independently carry out activities of daily living safely and to regain a functional level of ambulation. The benefits of an exercise program include increasing fitness, strength, and flexibility; improving function; preventing injuries and falls; and reducing the risk of recurrent stroke.

Patient M gradually resumes the ability to function independently, and after more than 2 weeks in the stroke rehabilitation unit, the score on the NIHSS has improved to 5. Before she is discharged to her home, the rehabilitation team provides instructions for exercises to continue at home and recommends moderate physical activity as a secondary prevention measure. The team also educates Patient M about the importance of maintaining a normal blood pressure through use of her antihypertension medication and lifestyle modifications. At a follow-up visit with her primary care clinician at 3 months, Patient M's blood pressure is 135/80 mm Hg, and she reports that she has been compliant with her antihypertension medicine and antiplatelet therapy and is functioning well at home.

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Nursing Care of patient Ischemic Stroke : Case Study

การพยาบาลผู้ป่วยโรคหลอดเลือดสมองตีบและอุดตัน: กรณีศึกษา.

• Pagamat Kongwicha Nonthai Hospital, Nakorn Rachasima Province

Cerebrovascular disease or Stroke is the second leading cause of death in the world and Thailand. Survivors have physical, mental, and social consequences such as disability, a burden on the family, loss of economic productivity. The cause is ischemic stroker is urgently treatment accessing and will be given by injecting recombinant tissue plasminogen activator (rt-PA) within 4.5 hours, so rapid delivery is an important factor in minimizing this effect. Stroke is the number 1 emergency disease among emergency and forensic accident department of Non Thai Hospital and number one in referrals to Maharat Nakhon Ratchasima Hospital. In between 2019 and 2023 had 172, 154,119, 135 and 139 cases, respectively, the coming by the Emergency Medical service (EMS) system within the response period within 8 minutes was 76.74%, 76.74%, 62.5%, 73.91% and 75.86% respectively. The study selected 1 stroke patient who was ischemic stroke and study in January to March 2021, the educational objective aimed to encourage stroke patients to receive quality and efficient services in the Stroke fast tract system. To improve the EMS response in time system, a case study of a 63-year-old Thai female patient who came for treatment on January 29, 2021 by the EMS service system with symptoms of weakness in her right and lower extremities, walking staggering, not speaking clearly, sent for treatment at the hospital. Great Brain radiograph There were no white patches or radiographs that were darker than normal. Received back for treatment in the hospital on January 30, 2021. The problem found was high blood pressure. high blood sugar levels, low potassium level also the right limb was weakness. She worried about getting sick. The doctor treated her with fluids, antiplatelet drugs, physical therapy, massage, compress, and provide nursing care. Consult a psychologist and nutritionist, morale boosting Results that physical, mental, and emotional disorders were gradually improve. The patient cooperates in the treatment plan as recommended by the multidisciplinary team. After providing nursing care, the patient's symptoms improved, shock none occurred, high blood sugar cured, none both of nausea and vomiting, no contractions, fatigue improved, and all looked good. High blood pressure was cured and slowdown into 130/70 -150/80 mmHg, Barthel Index increased. She stayed for 5 days of treatment and discharged. For caring acute stroke patients before the patient arrives at the hospital is important, also quickly symptom detection and access to a fast EMS service system and a quality service system would respond to reduce the impact on patients. Therefore, it should be used to adjust the service system to cover more all patients in the next period.

สุรเดช ดวงทิพย์สิริกุล, พรทิพย์ วชิรดิลก , ธีระ ศิริสมุด. รายงานการศึกษาสถานการณ์ บริการการแพทย์ฉุกเฉินและการพัฒนาคุณภาพปฏิบัติการฉุกเฉินผู้ป่วยโรคหลอดเลือดสมอง. [ม.ป.ท.]: [ม.ป.พ.]; 2565. หน้า 1-80.

สมศักดิ์ เทียมเก่า. อุบัติการณ์โรคหลอดเลือดสมองประเทศไทย. วารสารประสาทวิทยาแห่งประเทศไทย. 2565; 39(2): 39-46.

กองยุทธศาสตร์และแผนงาน สำนักงานปลัดกระทรวงสาธารณสุข. สถิติสาธารณสุข พ.ศ. 2564 [อินเตอร์เน็ต].; [ม.ป.ท.]: [ม.ป.พ.]; 2565. [เข้าถึงเมื่อ 30 ต.ค.2566]. เข้าถึงได้จาก https://bps.moph.go.th/new_bps/sites/default/files/2564.0.pdf

American Heart Association, A division of the American Stroke Association.[Internet] N.P.: Ischemic Stroke. American Heart Association. 2020. [cited 2023 Nov 6] Available from: https://www.stroke.org/en .

ทัศนีย์ ตันติฤทธิศักดิ์, ธน ธีระวรวงศ์, บรรณาธิการ. แนวทางการรักษาโรคหลอดเลือดสมองตีบหรืออุดตันสำหรับแพทย์. สถาบันประสาทวิทยา กรมการแพทย์. กรุงเทพฯ: ธนาเพรส.; 2562.

เยาวลักษณ์ โพธิดารา, ธัญญาสิริ ธันยสวัสดิ์. ผลของการใช้แบบประเมินผู้ป่วยภาวะวิกฤตตามแนวคิดแฟนคัสในกระบวนวิชาฝึกปฏิบัติการพยาบาล. พยาบาลสาร.2563; 47(2): 463-475.

ศุภร วงศ์วทัญญู. ทฤษฎีการพยาบาลของโอเร็ม . ใน ดลรัตน์ รุจิวัฒนากร และสาวิตรี พรสินศิริรักษ์ (ผู้รวบรวม), เอกสารการสอนวิชาบทนำวิชาชีพและมโนมติพื้นฐานทางการพยาบาล. [อินเตอร์เน็ต]: กรุงเทพฯ: โรงเรียนพยาบาลรามาธิบดี คณะแพทยศาสตร์โรงเรียนพยาบาลรามาธิบดี มหาวิทยาลัยมหิดล. 2564. [เข้าถึงเมื่อ 22 พฤศจิกายน 2566]. เข้าถึงได้จาก http://anyflip.com/quig/spms

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{{ (moduleVm.actions && moduleVm.changeStatus) ? moduleVm.status : '' }} Ischemic Stroke Management, Acute (Case Study)

Activity steps, description, learning objectives.

After completing this continuing education activity you will be able to:

• Identify the patient's prehospital symptoms as they relate to ischemic stroke.
• List priority diagnostic tests for a patient with ischemic stroke.
• Outline a plan of care to manage a patient with stroke to maximize neurologic function and minimize complications.

Learning Outcomes

Disclosures.

The authors and planners have disclosed that they have no significant relationship with, or financial interest in, any commercial companies pertaining to this learning activity.

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Peer-reviewed

Research Article

A qualitative study of stressors faced by older stroke patients in a convalescent rehabilitation hospital

Roles Formal analysis, Investigation, Methodology, Writing – original draft

* E-mail: [email protected]

Affiliation Department of Occupational Therapy, Tokyo Bay Rehabilitation Hospital, Narashino, Chiba, Japan

Roles Writing – review & editing

Affiliation Department of Occupational Therapy, Teikyo Heisei University, Toshima, Tokyo, Japan

Affiliation Department of Occupational Therapy, Saitama Medical Center, Kawagoe, Saitama, Japan

Affiliation Faculty of Human Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan

• Yuta Asada, 
• Kaori Nishio, 
• Kohei Iitsuka, 

• Published: August 26, 2024
• https://doi.org/10.1371/journal.pone.0309457
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This study aimed to explore the stressors experienced by older patients with stroke in convalescent rehabilitation wards in Japan. Semi-structured interviews were conducted with four stroke patients aged > 65 years who experienced a stroke for the first time in their lives. The interviews were analyzed using the Steps for Coding and Theorization method for qualitative data analysis. The results of the qualitative analysis demonstrated that patients experienced specific stressors, such as, difficulty in movement of the paralyzed hand, fear of stroke recurrence, and dietary problems. Some stressors were manageable through healthcare professionals’ active and sensitive communication strategies. These stressors were derived from the theoretical framework of “stressors related to hospitalization” and “stressors related to the illness”. Additional stressors emerged from the interaction between these two types within the theoretical framework. The results of this study contribute to a deeper understanding of the specific stressors experienced by older stroke patients during the recovery process.

Citation: Asada Y, Nishio K, Iitsuka K, Yaeda J (2024) A qualitative study of stressors faced by older stroke patients in a convalescent rehabilitation hospital. PLoS ONE 19(8): e0309457. https://doi.org/10.1371/journal.pone.0309457

Editor: Chinh Quoc Luong, Bach Mai Hospital, VIET NAM

Received: February 24, 2024; Accepted: August 13, 2024; Published: August 26, 2024

Copyright: © 2024 Asada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Stress is a nonspecific response of the body to external stimuli [ 1 ]. Stress varies as the stressors faced by individuals differ depending on their age, sex, and social role [ 2 ]. Stressors include physical, biological, chemical, psychological, and social factors. The accumulation of these stressors causes stress, which, if not adequately addressed, can lead to physical or mental health problems, such as cardiovascular disease and depression, respectively [ 3 ]. To prevent these stress-related diseases, it is imperative to identify and address the stressors.

Patients often face various stressors in inpatient settings as their physical and human environments differ significantly from those of their regular home settings [ 4 ]. As the length of the hospital stay increases, patients may become particularly vulnerable to stressors such as “concern for family” and “anxiety about financial situation” [ 4 ]. The severity of a stroke, the age of the patient, and the presence of underlying medical conditions are factors that tend to extend the duration of hospitalization [ 5 ]. The incidence of stroke increases with age and is more common among older adults [ 6 ]. Moreover, patients present with a variety of symptoms, such as motor paralysis and higher brain dysfunction, and their ability to perform activities of daily living (ADL) becomes more limited. In particular, convalescent rehabilitation hospitals have a prolonged hospital stay [ 7 ] as one of their goals is to help patients return to the community and their homes.

Much of what is known about stressors related to stroke involves the risk of stroke onset [ 8 , 9 ], and there are insufficient studies on the stressors faced by older stroke patients in hospitals. Clarifying these unspoken stressors can contribute to reducing the stress of hospitalization for older stroke patients during convalescent rehabilitation, meeting their true needs, and enriching their lives after discharge. Few studies have elicited patients’ true feelings regarding stressors in convalescent rehabilitation wards. The purpose of this study is to provide a deeper understanding of the specific stressors experienced by older stroke patients in convalescent rehabilitation wards during their hospital stay.

Materials and methods

We conducted a qualitative study and interviewed each participant separately. The interview transcripts were analyzed according to the “Steps for Coding and Theorization” method (SCAT), a sequential and thematic qualitative data analysis technique [ 10 – 12 ].

This study was conducted in accordance with the Consolidated Criteria for Reporting Qualitative Research (COREQ), a checklist designed to improve the transparency and reliability of qualitative research [ 13 ] (S1 Table in S1 File ).

Preparation for the study

The first author (hereafter, “the author”) is a M.S. student in comprehensive human sciences and male occupational therapist with six years of clinical experience in recovery rehabilitation. Before this study was conducted, the author reviewed the literature on SCAT, conducted an analysis, and attended a workshop for SCAT developers to deepen his understanding of the analysis methods to ensure the accuracy of the analysis [ 10 – 12 ].

Participants

Patients aged 65 years or older, experiencing stroke for the first time, and hospitalized in a recovery center were included in the study. Patients who had difficulty answering the interview questions owing to the effects of aphasia, hospitalized patients in the charge of an interviewer, patients diagnosed with dementia or psychiatric disorders, and patients who were hospitalized for a short period of approximately one month were excluded.

Patients were asked to cooperate in the study and fully informed about the purpose and significance of the study, research methods, voluntary nature of research cooperation and freedom to withdraw, and handling of personal information. Signing a consent form indicated patients’ willingness to cooperate in the study.

Interview procedure

Three interviews were conducted between June and November, 2022. The interviewer asked questions according to an interview guide. Semi-structured in-person interviews were conducted in a private room in the hospital that the author is affiliated with, involving the patients and interviewer only. The first interview was conducted at the time of hospital admission, and subsequent interviews were conducted several times, with a gap of approximately one month. The interviews were recorded with the participants’ consent using the voice recorder function of an iPad and transcribed afterwards. The interview transcripts were not returned to participants for comments or correction. The interviewer recited the patients’ statements to them and made efforts to confirm the content of the statements to ensure data accuracy.

The interview guide was developed based on a preliminary survey of two stroke patients to determine ease of response. The content of the interview guide was first explained to the participants through specific examples to help them fully understand the difference between “stress” and “stressors.” The guide began by explaining, through specific examples, what the stressors in this study were. To investigate the stressors faced by older stroke patients in recovery, we asked, “What comes to mind when you hear the term ‘stressors in hospitalization’?”

Data analysis

We predicted that the outcome of the interviews would be strongly influenced by the participants’ individual characteristics. Therefore, to obtain objective results, we used the SCAT technique that specializes in coding and theorization and can be applied to a small amount of data. The SCAT method consists of the following steps [ 10 – 12 ]:

Step 1: Focus words from within the interview texts.

Step 2: Words outside the text that can replace the words from Step 1.

Step 3: Words that explain the words in Step 1 and Step 2.

Step 4: Themes and constructs, including the process of writing a story and offering theories that weave the themes and constructs together.

As this study was designed to create multiple storylines from a single participant, we integrated those multiple storylines into a single storyline and wrote a theoretical description, ensuring no loss of chronological contextuality and individuality of the storylines. The data analysis and confirmation process were conducted by the author and three other authors who were not involved in the interview process.

Ethical considerations

This study was approved by the Ethical Review Committee (Approval No. 289–2) of Tokyo Bay Rehabilitation Hospital.

Basic attributes of the participants

Five participants who met the inclusion criteria were recruited for the study. One participant (female) was excluded owing to early discharge from the hospital on short notice. Thus, four patients (two male and two female) were included in the study. The participants’ average age was 79.3 years (range: 71–88 years). Their disabilities included cerebral hemorrhage (one patient) and cerebral infarctions (three patients).

The average duration of the series of 12 interviews was 20.3 minutes, ranging from 7.5 to 32.7 minutes.

Storyline and theoretical descriptions

In the sections below, the storylines and theoretical descriptions as well as quotes from each participant, are described.

Case 1: Mr. A, facing an inconvenient situation.

At the time of the first interview, Mr. A experienced stress owing to an inconvenient situation during hospitalization. He was unable to perform the activities he did before the onset of the disease, especially owing to the psychological burden caused by the inability to eat and drink according to his preferences. He also expressed dissatisfaction with the current situation, limitations in leisure-time activities, inconvenience of activities, and a sense of shame caused by assistance with bathing. Limited leisure-time activities resulted from challenges in moving his paralyzed hands. He specifically encountered difficulties in willingly engaging them to act. Furthermore, he was separated from his family as a result of hospitalization. Thus, he faced restrictions in eating and drinking luxury foods, lack of freedom in daily life, and lack of family time.

“ Not being able to do things freely is the biggest stressor. All in all, there’s nothing better than that. I can’t eat what I like, or drink a lot. Even if I have a computer, I can’t use my right hand. I can’t even do my own hobbies. And, it is still significant whether or not you have a wife nearby.”

At the time of the second interview, Mr. A experienced stress regarding eating and drinking, including dissatisfaction with the variety of meals compared to before the disease onset, and the psychological burden owing to meals not being replaced on a daily basis. This was also the minimum element that Mr. A looked for during hospitalization. Other stress factors included a feeling of disappointment owing to limited leisure-time activities, and feelings of activity limitation and resignation owing to the inability to walk independently.

“ The most important thing is the food. Anyway, there’s nothing to do, so at least a meal, you’d think, wouldn’t you? The food is different from when we’re at home. It doesn’t help that I can’t walk. And, I think it’s a bit hard not to have hobbies.”

At the time of the third interview, Mr. A expressed that his biggest stress factor was difficulty moving his paralyzed dominant hand. This significantly impacted his daily self-care, including toileting and grooming. He also encountered limitations in various leisure activities, such as reading books. Eating and drinking induced a significant psychological burden. He felt dissatisfied with the lack of variety in meals as he could not manage to eat as well as previously.

“ Whatever I do, my hands don’t work. For example, when you brush your teeth. It’s the same when you go to the toilet and wipe your bottom. I can’t use my right hand. Also, I like books and I want to read, but I can’t turn the pages. And, unlike in the past, I eat rice and side dishes every day. My eating habits have changed drastically.”

Case 2: Ms. B, facing stressors caused by communal living.

At the time of the first interview, Ms. B faced stressors related to basic lifestyle habits, such as falling asleep and toileting, in the hospital. Variations in individual lifestyles and environmental factors, like noise and room brightness, contributed to sleep deprivation in shared living arrangements. Furthermore, inadequate management of the paralyzed side during sleep led to anxiety and sleep deprivation. Problems related to toileting needs arose owing to overlap in toilet timings with roommates and assisted by staff of the opposite sex.

“ I sometimes have trouble sleeping well at night because of noises or brightness. Everyone is trying to go to the toilet before rehabilitation, so the timing is… And with male nurses, there was a bit of resistance to using the toilet. After all, in shared living arrangements, everyone has a different rhythm of life.”

During the second interview, Ms. B continued to face stress owing to communal living. Stressors included abnormal breathing noises caused by roommates when falling asleep, noise problems during roommates’ movements, and nocturnal awakenings caused by physical environmental factors such as differences in depth of sleep. Additionally, there were case of sleep problems caused by the staff’s response to a roommate’s problematic behavior, and case of nocturnal awakenings caused by noise from staff responses. Other issues included self-perceived persistent distress over defecation problems and dealing with defecation needs in a time-constrained environment, with a roommate.

“ Like last time, in shared living arrangements, everyone has a different rhythm of life, but it can’t be helped. Sleep, you know, because some people go to the toilet at night or early in the morning, so it’s quite noisy and you can’t sleep well. And the nurse puts the patient next to me to sleep, and there are all sorts of noises when she does that. We all have the same desire to go to the toilet before rehabilitation, so we don’t make it in time. Toilets are a perpetual problem.”

At the time of the third interview, Ms. B had problems with how he interacted with his roommates and stressors related to falling asleep at night. Ms. B was dissatisfied with differences in personal characteristics in communal living, and concerned about the deterioration of his relationship with his roommates over defecation. Furthermore, stress was caused by differences in lifestyle in communal living affecting sleep and awakening during the night owing to physical environmental factors such as noises made by roommates. Sudden changes in training hours also caused dissatisfaction.

“ Like how to communicate with people in the room. Like sleeping. Because of the lights and noise when my roommate goes to the toilet at night. Roommates have different living patterns. In rehabilitation, though, there were some questionable things like time changes.”

Case 3: Ms. C, facing an excrement problem and anxiety about stroke recurrence.

At the time of the first interview, Ms. C faced the problem of excrement in communal living. Dissatisfaction was caused by the suppression of excretory behavior and rejection of excretion in communal living, leading to anxiety. There were also conflicts and a psychological burden caused by the staff’s lack of information sharing, which led to restraining from defecating after unpleasant experiences.

“ I don’t like the situation of one toilet for four people. I and others are suffering. I thought it was hard. I didn’t know that you have to press the nurse call. Then I wished they had told me from the beginning. That was a bit of a shock.”

At the time of the second interview, Ms. C expressed dissatisfaction with their lack of independence in elimination. This led to a sense of aversion caused by dealing with the need to defecate frequently during the night and self-consciousness about requests for nighttime defecation assistance, which, in turn, led to resisting the need to defecate, a distressing experience unique to the patient.

“ I feel bad because I have to go to the toilet in the middle of the night. But I try to be patient. If it was during the day, I would ask the nurse to help me, but at night I would still feel sorry. It’s painful. You have to be experienced to understand.”

At the time of the third interview, Ms. C was anxious about the gap between their life at home after discharge and their life in the hospital and about the gradual decline of their brain functions. They also experienced anxiety owing to the fear of stroke recurrence and an undecided medical support system for the prevention of recurrence. These stressors were related to worry caused by a lack of information sharing by the staff and delays in sharing information about discharge from the hospital.

“ I have a little bit of anxiety about my future and my life. Because I’ve got comfortable here. And I don’t know what I would do if I fell ill again. No one is going to talk to me about it. I’m a bit worried about that. That’s what I’m most worried about.”

Case 4: Mr. D, facing a meal problem.

At the time of the first interview, Mr. D expressed their stress that they had to hold their toileting until the hospital staff arrived when they needed to defecate. This occurred as the hospital staff were extremely busy, and they experienced failure in excretory management. However, at the time of the interview, they were able to use the toilet independently.

“ I’ve had a leak before the nurse came. She can’t come right away, she’s too busy. It’s gone now.”

At the time of the second interview, Mr. D had a low appetite owing to low-temperature meals and refused to eat as a result of inappropriate meal temperature. Additionally, there were difficulties with grooming movements around the use of the wash basin and dealing with the need to defecate in communal living.

“ The rice and side dishes are cold. So I feel sorry to leave it. I can eat it beautifully when it’s warm. But when it’s cold, I just can’t. After the meal, I can’t wash my hands because some people wash their hands in their rooms first. When I want to go into the toilet, there are people ahead of me. It can’t be helped.”

In the third interview, Mr. D felt stress when the meal was not hot enough to eat and lost their appetite. He also felt stress when his mealtime was delayed as it that cause would take time for them to do their personal grooming after returning to their room where their roommate occupied t the wash basin.

“ Side dish is cold. Wish it was room temperature. I eat my meals late, so I’m the last one to go back to my room. So, I can’t wash my hands first.”

In this study, semi-structured interviews were conducted to identify the stressors faced by older patients with stroke during convalescent rehabilitation, throughout hospitalization; data analysis was conducted using SCAT.

Based on the storylines and theoretical descriptions, the stressors experienced by stroke patients were categorized into “stressors related to hospitalization” and “stressors related to the illness” [ 4 ].

Stressors related to hospitalization

The results of this study revealed that older stroke patients in convalescent rehabilitation face stressors related to ADLs, such as eating, sleeping, grooming, and toileting; leisure activities; problems with roommates in communal living; and inability to be with their family members. In this study, the first interview was conducted at the time of admission, and stressors were reported by all participants. Stress during hospitalization is caused by the fact that patients are forced to live a life with less freedom than before [ 4 ].

The psychological burden is particularly high for older adults as they have a reduced ability to adapt to changes in the external environment compared with younger patients [ 14 ]. In light of the above, older stroke patients may face a variety of stressors from the early stages of hospitalization compared with younger patients; therefore, intervention against these stressors is necessary from the early stages of hospitalization.

Factors such as relationships with roommates may lead patients to experience discomfort [ 15 ], and the way patients relate to their roommates is considered important. In this study, physical environmental factors caused by differences in lifestyle and the timing of toilet and wash basin use with roommates emerged as stressors. Additionally, these factors affected the participants’ ADL, such as grooming, toileting, and sleeping. Considering these findings, it is important for patients living together to consider each other’s needs. Therefore, it is necessary for patients to communicate with each other to deepen their understanding, and healthcare professionals are expected to play a role in building such relationships.

Furthermore, stressors such as meal variations and meal temperature emerged rather than stressors such as taste and preference. Older people tend to experience a decline in dietary variety owing to a decline in physical and oral functions and appetite [ 16 ]. Moreover, older patients undergoing treatment for cerebrovascular disease are more likely to experience changes in food preferences than younger patients [ 17 ], which is not consistent with the results of the present study. Given that the amount of food intake in a hospital setting is linked to the quality of food, including taste and the dining environment [ 18 , 19 ], there is a need for further research on qualitative aspects of meal preparation, such as food variations and appropriate temperatures. However, studies on meal variations and temperature are limited. In the future, these should be investigated in detail as characteristic stressors faced by older stroke patients during convalescent rehabilitation.

Stressors related to the disease

The results revealed that older stroke patients in rehabilitation face stressors such as difficulty moving the hand affected by motor paralysis, recurrent strokes, lack of information given by healthcare providers, and inappropriate actions or words of healthcare providers. Approximately 50% of stroke survivors experience unilateral motor paralysis [ 20 ]. Improvement in motor paralysis of the upper limbs and fingers contributes to greater independence in ADL [ 21 , 22 ]. It not only affects ADL but a wide range of activities, such as housework and leisure activities [ 23 , 24 ].

In this study, there were patients whose hobbies were limited by difficulty in moving the paralyzed hand. Additionally, based on the interviews at the time of admission, activity limitation caused by paralysis was a stressor faced from the time of admission itself. Therefore, early interventions and psychological support are needed for patients with paralysis.

A lack of information about the disease may also increase patient anxiety and cause dissatisfaction among healthcare providers [ 4 ]. Stroke recurs at a rate of 2.2% to25.4% within one year of disease onset, 12.9% within two years, and approximately 16% within five years [ 25 ]. Therefore, it is important to support stroke patients to prevent recurrence [ 26 ]. The participants were interviewed before discharge from the hospital about stressors such as recurrent stroke and lack of information provided by healthcare providers. This suggests that providing information to older patients with stroke undergoing convalescent rehabilitation to prevent recurrence is very important, especially for patients who are about to be discharged from the hospital, and that a lack of information can cause stress. Furthermore, communication between stroke patients and healthcare professionals does not always match [ 27 ]. Efforts should be made to prevent a lack of information, considering the patient’s cognitive function and the degree of higher brain dysfunction.

Additionally, stressors such as the personal care of patients by healthcare professionals of the opposite sex, and behaviors and words caused by misunderstandings on the part of healthcare professionals emerged. Patients may experience discomfort and high psychological distress owing to factors such as the attitudes and actions of healthcare workers [ 16 , 28 ]. An inadequate explanation or lack of consideration of shame may also arouse anger in patients [ 29 ]. Stroke patients are placed in a situation where they are prone to feelings of shame owing to assistance with ADL such as bathing and toileting. Therefore, healthcare professionals must be sensitive to patients when providing daily care. Stress can be prevented through appropriate attitude and information sharing.

Various symptoms, such as motor paralysis, sensory disturbance, higher brain dysfunction, and cognitive decline, appear as post-effects of stroke. The complex interplay between these symptoms causes a decline in the ability to perform ADL [ 30 – 32 ]. In this study, there were patients for whom difficulty in achieving independence in ADL was a stressor. Patients with higher levels of ADL independence had higher self-efficacy, and successful experiences were effective in forming self-efficacy [ 33 ]. This principle should be applicable to older stroke patients in convalescent rehabilitation hospitals. The positive outcomes of their hospital experience may be partially attributed to reduced stress.

Additionally, some patients faced limitations in self-care, stressors related to hospitalization owing to the aftereffects of stroke, and stressors related to illness. Given these findings, it was suggested that stroke patients may have been stressed by the interaction of “stressors related to the disease” and “stressors related to hospitalization.” However, if one of these stressors can be adequately addressed, it is likely that related stressors can be reduced.

Limitations

In conclusion, we clarified the stressors faced by older stroke patients in convalescent for rehabilitation. However, this study has some limitations. First, the study was severely limited by the small number of patients, which prevents us from drawing some important conclusions. The SCAT method can be used to analyze data from a small number of people because it provides a theoretical description from the participants’ storylines; however, the number of participants in this study was not sufficient to generalize the findings. Second, this study did not fully consider the participants’ individual characteristics, such as personality and background, nor did it analyze the patients in terms of their pathology and sequelae. Therefore, the results obtained should be interpreted carefully, as individual bias was not sufficiently eliminated. In future, it is necessary to select other participants and data analysis methods that consider participants’ individual characteristics and the aftereffects of stroke and recruit more participants to elucidate the stressors faced by older stroke patients in convalescent rehabilitation.

Stressors specific to older stroke patients were identified, including difficulty moving the paralyzed hand, recurrent stroke, and diet-related stressors. Stressors identified in this study can be broadly classified into “stressors related to hospitalization” and “stressors related to the disease,” consistent with previous studies [ 4 ]. However, it was found that stress is also caused by the interaction between “stressors related to hospitalization” and “stressors related to the disease.” To the best of our knowledge, thus far, no reports have identified the specific stressors faced by older stroke patients. Therefore, this study provides valuable information from a first-hand perspective that will lead to a deeper understanding of the specific stressors experienced by older stroke patients during recovery. Future studies should explore how various stressors lead to stress in older stroke patients at various types of rehabilitation hospitals.

Supporting information

S1 file. consolidated criteria for reporting qualitative studies (coreq): a 32-item checklist..

https://doi.org/10.1371/journal.pone.0309457.s001

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We thank all the participants who agreed to be interviewed for this study. We also thank the members of the Rehabilitation Science Degree Program, Graduate School of Comprehensive Human Sciences, University of Tsukuba, for their guidance and encouragement during this study.

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Targeted pathophysiological treatment of ischemic stroke using nanoparticle-based drug delivery system

• Wei Liu 1 , 2   na1 ,
• Lubin Liu 3   na1 ,
• Hong Li 4 ,
• Yutong Xie 3 ,
• Jialiang Guan 1 ,
• Hongzhao Qi 2 &
• Jinping Sun 1  

Journal of Nanobiotechnology volume  22 , Article number:  499 ( 2024 ) Cite this article

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Ischemic stroke poses significant challenges in terms of mortality and disability rates globally. A key obstacle to the successful treatment of ischemic stroke lies in the limited efficacy of administering therapeutic agents. Leveraging the unique properties of nanoparticles for brain targeting and crossing the blood–brain barrier, researchers have engineered diverse nanoparticle-based drug delivery systems to improve the therapeutic outcomes of ischemic stroke. This review provides a concise overview of the pathophysiological mechanisms implicated in ischemic stroke, encompassing oxidative stress, glutamate excitotoxicity, neuroinflammation, and cell death, to elucidate potential targets for nanoparticle-based drug delivery systems. Furthermore, the review outlines the classification of nanoparticle-based drug delivery systems according to these distinct physiological processes. This categorization aids in identifying the attributes and commonalities of nanoparticles that target specific pathophysiological pathways in ischemic stroke, thereby facilitating the advancement of nanomedicine development. The review discusses the potential benefits and existing challenges associated with employing nanoparticles in the treatment of ischemic stroke, offering new perspectives on designing efficacious nanoparticles to enhance ischemic stroke treatment outcomes.

Graphical Abstract

Introduction

Stroke represents a formidable challenge to global health, ranking as the world's second-leading cause of mortality and the primary cause of chronic disability. This condition poses a significant risk to patient safety and carries a substantial societal toll. With the global population aging, the incidence of stroke is on the rise, highlighting the pressing need for effective interventions and treatment strategies [ 1 ]. Among the various types of strokes, ischemic stroke (IS) is the most common, accounting for over 85% of cases. Characterized by acute and persistent cerebral ischemia and hypoxia, IS results in a detrimental disruption of brain blood circulation, leading to severe and often irreversible consequences [ 2 ].

Acute ischemic stroke (AIS) arises from the obstruction of blood flow in a cerebral artery due to a clot or embolus. This sudden blockage results in decreased perfusion to brain tissue, leading to reduced levels of oxygen, ATP, and glucose. Consequently, widespread neuronal death, brain tissue infarction, and subsequent neurological deficits ensue [ 3 ]. Although collateral circulation may offer partial compensation, it is often insufficient to salvage the entire ischemic injury area. The ischemic brain tissue can be categorized into two main regions: the ischemic core and the penumbra. The ischemic core, situated at the center of the injury, represents the most severely damaged area where nerve cells endure severe ischemia, leading to necrosis. Cells in the core zone have either perished or are nearing complete necrosis, rendering the damage irreversible. In contrast, the penumbra undergoes milder ischemia, where inadequate blood supply compromises normal neurophysiological function without prompting immediate cell death. Restoration of blood flow promptly allows cells in the penumbra to recover and regain normal function. Failure to restore blood flow promptly results in progressive degeneration and necrosis of neurons in the penumbra, ultimately contributing to the infarct core and worsening brain damage [ 4 ].

Recently, nanoparticle (NP)-based drug delivery systems have gained significant traction in biomedical applications as a result of their distinct physicochemical properties. These properties comprise their nano-scale dimensions, expansive surface area, and notable capacity for drug encapsulation, targeted delivery, and simultaneous administration of therapeutic agents. NPs also shield drugs from degradation, enable controlled release, extend circulation time, and diminish toxicity [ 5 , 6 ]. Consequently, diverse NP-based drug delivery systems, such as liposomes, micelles, dendrimers, nanogels, inorganic NPs, and natural NPs, have been investigated for therapeutic and diagnostic purposes in cerebral stroke [ 7 ]. The versatility of nanomaterials allows for customized design to meet specific therapeutic goals or modifications with various ligands and responsive linkers for intelligent drug delivery. This aids in their traversal across the blood–brain barrier (BBB), enhances drug accumulation in ischemic regions, and modulates drug release based on the pathological features of IS [ 8 ]. Research indicates that NPs, either independently or in conjunction with neuroprotective drugs, can effectively address challenges like short half-life, low water solubility, poor bioavailability, limited BBB permeability, and potential kidney and liver toxicity, thereby significantly improving the management of AIS [ 9 , 10 ]. This improvement encompasses promoting neuronal recovery, extending treatment windows, mitigating neuronal death in the ischemic penumbra, and enhancing patient prognosis. Moreover, NPs have substantially propelled the understanding of the pathogenesis of AIS and the creation of targeted pathophysiological treatments, ushering in new dimensions and innovative strategies for AIS management [ 11 , 12 ]. Overall, NPs show great promise in the treatment of IS, offering enhanced therapeutic approaches and better patient outcomes.

In this review, firstly, to intuitively grasp the current research focal points and trends of NPs in IS, we searched the Web of Science Core Collection for articles and reviews on the application of NPs in IS published from January 1, 2003 to February 29, 2024. Qualitative and quantitative analysis was conducted using CiteSpace and GraphPad prism 8 software. The results showed that 610 articles were included, and in the past 20 years, the number of publications on the study of NPs in IS has significantly increased (Fig.  1 A). The co-occurrence analysis of keywords showed the top ten most frequently occurring keywords. It is worth noting that, except for “ischemic stroke” and “nanoparticles”, “drug delivery”, “blood–brain barrier”, “cerebral ischemia” and “oxidative stress” are the most common keywords, indicating that they are currently the research hotspots of NPs in IS.

A Annual number of publications worldwide from January 1, 2003 to February 29, 2024. B The keyword co-occurrence analysis provides the top 10 keywords with co-occurrence frequency rankings. C Keyword co-occurrence analysis provides a centrality ranking of keywords. D Visualization of keyword co-occurrence analysis (The size of each node indicates the frequency of the word's occurrence in outputs, with larger circles representing higher frequencies. The thickness of the pink outer ring around each node signifies its centrality. The thickness of the connecting lines reflects the proximity of the relationship between two words)

(Fig.  1 B). In addition, keyword visualization shows the highest centrality in the BBB and drug delivery (Fig.  1 C). In short, considerable advancements have occurred in the past two decades within this research domain. The prominent focus in NP therapy for IS primarily revolves around enhancing drug delivery across the BBB. Secondly, the traditional treatment strategies for IS were reviewed, with a focus on its pathophysiological changes, as well as targeted therapy of NP-mediated drug delivery systems targeting specific pathological and physiological mechanisms of IS. Finally, we discussed the perspectives and prospects of NP-mediated delivery systems for the treatment of IS, providing insights into the future development of nanomaterial therapy for IS. In conclusion, we aspire for this comprehensive review to inspire researchers to purposefully design NP-based therapeutics based on the pathophysiological characteristics of IS, ultimately achieving effective treatment for this condition.

Traditional treatments for IS

Traditional treatments for IS encompass recanalization/reperfusion and neuroprotection, aiming to improve neurological outcomes [ 13 , 14 , 15 ]. Intravenous thrombolysis with rt-PA and mechanical thrombectomy are critical interventions for AIS, often used in combination to enhance efficacy and safety for selected patients (Fig.  2 ) [ 16 , 17 ]. Despite these advances, most patients are unable to benefit due to limitations such as narrow treatment time windows and adverse reactions. Research continues to focus on neuroprotective agents to extend treatment windows and promote recovery. Neuroprotective agents developed to enhance neuron survival post-IS, show promise in preclinical studies (Table  1 ) but have not demonstrated significant clinical benefits, primarily due to poor BBB penetration and inadequate animal model representation [ 18 , 19 ]. Pharmacotherapy for IS, including reperfusion and neuroprotective strategies, is vital for neuroprotection and brain function restoration but faces drawbacks such as poor solubility, short half-lives, toxicity, and low bioavailability. Monotherapies are inadequate for IS's complex pathophysiology, necessitating higher doses and combination therapies. Moreover, the BBB hinders effective drug delivery to ischemic regions, limiting treatment efficacy. Although transiently compromised during IS, the BBB's permeability is insufficient for optimal drug concentrations. NP-based drug delivery systems offer a promising solution to enhance drug delivery and therapeutic outcomes in IS treatment [ 20 ].

A Schematic representation of the principle of intravenous thrombolysis for the treatment of AIS. B Schematic diagram of mechanical thrombectomy for IS. C A schematic diagram of the combined treatment (bridging therapy) of intravenous thrombolysis and mechanical thrombectomy for IS

NP-based targeted pathophysiological therapy for IS

In recent times, there have been notable advancements within the biomaterials sector concerning the creation of therapeutic drug delivery systems aimed at treating IS [ 33 ]. Among the various biomaterials explored, those based on NPs have emerged as a particularly promising avenue. Nanoparticles (NPs), defined as ultrafine particles with dimensions ranging from 1 to 100 nm (nm), exhibit distinct physical and chemical properties due to their high surface area to volume ratio and come in various types including metallic NPs like gold and silver, metal oxide NPs such as iron oxide and titanium dioxide, carbon-based NPs like fullerenes and carbon nanotubes, polymeric NPs made from organic polymers, and ceramic NPs including silica and alumina. In medicine, these versatile particles are employed for targeted drug delivery systems that enhance therapeutic efficacy and minimize side effects by delivering drugs directly to diseased cells, improved imaging techniques such as enhanced MRI and CT scans that offer higher resolution and better contrast, and innovative therapeutic approaches like photothermal therapy for cancer where NPs generate heat to selectively destroy cancer cells, while also being used in biosensing for detecting biomarkers and in the creation of scaffolds for tissue engineering, all of which highlight their significant potential in advancing medical diagnostics and treatments [ 34 , 35 , 36 ]. The unique localization of NPs is that they are smaller than cells but larger than most small-molecule substances. This allows them to act as efficient drug carriers, capable of controlling the release of therapeutics, which can lead to enhanced treatment outcomes across a spectrum of diseases [ 37 , 38 , 39 ]. Moreover, NPs are capable of being taken up by various cell types through a process known as clathrin-mediated endocytosis [ 40 ]. Following internalization, NPs navigate the intracellular environment via the endolysosomal pathway. This journey culminates in the fusion of NP-loaded vesicles with the abluminal membrane of the BBB, facilitating the transport of NPs into the CNS [ 41 ]. Under the conditions of AIS, the paracellular permeability of the BBB is significantly increased due to the disruption of tight junctions (TJs) [ 42 ]. This disruption can further augment the delivery of NPs to the brain. Consequently, NP-based drug delivery systems hold the potential to address the current treatment challenges associated with IS.

Superlative NP-based drug delivery systems must harness and regulate the aberrant pathophysiological features of IS. Consequently, a thorough comprehension of the pathophysiological traits associated with IS is fundamental for the development of such systems. In IS, the blockage of a cerebral artery results in the disruption of blood flow, leading to insufficient delivery of oxygen and glucose to neurons and other brain cells. Consequently, this deprivation leads to disrupted ATP synthesis, energy deficiency, compromised ion balance, and acid–base disturbances [ 43 , 44 ]. All of these functional impairments can lead to neuropathological changes in the brain, ultimately resulting in severe neurological damage and defects [ 45 ].

This section will comprehensively explore various pathophysiological changes related to IS, including glutamate excitotoxicity, neuroinflammation, BBB disruption, oxidative stress, mitochondrial dysfunction, and cell death (Fig.  3 ), as well as the application of NP-based drug delivery systems targeting the aforementioned pathophysiological treatments for IS.

Schematic diagram of the pathophysiological mechanisms involved in IS

Oxidative stress and mitochondrial dysfunction

The pathological mechanism of oxidative stress.

Oxidative stress, stemming from disrupted redox reactions, generates harmful free radicals damaging cellular structures. In IS, ischemia/reperfusion exacerbates oxidative stress, compromising BBB integrity and triggering neuroinflammatory responses [ 46 ]. Uncontrolled ROS production leads to red blood cell membrane peroxidation, impairing gas exchange and red blood cell function [ 47 ]. This contributes to microthrombosis, exacerbating cerebral ischemic damage. Oxidative stress, primarily from heightened ROS production via mitochondrial oxidative phosphorylation, intertwines with various pathological mechanisms in IS [ 48 ]. Mitochondria, double-membraned organelles found in all eukaryotic cells except mammalian red blood cells, play a crucial role in ATP production via oxidative phosphorylation. The outer membrane, with its channel structures, allows molecules under 10 kDa to pass, while the inner membrane hosts the electron transport chain (ETC) and ATP synthase complexes, facilitating oxygen, carbon dioxide, and water movement. In IS, mitochondria are highly susceptible to damage from ROS bursts, calcium overload, and excitotoxicity, leading to structural and functional abnormalities. These include deformation of the inner mitochondrial membrane (IMM), increased ROS production, and calcium overload. Mitochondrial responses to these stressors include mitochondrial enlargement, increased cytoplasmic density, and disruption of the mitochondrial membrane potential (ΔΨm), which activates the mitochondrial permeability transition pore (MPTP) [ 49 , 50 ]. This leads to a cycle of heightened ROS production, reduced ATP synthesis, PINK1 accumulation, and activation of the unfolded protein response (UPR), culminating in mitophagy [ 51 ]. Mitophagy is further stimulated by autophagosome formation from mitochondrial DNA damage due to excess ROS. The opening of the MPTP releases cytochrome C and ROS, activating caspases and leading to cellular apoptosis and necrosis (Fig.  4 ) [ 52 ].

Oxidative stress and mitochondrial dysfunctions in IS

In essence, the relationship between oxidative stress and mitochondria is intricately intertwined in the context of IS. Oxidative stress significantly impacts mitochondrial function, potentially causing mitochondrial dysfunction, which in turn can compromise cell viability and operation. Conversely, mitochondrial dysfunction can also contribute to oxidative stress, given that the oxidative phosphorylation process within mitochondria stands as a primary generator of free radicals. Consequently, a detrimental cycle forms between oxidative stress and mitochondria, amplifying cellular harm and mortality while worsening the condition of IS [ 53 ].

NP-based therapeutics in antioxidant therapy for IS

The use of antioxidant therapy to neutralize excess ROS has been shown to mitigate oxidative stress damage and decrease subsequent apoptotic and inflammatory reactions. As a result, this form of therapy has emerged as a principal approach for addressing injuries sustained from ischemia and reperfusion [ 54 ]. In preclinical studies, antioxidants typically encompass small molecular compounds, antioxidant enzymes, and various organic/inorganic substances. NPs have the potential to enhance the pharmacokinetic properties of antioxidants, facilitating their passage across the BBB and enabling them to concentrate in the affected areas of the brain [ 55 ].

Small-molecule antioxidants are frequently utilized for the antioxidant therapy of IS. The utilization of the NP-based drug delivery system is chiefly intended to improve the bioavailability of the therapeutic agents. Ashafaq and colleagues developed a nanostructured lipid carrier (NLC) encapsulating resveratrol (NR) and tested its neuroprotective effects in a rat model of MCAO [ 56 ]. Polysorbate-80 coating on NPs enhanced brain targeting and BBB penetration. NR reduced oxidative stress by increasing glutathione (GSH) levels and protecting antioxidant enzyme activity. The efficacy of 250 μg of encapsulated resveratrol was comparable to 20 mg of free resveratrol, showing NR to be 40–160 times more effective than free resveratrol in previous studies, significantly improving its bioavailability and therapeutic potential. Further investigations into the therapeutic efficacy and post-treatment protocols are needed to confirm whether NR treatment could be a promising candidate for a stroke. EDV, the sole neuroprotective drug approved for clinical use, neutralizes ROS to protect ischemic brain tissue. Jin et al . developed a micelle NP loaded with EDV-AM to enhance BBB crossing and neural protection during IS [ 57 ]. The EDV-AM significantly increased the permeability of the endothelial monolayer in vitro, leading to EDV concentrations that were 2.0 and 7.7 times higher than those of EDV-PM and unencapsulated EDV, respectively. HPLC studies revealed that EDV-AM delivered more EDV to brain ischemia than free EDV following intravenous injection. Furthermore, magnetic resonance imaging showed that EDV-AM more rapidly salvaged ischemic tissue compared to free EDV. Diffusion tensor imaging demonstrated that EDV-AM was most effective in accelerating axonal remodeling in the ipsilesional white matter and improving functional behaviors in IS models. This agonistic micelle shows promise in enhancing the therapeutic efficacy for IS patients who miss the window for thrombolytic treatment.

Small-molecule antioxidants frequently necessitate targeting specific pathways or signaling targets, potentially resulting in drug resistance. Consequently, addressing how NP-based drug delivery systems can overcome the resistance that may develop from prolonged small-molecule antioxidant use stands as a crucial challenge to be tackled in the future. Furthermore, in addition to a single small-molecule antioxidant, multiple small-molecule antioxidants could be co-delivered by NPs to synergistically treat IS. The co-delivery of multiple drugs by NPs can not only improve the therapeutic effect, but also reduce side effects, and provide new possibilities for the treatment of IS through precision treatment and the integration of diagnosis and treatment.

Macromolecular antioxidants, such as melanin (Me) and superoxide dismutase (SOD), are known for their excellent biocompatibility and potent antioxidant properties. Despite these benefits, their clinical application in treating strokes is significantly hindered by their brief biological half-lives and the low permeability of the BBB. To overcome these challenges, a novel approach involving NP-based delivery systems that harness these macromolecular antioxidants has been devised for the antioxidant treatment of IS. Reddy and colleagues developed SOD-encapsulated biodegradable NPs (SOD-NPs) using PLGA and tested their efficacy in a rat model of transient focal cerebral I/R [ 58 ]. SOD-NPs preserved the integrity of the BBB, preventing edema, reducing the levels of ROS produced after reperfusion, and protecting neurons from apoptosis. Animals treated with SOD-NPs showed significantly higher survival rates compared to those treated with saline control (75% vs. 0% at 28 days) and eventually regained most critical neurological functions. SOD-NPs could be an effective treatment option when used alongside a thrombolytic agent for stroke patients. In addition, the biodegradability of PLGA may bring greater advantages to this system. Besides SOD, other antioxidant enzymes like catalase and glutathione peroxidase can be employed in the treatment of IS through NP-based delivery. However, these proteins are prone to degradation, thus requiring careful consideration when employing NPs for their encapsulation.

In contrast, melanin, a polyphenolic polymer, exhibits greater resistance to degradation and enhanced load operability. Liu et al . developed PEG-coupled melanin NPs (PEG-MeNPs) and evaluated their antioxidative potential in IS [ 59 ]. PEG-MeNPs effectively countered various reactive oxygen and nitrogen species (RONS) and demonstrated neuroprotective and anti-inflammatory effects in vitro. In vivo results further confirm that the distinctive multi-antioxidative, anti-inflammatory, and biocompatible properties of MeNPs effectively protect ischemic brains while causing negligible side effects. This innovative approach combines melanin's natural antioxidant properties with sustained NP release, enhancing IS treatment.

In addition to serving as carriers, NPs can synergize with antioxidants for enhanced efficacy. Varlamova et al . developed Se-TAX, a nanocomposite of selenium NPs (SeNPs) and taxifolin (TAX), to improve neuroprotection in ischemic/reoxygenated cortical cells [ 60 ]. Se-TAX, TAX, and SeNPs all reduced ROS in neurons and astrocytes under oxidative stress, with Se-TAX showing superior performance and minimal pro-oxidant activity. Se-TAX activated antioxidant enzymes and inhibited ROS-generating systems during OGD/reoxygenation, outperforming its components. Unlike SeNPs alone, which partially inhibited Ca 2+ increase, Se-TAX mitigated both calcium surges and hyper-excitation. TAX was effective only against hyper-excitation. Se-TAX also significantly reduced necrosis and apoptosis post-OGD/reoxygenation, ranking in effectiveness as Se-TAX > SeNPs > TAX. Combining SeNPs with taxifolin creates a promising neuroprotective strategy for brain ischemia with low toxicity. However, further research is needed to explore the neuroprotective effects of this stroke model in vivo .

In biomedicine, inorganic NPs are popular due to their large surface area, customizable architecture, versatile surface chemistry, and unique optical and physical properties. Many have been engineered for antioxidant treatments targeting IS. Tian et al. created selenium-containing metal–organic framework-coated dual-iron-atom nanoenzymes (Fe 2 NC@Se NPs) with multi-enzymatic cascade activities to mimic natural antioxidants [ 61 ]. These NPs showed superior SOD, catalase, and oxidase activities compared to single-atom iron counterparts, with the Se-MOF layer enhancing stability and biocompatibility. Density functional theory suggests a synergistic effect boosts Fe 2 NC activity. In vitro and in vivo studies demonstrated that Fe 2 NC@Se NPs effectively reduce oxidative damage and neuronal apoptosis post-cerebral I/R injury by scavenging ROS and inhibiting the ASK1/JNK apoptotic pathway. These NPs significantly reduced cerebral infarction and edema, suggesting their potential for novel antioxidant therapies to improve IS treatment.

Inorganic NPs can catalyze the decomposition of ROS directly and can also release specific elements or ions that regulate molecules or pathways associated with ROS. Huang et al . developed a bioinspired manganese oxide nanoenzyme (HSA-Mn 3 O 4 ) to mitigate reperfusion damage post-IS [ 62 ]. This nanosystem demonstrates reduced inflammation, extended circulation time, and robust ROS scavenging capabilities. HSA-Mn 3 O 4 effectively prevents cell apoptosis and endoplasmic reticulum (ER) stress induced by oxygen and glucose deprivation, showcasing its neuroprotective effects against IS and reperfusion injury in brain tissue. Additionally, it facilitates the release of Mn ions, enhancing SOD 2 activity. Thus, HSA-Mn 3 O 4 mitigates brain tissue damage by mitigating cell apoptosis and ER stress in vivo. Overall, this research not only informs the design of biomimetic and translational nanomedicine but also elucidates the mechanisms underlying its neuroprotective effects against IS and reperfusion injury.

In addition to inorganic NPs, some organic NPs can also directly promote the decomposition of ROS. Hosoo et al . developed nitroxide radical-containing NPs (RNPs) embedded with TEMPOL to neutralize ROS and provide neuroprotection [ 63 ]. Their study showed RNPs significantly reduced superoxide anions in both the peri-infarct zone and ischemic core, confirmed by decreased oxidative DNA damage via 8-OHdG staining. Compared to PBS-treated controls, arterial RNP administration significantly reduced BBB permeability, improved neurological function, and decreased infarct volume. Additionally, RNPs reduced neuronal apoptosis near the infarct. This study demonstrates that RNPs, as high-performance antioxidants, can effectively exert their effects while prolonging the half-life and circulation time of TEMPOL in vivo, reducing its toxicity. These findings highlight the potential of RNPs as a therapeutic intervention for cerebral I/R injuries, with intra-arterial RNP injection emerging as a novel approach to protect the neurovascular unit by reducing infarct size, BBB damage, and scavenging multiple ROS.

It should be noted that organic/inorganic NP-based nanoenzymes have been widely studied, but a major obstacle for these nanoantioxidants is their high specificity in antioxidant activity against ROS (mainly H 2 O 2 ). Considering the multiple ROS produced in diseases, it may not be able to fully prevent oxidative damage. By comparison, the advantages of endogenous antioxidant-based NPs are as follows: (i) Strong clearance of multiple primary and secondary ROS and reactive nitrogen species (RONS); (ii) Highly stable antioxidant activity against oxidative damage; (iii) Good biocompatibility. Therefore, it is necessary to consider the pathophysiological characteristics of IS and the physicochemical properties of NPs in selecting the system for IS treatment.

The above research indicates that NP-based treatment methods can help various antioxidant drugs cross the blood–brain barrier, improve the efficacy and bioavailability of antioxidant drugs in vitro and in vivo treatment of IS, and help explore some antioxidant mechanisms, contributing new content to the antioxidant treatment of IS. However, the cascade reaction of ischemic pathology is complex and the targeting efficiency of drugs on ischemic penumbra needs to be further improved. To further improve the brain penetration and therapeutic effect of ischemic injury, NP-based drugs with precise targeted pharmacological effects have been designed and developed recently.

Smart-responsive NPs are already being used to deliver antioxidants for IS treatment. Wu et al . developed PEG-terminated poly (2,2'-thiodiethylene 3,3'-thiodipropionate) (PEG-PTT) polymers with ROS-sensitive thioether motifs and thrombin-sensitive peptides, creating NPs that shrink in response to thrombin in ischemic environments [ 64 ]. To enhance brain penetration, AMD3100, which binds to the upregulated CXCR4 receptor in ischemic areas, was grafted onto these NPs (ASPTT NPs). In MCAO-induced stroke models in mice, ASPTT NPs selectively accumulated in the ischemic brain and exerted strong antioxidant effects. This work shows ASPTT NPs are capable of efficient encapsulation and delivery of glyburide to achieve anti-edema and antioxidant combination therapy, resulting in therapeutic benefits significantly greater than those by either the NPs or glyburide alone. ASPTT NPs can encapsulate and deliver glibenclamide, an antiedematous agent that has shown promise in human patients. Despite its limited brain penetration, encapsulating glibenclamide within the Np provides additional therapeutic benefits. ASPTT NPs demonstrated exceptional brain penetration and therapeutic benefits, making them a promising platform for targeted stroke therapies and potential clinical translation for effective stroke management.

The current trend in the development of NP-based drug delivery systems is transitioning gradually from single to multiple targeting, a shift with significant implications for precision targeted therapy. Dong et al . developed a biomimetic drug delivery platform, stroke-homing peptides (SHp)-NM@Edv/RCD (SNM-NPs), for advanced, multi-phased targeting [ 65 ]. Firstly, by NM encapsulation, SNM-NPs can successfully penetrate the BBB and target inflammatory sites. Secondly, SHp modification allows SNM-NPs to specifically target damaged neurons at CIRI sites. In addition, SNM-NPs significantly reduced the drug concentration in vivo by stepwise targeting and inhibited neuroinflammation by scavenging excessive ROS. Furthermore, the scavenging of ROS upregulated Bcl2 expression, inhibited Bax function, and further inhibited Caspase 3 activation, thereby suppressing neuronal apoptosis and neuronal microtubule repair. Preliminary experiments also showed that SNM-NPs exhibited a good safety profile both in intravenous therapy and in vitro cell experiments; therefore, they can be further developed as effective and safe agents for targeted therapy of CIRI. In addition, stepwise targeting and precision drug delivery strategy can be used for the precision treatment of other diseases related to local oxidative stress and inflammation in the brain.

Hypoxia occurring in AIS before thrombolysis or the subsequent increase in oxygen levels post-thrombolysis can lead to elevated levels of free radicals, causing successive damage to neurocytes. Shi et al . introduced engineered nano-erythrocytes for AIS and I/R injury treatment by encapsulating Mn 3 O 4 within natural erythrocytes and attaching T7 peptides for BBB penetration, forming Mn 3 O 4 @nanoerythrocyte-T7 (MNET) (Fig.  5 A) [ 66 ]. MNET exhibited efficient localization within infarcted areas, leveraging the stealth effect of erythrocytes and the BBB-penetrating ability of T7 peptides (Fig.  5 B). MNET significantly inhibited phagocytosis and enhanced BBB traversal, effectively eliminating free radicals and mitigating cellular hypoxia in vitro (Fig.  5 C). In vivo, MNET provided therapeutic benefits by salvaging neurocytes before thrombolysis through rapid free radical clearance and oxygen delivery, and post-thrombolysis by curbing oxygen influx and neutralizing free radicals to prevent reperfusion injuries (Fig.  5 D, E). MNET's dual ability to scavenge free radicals and absorb oxygen offers a promising stepwise approach for IS management. It is crucial to highlight that during the treatment of IS, the primary objective is to promptly restore flow in occluded blood vessels. Nevertheless, the oxidative stress induced by surplus oxygen post-reperfusion must not be overlooked. Consequently, strategically managing oxygen levels pre- and post-reperfusion of blood vessels could potentially be a pivotal approach in utilizing NPs for the treatment of IS. Currently, normobaric hyperoxia (NBO) is the primary treatment for reducing penumbral tissue hypoxia. However, as previously reported, NBO can cause side effects due to the risk of systemic exposure to high-dose oxygen. The oxygen sponge effect of MNET has effectively regulated oxygen levels before and after thrombolysis in ischemic stroke, showing promising clinical application potential. The elegant design, straightforward preparation process, and encouraging results of the nanosystem proposed in this study offer an effective therapeutic strategy with broad potential for clinical application in IS.

Copyright © 2020, American Chemical Society

Bioinspired nanosponge for salvaging IS via free radical scavenging and self-adapted oxygen regulating. A Schematic diagram of MNET salvaging in an acute IS via combining free radical scavenging and natural oxygen sponge effect. B Blood stability and BBB-crossing ability of MNET. C Protective effect of MNET via ROS scavenging and hypoxia relief in vitro. D The therapeutic effect of MNET in vivo for rescuing IS before thrombolysis. E The therapeutic effect of MNET in vivo for rescuing IS after thrombolysis.

In addition to various peptide-mediated and receptor-mediated NPs targeting the ischemic site of the brain, NPs with organelle targeting (especially mitochondrial targeting) function are designed to more accurately regulate and treat the pathological and physiological processes of IS. Liao et al . designed and synthesized a nanoplatform based on ceria nanoenzymes TPP@(CeO 2  + ROF) that exerts mitochondria-targeting and antioxidant activities [ 67 ]. This system consists of triphenylphosphine-modified ceria and is loaded with the PDE4 inhibitor roflumilast. This innovative design offers multiple advantages, including enhanced biocompatibility, mitochondrial targeting, excess ROS scavenging, mitochondrial function restoration, anti-inflammatory activity, antioxidant synergism, and microglial cell phenotype and cytokine secretion modulation. Their results suggest that TPP@(CeO 2  + ROF) effectively mediates mitochondrial damage, attenuates oxidative damage and apoptosis, reduces cerebral infarct volume and BBB injury, and has a favorable biosafety profile. Transcriptome analysis further elucidated the neuroprotective mechanism of TPP@(CeO 2  + ROF). We believe that this nanoplatform is potentially a promising strategy for the treatment of IS. Zhang et al . developed multifunctional nanocarriers (SPNPs) for I/R injury treatment, targeting mitochondria, responding to ROS, and providing antioxidative effects (Fig.  6 A) [ 68 ]. The thioketal cross-linked SPNPs reacted to ROS, neutralizing them and releasing the therapeutic compound PU. The SS-31 peptide enabled mitochondrial targeting. Integrated into a thermosensitive hydrogel for intranasal administration, SPNPs protected SH-SY5Y cells from oxidative damage and effectively transported them to ischemic regions in MCAO rats (Fig.  6 B, C). The ROS-triggered release of PU restored mitochondrial function, sustained ATP production, preserved membrane integrity, and inhibited apoptosis. In vivo, SPNPs improved neurological scores, reduced infarct volumes, and mitigated brain swelling (Fig.  6 D). By utilizing intranasal administration, SPNPs encapsulated in the thermosensitive gel can bypass the BBB and directly target the mitochondria of ischemic penumbra neurons, thereby enhancing delivery efficiency. This groundbreaking method provides substantial therapeutic advantages for treating ischemic damage and other CNS disorders.

© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V

Mitochondrial-targeted and ROS-responsive nanocarrier via nose-to-brain pathway for IS treatment. A Schematic illustration of targeted treatment of IS by ROS-responsive NPs loaded with PU and decorated with SS31. B Neuroprotection on SH-SY5Y cells simulated oxidative stress environment after acute IS. C Characterization of thermo-sensitive gels containing different therapeutic agents and ex vivo biodistribution of therapeutic NPs. D In vivo anti-IS efficacy.

In recent years, advancements in materials science and biology have facilitated the transition of NP-mediated oxidative stress regulation in IS from a macroscopic to a microscopic scale. The targeting of NPs in IS has progressed from ischemic site targeting to precise cell and organelle targeting. Future NP designs must exhibit precise molecular targeting capabilities related to oxidative stress. Moreover, the mechanisms through which NPs regulate oxidative stress demand further elucidation through genomics, proteomics, metabolomics, and other analytical approaches.

The current approach to treating IS with NPs primarily revolves around enhancing the permeability of the BBB and increasing the bioavailability of established antioxidant medications. Additionally, there is a focus on developing novel NP-based drug delivery systems with superior antioxidant capabilities. Particularly noteworthy are the single and multi-targeted NPs that specifically target the ischemic region and mitochondria, thereby augmenting both the permeability of the BBB and the precise therapeutic impact of the medication. Moreover, the combined benefits of multifunctional NPs, acting as antioxidants while also releasing oxygen and reducing edema, have resulted in more favorable treatment outcomes for IS. Future NP designs must demonstrate precise molecular targeting capabilities associated with oxidative stress, rather than only targeting free radicals.

Glutamate excitotoxicity

The pathological mechanism of glutamate excitotoxicity.

Glutamate, a key excitatory neurotransmitter in the CNS, is crucial for synaptic transmission, learning, memory, movement, cognition, and development [ 69 ]. Approximately 50% of glutamate is involved in synaptic transmission regulation. Since it cannot cross the BBB, glutamate is synthesized in the CNS from glucose, which undergoes glycolysis and the TCA cycle to form α-ketoglutarate (α-KG), the precursor for glutamate [ 70 ]. This synthesis is catalyzed by glutamate dehydrogenase (GDH). Another synthesis route involves the glutamate-glutamine cycle: glutamate is absorbed into astrocytes and converted to glutamine-by-glutamine synthetase (GS). Glutamine is then transported to neurons via transporters like the SLC38 family (SNAT) [ 71 ]. In neurons, glutaminase (GLS) converts glutamine back to glutamate and ammonium ions [ 72 ]. Additionally, glutamate can be converted to α-KG through GDH or aspartate aminotransferase (AAT) [ 73 ]. This intricate exchange network, known as the "glutamate-glutamine cycle," is essential for maintaining glutamate balance and provides neuroprotection for post-cerebral ischemia. During cerebral ischemia and hypoxia resulting from IS, diminished ATP synthesis in neurons results in energy deficiency, causing the malfunction of key proteins such as Na + /K + -ATPase (NKA), Na + /Ca 2+ exchanger (NCX), and Ca 2+ -ATPase across both plasma and intracellular organelle membranes. The disrupted ionic balance leads to heightened glutamate release and impaired glutamate reuptake, leading to aberrant glutamate processing. Additionally, it induces intracellular calcium overload, triggering excessive glutamate secretion and activation of calcium-dependent enzymes. Elevated levels of glutamate in the synaptic cleft overstimulate the N-methyl-D-aspartate receptor (NMDAR) on the postsynaptic membrane, initiating cellular demise. Moreover, NMDAR hyperactivation exacerbates intracellular Ca 2+ accumulation, exacerbating the progression of cell death. The sequence of excitotoxic events in IS predominantly entails the death of postsynaptic cells mediated through the glutamate-NMDAR pathway (Fig.  7 ).

The cascade of glutamate excitotoxicity in IS

In summary, prolonged exposure to elevated extracellular glutamate levels during IS causes significant Ca 2+ influx into neurons and glial cells, triggering neurotoxic events. This excess Ca 2+ activates proteases, phosphatases, endonucleases, and lipases, leading to the overproduction of free radicals, mitochondrial damage, membrane disruption, and DNA fragmentation, ultimately resulting in apoptotic or necrotic cell death.

NP-based therapeutics in excitotoxicity therapy for IS

Excitotoxicity mediated by glutamate is a key mechanism in IS, triggering early stroke damage. Regulating this process can improve intervention outcomes. Glutamate receptor antagonists and calcium channel blockers reduce excitotoxicity, offering neuroprotection for IS treatment [ 74 ]. However, current therapies face challenges like limited duration, poor targeting, and inadequate drug release control. To address these issues, NPs based on excitotoxicity inhibitors have been developed to enhance IS treatment efficacy.

Enhancing the solubility and BBB permeability of glutamate receptor antagonists using NP-based delivery systems can improve IS treatment efficacy. PSD-95 activates neuronal nitric oxide synthase (nNOS) via the NMDA receptor, forming the NMDAR/PSD-95/nNOS complex. Disrupting this interaction can reduce excitotoxic damage. Drugs like ZL006 and NR2B9C selectively block the nNOS-PSD-95 interaction but face challenges in penetrating the ischemic brain effectively. Zhao et al . developed T7 and SHp dual-conjugated PEGylated liposomes (T7&SHp-P-LPs) for targeted delivery of ZL006 to treat IS [ 75 ]. In vivo imaging showed efficient BBB crossing and accumulation in the ischemic area of MCAO rats. The treatment reduced infarct size, improved neurological function, and alleviated histopathological damage. Cellular studies confirmed enhanced BBB crossing and cellular uptake of T7&SHp-P-LPs/ZL006, reducing glutamate-induced cell apoptosis. The research findings indicate that dual-targeted liposomes, modified with T7 and shp, can transport more drugs to the brain and selectively deliver them to ischemic tissue. This approach increases the local drug concentration while minimizing side effects. To further improve the therapeutic effect of drugs, Lv et al . developed SHp-modified RBC membrane-coated ROS-responsive NPs (SHp-RBC-NP/NR2B9C) for delivering the neuroprotective drug NR2B9C to treat ischemic brain injury (Fig.  8 A) [ 76 ]. SHp-RBC-NPs enhanced NR2B9C transport across the BBB, targeting injured neurons in the ischemic region. SHp-RBC-NP/NR2B9C improved PC-12 cell performance under glutamate-induced stress, suggesting a protective role (Fig.  8 B). Pharmacokinetic studies showed extended circulation time (beyond 48 h) for both RBC-NP/NR2B9C and SHp-RBC-NP/NR2B9C groups. The SHp-RBC-NP group demonstrated higher fluorescence intensity in ischemic brain regions, indicating precise targeting (Fig.  8 C). SHp-RBC-NP/NR2B9C significantly improved neurological impairments and reduced cerebral infarct size in I/R models (Fig.  8 D). This system prolongs the circulation time of NR2B9C in the body and enhances its targeting ability and greater neuroprotective effect. Therefore, it suggested that SHp-RBC-NPs may be utilized as a potential formulation strategy to enhance the treatment of IS in the clinic.

Copyright © 2018, American Chemical Society

Bioengineered boronic ester-modified dextran polymer NPs as ROS responsive nanocarrier for IS treatment. A Schematic design of the SHp-RBC-NP/NR2B9C. B In vitro cell-based studies. C In vivo pharmacokinetics and fluorescent image of rhodamine-labeled free NR2B9C, NP, RBC-NP, and SHp-RBC-NP in the ischemic brain sections. D The neuroscore and infarct size were evaluated 24 h after the I/R and in vivo safety evaluation.

Ca 2+ channel blockers reduce excitatory amino acid release, prevent excessive intracellular Ca 2+ accumulation, and promote cerebral blood flow through vasodilation [ 77 ]. However, their use is limited by low bioavailability and gastrointestinal side effects. Advances in neuroprotective treatments for IS have been made with NP-based Ca 2+ antagonists. Nimodipine, an L-type voltage-gated calcium channel inhibitor, reduces excessive Ca 2+ in nerve cells but causes gastrointestinal side effects when taken orally. Orsolya et al . addressed this by using pH-responsive chitosan NPs to deliver nimodipine, mitigating nerve damage from cerebral ischemia [ 78 ]. Their study showed that nimodipine remained encapsulated at neutral pH and was released during ischemia-induced acidosis, increasing cerebral blood flow and blocking Ca 2+ influx. The chitosan NPs prevented depolarization without causing neuro-immune reactions, effectively reducing excitotoxicity. In summary, the data from this study avoided gastrointestinal side effects and accurately delivered nimodipine to the ischemic site. This method can pave the way for the development of an intelligent drug delivery system that can selectively target the ischemic penumbra in IS.

Glyburide acts by obstructing the influx of calcium ions, a mechanism that involves the inhibition of the Trpm4 channel, which is a non-selective cation channel regulated by the sulfonylurea receptor 1 (Sur1-Trpm4 or Sur1-NCCa-ATP). To enhance delivery precision, Ma et al . encapsulated glyburide in PLGA NPs coated with neuronal stem cell membranes, creating Gly-CMNPs [ 79 ]. These engineered NSC membranes, overexpressing CXCR4, improved the homing ability of PLGA NPs to ischemic regions via CXCR4 and SDF-1 chemotaxis. In vivo trials with Gly-CMNPs showed improved survival rates, reduced infarct volumes, and better neurological scores in MCAO mice compared to free glyburide. This novel formulation could significantly enhance IS treatment options. The study suggests a new approach to improving drug delivery to the ischemic brain and establishes a novel formulation of glyburide that can be potentially translated into clinical applications to improve the management of human patients with stroke.

In summary, numerous studies have convincingly demonstrated the significant promise of NPs carrying excitotoxicity inhibitors for the treatment of IS. Despite this potential, the development of such targeted NPs remains relatively uncommon. One critical aspect to consider is the timing of administration, as the efficacy of neurotoxicity-blocking agents is closely tied to their delivery within a specific window following the onset of a stroke event. Delaying this administration may reduce the protective effects, thereby restricting both the duration and method of action of NPs. Moreover, the pathophysiological mechanisms underlying excitotoxicity are multifaceted and intricate. As such, NPs must possess a versatile design to effectively inhibit this complex process. Hence, from our perspective, the advancement of NPs engineered with excitotoxicity inhibition capabilities signifies a highly promising avenue for the future treatment of IS.

The BBB breakdown and neuroinflammation

The pathological mechanism of neuroinflammation.

The CNS features protective barriers, notably the BBB, which consists of endothelial cells (ECs) with TJs, pericytes, astrocytic endfeet, and ECM components [ 80 ]. ECs form vessel linings, pericytes are within the basement membrane, and astrocytic processes envelop capillaries. While ECs and TJs primarily block permeability, pericytes and astrocytes regulate it. The BBB is crucial for maintaining CNS homeostasis by controlling fluid, solute, and cell movement at the blood–brain interface. In IS, the BBB undergoes significant damage due to glucose and oxygen deprivation followed by reperfusion injury, leading to local energy disturbances and oxidative stress. This causes deterioration of vascular endothelial cells and disruption of TJs, increasing BBB permeability [ 81 ]. The BBB breakdown facilitates continuous inflammatory pathway activation by inflammatory factors from infiltrating peripheral cells and CNS-activated cells [ 82 ]. Early IS-induced excitotoxicity and oxidative stress trigger the release of cytokines, MMPs, and GFAP from microglia and astrocytes, prompting endothelial cells to elevate cell adhesion molecules like selectins, VCAM, and ICAM. This promotes white blood cell attachment and immune cell infiltration [ 81 ]. Dying neurons release DAMPs, further activating microglia and peripheral immune cells, which produce additional pro-inflammatory factors, exacerbating BBB damage [ 83 ]. This creates a vicious cycle where initial inflammation disrupts the BBB, enabling peripheral white blood cells to migrate to the injured brain, releasing pro-inflammatory cytokines, ROS, and MMPs, which further damage the BBB and perpetuate inflammation (Fig.  9 ) [ 84 ].

© By Figdraw

The BBB breakdown and neuroinflammation in IS.

In brief, dysfunction of the BBB, characterized by the structural breakdown of TJs and heightened permeability, stands out as a key pathological feature in IS. The compromise of the BBB is not solely a consequence of injury, rather, it actively contributes to the damage and often correlates with a bleak prognosis [ 85 ]. In the context of IS, various blood-borne elements such as cells, chemicals, and fluids breach the BBB and enter the brain tissue due to increased paracellular and transcellular permeability, as well as substantial damage to the endothelium [ 86 ]. This breach disrupts the balance of water and ions in the brain, leading to cerebral edema. Furthermore, the migration of infiltrating leukocytes intensifies inflammatory responses, worsening brain injury [ 87 ]. Although numerous consequences of BBB dysfunction are negative, one potential benefit is that it could enhance the targeted transportation of therapeutic substances to specific locations within the brain.

NP-based therapeutics in anti-inflammatory therapy for IS

Neuroinflammation significantly contributes to neuronal cell death in IS, with initial neuron death triggering an immune and inflammatory response involving microglia/macrophages and pro-inflammatory cytokines [ 88 ]. Anti-inflammatory drugs like fingolimod, glycyrrhizic acid, and ligustrazine show promise in preclinical IS studies by modulating microglial polarization and reducing inflammatory mediators and cell infiltration. However, their clinical use is limited by poor bioavailability, high lipophilicity, low solubility, and rapid clearance. To address these issues, various nano-formulations have been developed to enhance the therapeutic properties and bioavailability of these agents.

Polymers such as PEG are often used to construct nanomedicine carriers. Wang et al . developed mPEG-b-PLA copolymer NPs (NPcurcumin) to enhance curcumin delivery for IS treatment, showing improved therapeutic effects, BBB protection, and reduced neuroinflammation by modulating microglial activity, aiding neurological recovery in mice post-I/R injury [ 89 ]. NPcurcumin effectively addresses the challenges posed by curcumin's poor water solubility and unstable chemical properties. It enhances curcumin's stability, prolongs its circulation time in vivo, and amplifies its therapeutic efficacy. Similarly, Thomas et al . demonstrated that atorvastatin in PEG-modified liposomes (LipoStatin) reduced brain damage and improved neurological recovery in rats with cerebral I/R injury [ 90 ]. It efficiently accumulated at the ischemic injury site, significantly reducing infarct volume and improving neurological function recovery compared to the control group. Additionally, LipoStatin markedly improved brain metabolism and demonstrated significant anti-inflammatory effects. Protein analysis indicated considerable recovery of blood–brain barrier integrity and endothelial function. PEGylated LipoStatin can be more effectively delivered to the ischemic brain and have significant neuroprotective effects. Thus, PEGylated LipoStatin can be further developed as a promising targeted therapy for IS and other major vascular diseases.

Furthermore, polymer NPs can facilitate the co-delivery of multiple drugs. Zhu et al . developed an amphiphilic polymer with a Ce 4+ ligand, forming NTA/Ce 4+ /C-176 NPs to co-deliver drugs for IS treatment (Fig.  10 A) [ 91 ]. These NPs counteract neuroinflammation by inhibiting dsDNA accumulation and STING protein overexpression (Fig.  10 B). In vivo studies showed that intraventricular injection of these NPs at the stroke site effectively reduced neuroinflammation, promoted neurogenesis, and improved motor function in a MCAO model (Fig.  10 C). This approach resulted in a smaller ischemic penumbra and better recovery than standard NP treatments. This strategy offers a promising new avenue for modulating CNS inflammatory pathways and improving stroke prognosis, despite potential tissue damage risks from the intraventricular injection.

© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd

C-176-loaded Ce 4+ DNase NPs synergistically inhibit the cGAS-STING pathway for IS treatment. A The therapeutic mechanism of NTA/Ce 4+ /C-176 NPs. B NTA/Ce 4+ /C-176 decreased neuroinflammation and increased neurogenesis in vivo. C Effect of NTA/Ce 4+ /C-176 on brain infarct volume and functional motor recovery after stroke.

Besides small-molecule drugs, macromolecular drugs including protein drugs and nucleic acid drugs can be delivered by polymer NPs. Jin et al . enhanced IVIg delivery to ischemic regions by creating MPC-n (IVIg) nanocapsules via in situ polymerization with MPC monomer and EGDMA [ 92 ]. These nanocapsules crossed the BBB through high-affinity choline transporter 1 (ChT1) in ischemic endothelial cells, targeting IVIg accumulation. Early MPC-n (IVIg) administration reduced stroke-induced inflammation by suppressing neural C3 complement activation, monocyte/macrophage infiltration, and glial cell activation, while promoting a protective microglial phenotype. This treatment decreased neurological deficits, infarct volume, and mortality rates, effectively reducing inflammation-induced brain damage and improving outcomes. In summary, MPC-n (IVIg) can effectively and selectively deliver therapeutic IVIg to the ischemic region following a stroke. Even at low doses, it can penetrate the BBB and accumulate in the ischemic area, enhancing its clinical feasibility. Phosphatidylcholine (PC), a key component of cell membranes, is commonly utilized to modify NPs to evade the reticuloendothelial system and prolong systemic circulation time. Our study has further revealed that PC can actively cross the BBB via receptor-mediated transport, indicating its promise as a feasible candidate for the development of nanomedicines for IS treatment [ 93 ].

Nucleic acid-based drugs are gaining prominence in drug development due to their precise targeting, broad therapeutic applications, sustained effects, potential for personalized medicine, low drug resistance, minimal off-target effects, and the ability to modify diseases. Choi et al . developed PLGA NPs encapsulating PINK1 siRNA (PINK1 NPs) to target PINK1 in mitochondrial autophagy within microglia, offering neuroprotection in a photothrombotic-induced IS mouse model [ 94 ]. PINK1 NPs promoted anti-inflammatory microglia states, reduced microglial migration, and increased phagocytic activity, preventing delayed neuronal loss. Pre-stroke administration of PINK1 NPs decreased mitochondrial autophagy factors, reduced infarct volume, and improved motor deficits. In summary, to effectively apply gene therapy in clinical practice, a technology minimizing non-specific gene expression and dysfunction in normal cells has been developed. NPs enhance drug therapeutic efficacy and offer benefits in cost, economy, and productivity. PLGA polymers, approved by the FDA and EMA for various therapeutic applications, are a promising gene delivery vector. PLGA NPs protect delivery materials from external stress in vitro and in vivo and maintain circulation until reaching the target site. This study leverages these advantages to deliver siRNA from PLGA NPs specifically to microglia, demonstrating that PINK1 is a key signaling molecule in mitochondrial autophagy dysregulation induced by IS, potentially identifying a neurotoxic mechanism of the condition.

Wang et al . demonstrated the potential of C3-siRNA-encapsulated NPs (NPsiC3) to suppress IS-induced inflammation [ 95 ]. Using BHEM-Chol and PEG-PLA, NPsiC3 efficiently inhibited C3 expression increase in microglia during hypoxia/re-oxygenation, reduced C3b accumulation on neurons, and alleviated microglia-induced neuronal injury. NPsiC3 crossed the BBB, delivering C3-siRNA to the ischemic penumbra, reducing C3 expression in microglia and brain tissues. This decreased inflammatory cell infiltration, pro-inflammatory factors, neuronal apoptosis, and ischemic area size, while improving functional recovery post-ischemia/reperfusion injury, suggesting NPsiC3 as an effective IS therapy. The BBB poses a significant obstacle to using C3 inhibitors for stroke treatment, resulting in a lack of effective methods to inhibit microglial neurotoxicity following brain I/R injury in clinical practice. This study explores the use of PEG NPs as a brain delivery system to transport siRNA across the BBB. This approach can modify NPs distribution, extend their circulation half-life, and enhance drug delivery within the BBB, offering an innovative alternative strategy for drug delivery. It is worth considering that as an acute-onset disorder, the timely efficacy of nucleic acid drugs in the treatment of IS is a matter of concern. The potential of nucleic acid drugs may lie more prominently in the realm of preventive interventions for IS.

Natural polymer-based NPs, such as those from chitosan, hyaluronic acid, and sodium alginate, are increasingly favored for drug delivery. These renewable biopolymers offer high hydrophilicity, viscoelasticity, biodegradability, low allergenic potential, excellent biocompatibility, and unique targeting abilities, making them ideal for pharmaceutical applications. Zhao et al . developed carboxymethyl chitosan NPs (GA-NPs) to deliver Gallic acid (GA) for neuroprotection in IS [ 96 ]. GA-NPs demonstrated high encapsulation efficiency, sustained release, and extended GA half-life. The pharmacological findings, which include assessments of neurological deficits, cerebral infarction, inflammation levels, and oxidative stress, demonstrate that GA-NP exhibits superior neuroprotective effects compared to GA alone. This encapsulation method enhanced GA bioavailability and neuroprotective effects. However, the brain penetration mechanism of GA-NPs remains unclear, and the capabilities of natural polymers in this regard need to be further explored.

Jin and colleagues developed ROS-sensitive 18 β-glycyrrhetinic acid-conjugated DEAE-dextran NPs (DGA) for neuroprotection in IS by suppressing HMGB1 and promoting anti-inflammatory M2 microglial phenotypes [ 97 ]. In vitro, GA effectively targeted and restrained intracellular HMGB1. In vivo testing demonstrated the therapeutic effect on stroke mice, with smaller infarct volume, better motor function, and more neurogenesis. This study avoided the limitations of non-specific drug release and rapid plasma elimination to reduce side effects while achieving effective concentrations. The dextran-based nanomaterials show promise for mitigating CNS inflammation and advancing nerve repair. Similarly, the BBB traversal mechanism is unclear, it is hypothesized that NPs passively target stroke sites via abnormal blood vessel permeation, with active targeting enhancing efficiency.

Zhao et al . developed a triple-targeted drug delivery system based on hyaluronic acid and rutin (SHR) for treating cerebral ischemia [ 98 ]. Utilizing short peptides, SS31, and CD44-mediated endocytosis, this delivery vector can effectively penetrate the blood–brain barrier, target brain injury sites, and accumulate in damaged mitochondria. Hyaluronidase 1-mediated degradation and the acidic environment synergistically promote the sustained release of rutin in the ischemic brain area. This study revealed for the first time that rutin effectively binds to ACE2. Experimental results indicate that SHR micelles have significant anti-inflammatory, antioxidant, angiogenic, and vascular normalization effects, synergistically restoring damaged penumbra tissue by activating ACE2 and TFEB signals (Fig.  11 A, B). It also confirms that ACE2 mediates the crosstalk between BMEC and microglia during SHR treatment. This study also addressed the issues of rutin's low water solubility and difficulty penetrating the BBB. Therefore, SHR's impact on vascular normalization offers potential treatment options for comorbidities such as cerebral ischemia and tumors.

© 2023 The Authors. Published by American Chemical Society

A triple-targeted rutin-based self-assembled delivery vector for treating IS by vascular normalization and anti-inflammation via ACE2/Ang1‑7 signaling. A SHR micelles promoted microglial transformation. B SHR anti-inflammation effect.

Besides polymer NPs, many inorganic NPs are also used for the anti-inflammatory treatment of I/R injury. First, many NPs exhibit anti-inflammatory properties by releasing specific elements, such as selenium (Se) and zinc (Zn), that facilitate the direct treatment of IR. Amani et al . synthesized OX26-PEG-Se NPs, monoclonal antibodies targeting transferrin receptors conjugated with PEG selenide NPs, for IS treatment [ 99 ]. The surface modification of the OX26 antibody significantly enhances the targeted transport of Se NPs to the brain via transferrin receptor-mediated endocytosis. In vitro analysis showed that the NPs primarily localized in the nucleus. More importantly, Se NPs regulate the cellular metabolic state (TSC1/TSC2, p-mTOR, mTORC1), oxidative defense system (FoxO1, β-catenin/Wnt, Yap1), inflammatory response (jak2/stat3, ADAMS-1), autophagy, and apoptotic cell death (Mst1, ULK1, MTORC1) by targeting Bax, Caspase-3, and Bcl-2. They also influence various cellular signaling pathways in hippocampal neurons (rictor/mTORC2) to promote neuronal survival. The design of these NPs ensures efficient targeting with minimal side effects, presenting a promising new approach for stroke treatment.

Moreover, inorganic NPs are commonly utilized as passive carriers. Xiao and team developed SiO 2 @PAA-MT/ACh-aC5a nanospheres, which load melatonin (MT) and acetylcholine (ACh), to treat cerebral ischemia/reperfusion injury [ 100 ]. ACh stimulates the α7 nicotinic acetylcholine receptor (α7nAChR) on microglia, shifting them from pro-inflammatory (M1) to anti-inflammatory (M2) phenotypes, reducing pro-inflammatory cytokines. MT provides antioxidant properties, neutralizing ROS. The inclusion of aC5a aptamers ensures targeted delivery by binding to C5a, blocking its inflammatory effects. These nanospheres effectively mitigate the side effects of rhythm disorders caused by intravenous injection of MT, a circadian rhythm-dependent hormone. They address the critical issue of safely concentrating MT at an effective dose for treating I/R at the site of cerebral ischemia. However, the gradual degradation and potential long-term toxicity of inorganic NPs need careful consideration.

In recent years, several new types of NPs have emerged, especially those based on cells or cell membranes. These NPs with biomimetic properties offer significant advantages in the treatment of IS. As an example, the targeting capability of these NPs to ischemic sites, endowed by membrane proteins, exceeds that of other NPs. Dong et al . developed Resolvin D2-loaded nanovesicles (RvD2-HVs) to mitigate brain damage in IS [ 101 ]. These neutrophil-derived nanovesicles target inflamed endothelium by modulating adhesion molecules and integrins. Both in vitro and in vivo studies showed that RvD2-HVs enhance RvD2 delivery to the brain, reducing neutrophil infiltration at ischemic lesions, decreasing cerebral infarction size, and improving neurological recovery. The design of RvD2-HVs addresses the issue of Resolvin binding directly to plasma proteins, which reduces its bioavailability after intravenous administration. This research highlights the potential of neutrophil membrane-based nanocapsules for developing personalized nanomedicines for inflammatory diseases.

Besides neutrophil membranes (NMs), neutrophils can serve as direct vehicles for mediating NPs to ischemic sites. Mu et al . developed a cinnamyl-functionalized D-phenylalanine (CFLFLF) modified, ROS-responsive NP encapsulating ligustrazine (T-TMP) for treating cerebral I/R injuries by targeting neutrophils [ 102 ]. Given the presence of formyl peptide receptors (FPRs) on the surface of neutrophils, this study modified nanoplatforms by incorporating the peptide cinnamyl-F-(D)L-F-(D)L-F (CFLFLF), which specifically binds to FPRs. After intravenous injection, these NPs effectively adhere to neutrophils in peripheral blood via FPR, allowing them to "ride" with neutrophils and accumulate more efficiently at the inflammatory site of cerebral ischemia. The NP shell is composed of a polymer with reactive oxygen species (ROS)-responsive bonds, encapsulating ligustrazine, a natural neuroprotective product. This strategy overcomes the limitations of TMP, such as short half-life, poor water solubility, and low bioavailability, enhancing its bioavailability and targeting ability for cerebral ischemia. This innovative drug delivery system offers a universal platform for treating IS and other inflammation-related diseases using modern drug preparation technology.

Neutrophils possess robust phagocytic capabilities that can be harnessed to achieve the ‘Trojan Horse’ effect. Pan et al . developed OMV@PGZ, a brain-targeted nanoplatform using bacterial outer membrane vesicles (OMVs) loaded with pioglitazone (PGZ) for IS treatment [ 103 ]. Neutrophils take up OMV@PGZ via LPS-TLR4 interaction and transport it across the BBB to ischemic sites. PGZ activates PPARγ, reducing inflammation and oxidative stress, and promoting anti-inflammatory agents. It also restores mitochondrial activity and prevents ferroptosis, protecting the nervous system. Notably, the transcription factors Pou2f1 and Nrf1 of oligodendrocytes are identified for the first time to be involved in this process and promoted neural repair by single-nucleus RNA sequencing (snRNA-seq). OMV@PGZ shows promise for IS treatment with a good biosafety profile and potential for broader neurological disorder therapies.

Summarizing the aforementioned research findings, it can be observed that there are two primary strategies to mitigate inflammation. First, to limit the influx of inflammatory cells from the bloodstream into the site of injury, and second, to suppress the activation and multiplication of inflammatory cells at the site of focus. The vast majority of studies have adopted either one strategy or the other. However, employing both strategies concurrently may yield superior outcomes. Wang et al . engineered McM/RNPs, combining monocyte membrane-coated PLGA NPs with rapamycin to create targeted anti-inflammatory ‘shield and password’ nano-soldiers [ 104 ]. These NPs adhere to inflamed endothelial cells, preventing further inflammatory cell infiltration into the brain. Upon reaching the injury site, they release rapamycin, curbing inflammation by limiting microglial cell proliferation. McM/RNPs have shown promise in reducing inflammation, enhancing neurological scores, and decreasing infarct volume post-surgery for MCAO. This dual-functional monocyte membrane-functionalized drug delivery system (MCM/RNPs) achieves synergistic immunochemotherapy for IS. Thus, MCM/RNPs present a promising formulation strategy for enhancing the clinical treatment of IS.

In conclusion, various NPs, such as polymer-based, biomimetic, and inorganic types, are used for the anti-inflammatory treatment of IS. They improve drug delivery through the BBB, increase bioavailability, and target ischemic areas and inflammatory cells effectively. NPs modulate microglia activation to combat neuroinflammation, overcoming the limitations of traditional therapies. These innovative strategies promise improved outcomes for IS management through enhanced specificity and bioavailability.

Inflammation plays a dual role, acting as either a component of the body's reparative mechanisms or a potential cause of local tissue damage. Therefore, it is imperative to strike a balance between suppressing the inflammatory process and upholding normal immune function in the management of IS. NP-based drug delivery systems must be precisely targeted to the inflammatory sites to prevent harm to healthy tissues. Consequently, nanotechnology is leveraged to engineer more accurate and effective NPs to mitigate adverse effects on normal tissues. Moreover, the incorporation of molecular imaging technology into NP-based drug delivery systems is envisaged for real-time monitoring and assessment of inflammatory responses, thus guiding the therapeutic regimen for IS.

The pathological mechanism of cell death

The damage resulting from mitochondrial dysfunctions, oxidative stress, inflammation, and excitotoxicity in IS can trigger a range of cellular signaling cascades. These events can drive neural cells to experience programmed cell death, such as apoptosis and autophagy, which are intrinsic cellular processes, or unprogrammed cell death, like necrosis, often instigated by external influences [ 105 ]. Necrosis is a form of pathological cell death triggered by severe physical, chemical, or other pathological stressors [ 106 ]. Necrotic cells experience an increase in membrane permeability, resulting in cell swelling, organelle distortion or enlargement, early absence of nuclear morphological changes, and eventual cell membrane rupture (Fig.  12 A). The release of cellular contents through lysis by necrotic cells incites an inflammatory response [ 107 ]. Subsequent tissue and organ healing often involves fibrosis, leading to scar formation. Autophagy represents a crucial evolutionary mechanism for the turnover of intracellular components in eukaryotic organisms [ 108 ]. Within this process, impaired proteins or organelles are encapsulated by autophagic vesicles characterized by a double-layered membrane structure. Subsequently, these vesicles are directed to lysosomes for degradation and recycling [ 109 ]. The essence of autophagy is the membrane rearrangement in the cell, and its occurrence process can be roughly divided into the following four stages (Fig.  12 B): (1) Initiation of autophagy. (2) Formation of isolation membranes and autophagosomes. (3) The autophagosome fuses with the lysosome. (4) Cleavage of autophagosomes [ 110 ]. Apoptosis, regulated by environmental cues, progresses through stages (Fig.  12 C): activation, apoptotic body formation, and phagocytosis. Cells undergo volume reduction, cytoplasmic changes, mitochondrial dysfunction, and DNA fragmentation. Phosphatidylserine shifts outward, maintaining membrane integrity [ 111 ]. Apoptotic bodies form without inflammation, apoptosomes can be quickly engulfed by surrounding full-time or part-time phagocytes [ 112 ]. In circumstances where the ischemic core lacks sufficient oxygen and glucose, irreversible necrosis typically ensues. Conversely, minor injury in the penumbra area can trigger reversible cellular death mechanisms such as apoptosis and autophagy [ 113 ].

Cell death process involved in IS.

NP-based therapeutics in neuron regeneration therapy for IS

IS-induced CNS damage contributes to mortality and disability due to limited neuronal regeneration and glial scarring. Exogenous stem cell transplantation and gene therapy show promise in promoting neuronal regrowth and tissue restoration post-IS. NPs incorporating stem cells and gene therapy offer a cutting-edge approach to enhance neural recovery after cerebral ischemia, addressing the limitations of conventional treatments.

Stem cells, including neural stem cells (NSCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and endothelial progenitor cells (EPCs), hold promise for treating IS by promoting neural recovery [ 114 ]. However, challenges such as the hostile post-IS environment, limited endogenous NSCs, lack of neural differentiation factors, and preferential astrocytic differentiation of transplanted NSCs hinder their therapeutic efficacy [ 115 ]. Complications like fibrosis, functional loss, and immune rejection further impede treatment success [ 116 ]. Innovative strategies, such as embedding functional NPs within stem cells, have shown promise in overcoming these barriers. This approach can boost the robustness and cytokine-secreting capacity of the stem cells, thereby enhancing their overall reparative potential for IS.

Jiang et al . developed a novel strategy using a ROS-responsive polymer, B-PDEA, to deliver BDNF plasmid DNA into NSCs, enhancing BDNF secretion [ 117 ]. The polyplex NPs disassembled within cells due to ROS, releasing the DNA for effective gene delivery. Transplanting BDNF-modified NSCs into mice increased brain BDNF levels significantly. BDNF-NSC administration improved outcomes in cerebral ischemia mice compared to non-transfected NSCs. The B-PDEA/pBDNF polyplex-transfected NSCs showed increased BDNF secretion in vitro and in vivo, leading to better recovery of neurological and motor functions and reduced mortality in MCAO mice. In conclusion, the present study investigates the ROS-responsive charge-reversal polymer B-PDEA as the first successful nonviral vector for effective genetic transfection of NSCs. Consequently, the B-PDEA/pBDNF polyplex-transfected NSCs secreted significantly more BDNF in vitro and in vivo in ischemic brain regions, leading to notably decreased mortality of MCAO mice and the improved reconstruction of neurological and motor functions.

Extracellular vehicles (EVs) represent an innovative cell-free therapeutic alternative for the treatment of IS, offering benefits such as comparable physiological functions to parent cells, minimal volume, reduced immunogenicity, and the capacity to cross the BBB, a distinct advantage over traditional stem cell therapies. Ruan et al . utilized copper-free click chemistry to modify extracellular vesicles (EVs) from M2 microglia with the high-affinity ligand DA7R targeting damaged blood vessels and a variant of SDF-1 to attract NSCs, creating Dual-EVs for IS treatment (Fig.  13 A) [ 118 ]. These engineered EVs enhanced NSC neuronal differentiation without compromising their functionality (Fig.  13 B). The DA7R-modified EVs effectively targeted HUVECs, with the additional SDF-1 modification increasing uptake and promoting NSC migration (Fig.  13 C). In a mouse tMCAO model, Dual-EVs carrying both ligands improved neurological recovery by enhancing NSC attraction to the ischemic site, stimulating neurogenesis, and improving overall neurological function (Fig.  13 D). These Dual-EV nanocarriers offer new insights into treating neuronal regeneration following CNS injuries and targeting endogenous stem cells. The use of click chemistry with EV/peptide/chemokine and related nanocarriers represents a promising approach for enhancing human health.

Click chemistry extracellular vesicle/peptide/chemokine nanocarriers for treating central nervous system injuries. A Schematic illustration of DA7R-SDF-1-EV nano-missile (Dual-EV) treatment on IS. B Effect of M2-EV on NSC differentiation. C Internalization of different EVs by HUVECs and its recruitment effect on NSCs. D Ischemic brain-targeting ability of Dual-EV in vivo.

Cerebral ischemia can alter gene expression, prompting the use of gene therapy to introduce exogenous genes or modulate existing ones in the ischemic penumbra. This aims to reduce neuronal damage by enhancing blood flow or modifying cellular processes. Genes related to angiogenesis, antioxidant defense, anti-apoptosis, and hypoxia response, like VEGF, show promise in post-stroke treatment. However, gene therapy faces challenges due to poor targeting and transfection efficiency of DNA or RNA alone. NPs have emerged as crucial carriers for gene delivery, enhancing the success of gene therapy for IS.

Hypoxia-inducible factor 1-alpha (HIF-1α) plays a crucial role in angiogenesis post-ischemia. Deng et al . developed RGD-DMAPA-Amyp NPs by attaching RGD peptides to a cationic polymer, enhancing targeted HIF-1α delivery [ 119 ]. The results demonstrated that RGD-DMAPA-Amyp has good biocompatibility and a high cell uptake rate, indicating it is a safe nonviral gene vector for human cell endocytosis. In rat models of IS, RGD-DMAPA-Amyp NPs accumulated more in vascular endothelial cells of the peri-infarct region compared to the non-targeted nanocarrier group, significantly improving neurological function recovery. The RGD-modified nanomedicine promotes nerve function recovery more efficiently and shows the potential to significantly promote new blood vessel formation in vivo. These findings suggest that the RGD-modified nonviral gene vector containing HIF-1α-AA is a safe and promising therapeutic strategy for IS gene therapy.

Heme oxygenase-1 (HO1) is an important antioxidant enzyme that breaks down heme into carbon monoxide, biliverdin, and iron ions, leading to anti-inflammatory effects. Increasing HO1 expression in penumbral regions could help reduce reperfusion injury post-IS. Oh et al . developed self-assembling NPs (HSAP-NP/pHO1) containing hypoxia-targeted anti-RAGE peptides (HSAP), deoxycholate-conjugated polyethylenimine-2 k (DP2k), and an HO1 plasmid (pHO1) for IS treatment [ 120 ]. These NPs showed superior gene delivery and expression compared to HSAP or DP2k/pHO1 alone in ischemic areas. In rat models of MCAO, stereotaxic injection of HSAP-NP/pHO1 NPs had a significant therapeutic effect. Therefore, HSAP-NP may be a useful gene and peptide therapy system for stroke therapy with dual functions of hypoxia-specific gene delivery and cytoprotective effects. This system holds promise as an advanced platform for combined gene and peptide delivery in stroke therapy, offering precise gene transfer to hypoxic regions and enhanced cellular protection.

HMGB1 is a DAMP released by dying cells and immune cells, exacerbating inflammation in IS. Kim et al . used e-PAM-R dendrimers for intranasal delivery of HMGB1 siRNA in MCAO rats, achieving knockdown and reducing brain damage [ 121 ]. FITC-labeled control siRNA was intranasally delivered in normal adult rats using e-PAM-R, a biodegradable PAMAM dendrimer, as a gene carrier. Within 1 h fluorescence-tagged siRNA was observed in neurons and glial cells across various brain regions. The fluorescence persisted for at least 12 h. Intranasal delivery of siRNA targeting HMGB1 significantly reduced its expression in brain regions like the prefrontal cortex and striatum. Importantly, this approach markedly reduced infarct volume in postischemic rat brains (up to 42.8 ± 5.6% reduction at 48 h post-MCAO), leading to improvements in neurological and behavioral deficits. These results indicate that the intranasal delivery of HMGB1 siRNA offers an efficient means of gene knockdown-mediated therapy in the ischemic brain.

tFNAs, a type of DNA nanomaterial, have shown promise in enhancing NSCs proliferation, migration, and neuronal differentiation. Zhou et al . studied the neuroprotective effects of tFNAs on IS using a rat tMCAO model (Fig.  14 A) [ 122 ]. tFNAs were able to penetrate the brain tissue, cross the BBB, and protect neuronal cells from apoptosis in an OGD/R model by disrupting the ischemic cascade (Fig.  14 B). They improved the ischemic microenvironment by upregulating erythropoietin and reducing inflammation, leading to decreased neuronal loss, cell apoptosis, infarct volume reduction, and neurological deficit improvement in the tMCAO rat model (Fig.  14 C). Inhibition of the TLR2-MyD88-NF-κB pathway may be a key mechanism of tFNAs' neuroprotective effects (Fig.  14 D). tFNAs are a safe and versatile nano-neuroprotective agent for IS therapy. However, the absence or presence of normal function in these regenerated neurons that were induced by tFNAs requires further exploration.

© 2021 American Chemical Society

A DNA nanostructure-based neuroprotectant against neuronal apoptosis via inhibiting toll-like receptor 2 signaling pathway in acute IS. A Schematic diagram of tFNAs as neuroprotective agents for the treatment of IS. B Protection of tFNAs for apoptosis of SH-SY5Y cells via interfering with the ischemia cascades in OGD/R models in vitro. C tFNAs reduce the infarct volume, alleviate mortality, and ameliorate functional outcomes of tMCAO models. D Potential mechanism of the protective effects of tFNAs on IS.

In addition, gene delivery based on NPs combined with NSC is used for neuronal regeneration therapy in IS. The regenerative processes following IS can be hindered by myelin-associated inhibitors (MAIs) such as oligodendrocyte myelin glycoprotein and Nogo-A, which are known to impede axonal regeneration and neuronal differentiation. Targeted therapies that aim to knock down the expression of genes related to these inhibitory proteins could potentially enhance neural regeneration and recovery. Lu et al . developed a novel strategy using a block copolymer PEI-PLA combined with SPIONs to create an MRI-visible nanocarrier (SPION-CP) for siRNA delivery targeting the NgR gene [ 123 ]. MRI demonstrates that nanomedicine provides non-invasive imaging of NSC migration and homing. Additionally, epigenetic downregulation of NgR genes in NSCs counteracts the inhibitory microenvironment of stroke, significantly enhancing neuronal differentiation of exogenous NSCs and promoting functional recovery in acute IS. The therapeutic potential of our siRNA nanomedicine allows for controlled stem cell differentiation, easily tracked by MRI. This has significant implications for developing new stem cell therapy paradigms for stroke and other neurological disorders.

Lin et al . developed an MRI-detectable nanocarrier for the simultaneous delivery of siRNA/ASO and SPIO NPs into NSCs targeting Pnky lncRNA in a mouse model of AIS (Fig.  15 A) [ 124 ]. Pnky-SPIO-PALC nanocarriers increased neuronal differentiation and showed migration from the infarct core to the periinfarct cortex (Fig.  15 B). Confocal microscopy revealed lysosomal localization of siRNA/ASO. Inhibition of Pnky lncRNA by SPIO-PALC complex reduced Pnky levels. Mice treated with Pnky-SPIO-PALC NSCs exhibited improved recovery compared to control (SCR)-SPIO-PALC (Fig.  15 C). This multifunctional nanomedicine can be used to direct stem cell differentiation and in vivo track the stem cells after transplantation, which highlights its great potential as a promising platform to regulate the stem cell fate and thus lays down a foundation for developing stem cell-based therapies for strokes and other neurologic diseases.

Nanomedicine directs neuronal differentiation of neural stem cells via silencing long noncoding RNA for stroke therapy. A Schematic illustration of the preparation for MRI-Visible siRNA/ASO complexed nanomedicine, directed neuronal differentiation of transplanted NSCs by silencing pnky lncRNA and MRI tracking of NSCs in a mouse stroke model. B In vitro and in vivo neuronal differentiation mediated by Pnky downregulation. C Safety and efficiency of Pnky knockdown with MRI-visible nanomedicine.

Yang et al . used Ca-MOF to develop an effective miR-124 nano-carrier system (Ca-MOF@miR-124) for treating IS [ 125 ]. At safe concentrations, Ca-MOF@miR-124 NPs promoted NSC proliferation by releasing miR-124, which was internalized via endocytosis. The acidic lysosomal environment facilitated miR-124 release into the cytoplasm, accelerating neuronal differentiation. Ca-MOF@miR-124 NPs enhanced NSC maturation into functional neurons within 5 days, surpassing control group differentiation rates. Treatment with Ca-MOF@miR-124 NPs reduced ischemic brain area, leading to significant recovery by day 7. Ca-MOF@miR-124 NPs effectively overcome the instability of naked miR-124 degraded by nucleases and the difficulty in internalizing it through the cell membrane due to its multiple anionic charges, making it widely applicable in clinical treatment based on the characteristics of miR-124. Combining Ca-MOF@miR-124 NPs with NSC therapy shows promise for enhancing traumatic neural injury and neurodegenerative condition treatments, improving patient outcomes.

Regenerative medicine, focusing on stem cells and gene therapy, shows promise for nerve regeneration and treating IS and other nerve injuries. Stem cell and gene therapy NPs offer innovative treatments, aiming for nerve recovery. IS results from brain blood flow obstruction, causing neuronal damage and functional loss. Combining stem cell therapy, gene therapy, and nanotechnology offers a multi-modal approach to enhance recovery and regeneration post-IS. Furthermore, EVs isolated from various sources, including animal cells, plant cells, and bacteria, exhibit promising potential as NP-based drug delivery systems. These vesicles harbor bioactive constituents inherited from parent cells, enabling them to act as natural therapeutic agents. And they can take advantage of their natural structure to facilitate the transport of exogenous drugs. Consequently, we believe that EVs have significant utility in attenuating cell death and managing IS.

NPs-mediated combination therapy for IS

Integrating neuroprotective agents with distinct modes of action into a single formulation capable of influencing multiple pathological states can markedly amplify the therapeutic benefits in the management of IS. Yuan's team has developed TPCD NPs, which are nano-therapies with multi-targeted pharmacological actions for AIS. TPCD NPs are synthesized using an active oligosaccharide base, TPCD, covalently bonded with Tempol and phenylboronic acid pinacol ester (PBAP) on β-cyclodextrin [ 126 ]. These NPs reduce oxidative stress, enhance antioxidant enzyme expression, and reduce inflammation at the cellular level, preventing neuronal cell death (Fig.  16 A, B). Intravenously delivered TPCD NPs target ischemic brain damage in MCAO mouse models, reducing tissue death and restoring neurological functions. They act as ROS-sensitive nanocarriers for the controlled release of the anti-inflammatory peptide Ac2-26, forming the ATPCD NP. In vivo tests show that ATPCD NP outperforms TPCD NP due to its superior anti-inflammatory efficacy. In summary, ATPCD NP integrates anti-inflammatory, antioxidant, and anti-apoptotic "three carriages" for precise targeted pathological and physiological treatment of IS, significantly improving in vivo efficacy. Therefore, TPCD NP-derived nanomedicines can be further developed as promising targeted therapies for stroke and other inflammation-related cerebrovascular diseases.

Copyright © 2021, American Chemical Society

Targeted treatment of IS by bioactive NP-derived ROS-responsive and inflammation-resolving NPs. A TPCD NP inhibited microglial activation. B TPCD NP attenuated oxidative and inflammatory responses in MCAO mice.

Liu et al . developed a neutrophil-mimicking nanobuffer (LA-NM-NP/CBD) to counteract the negative effects of elevated pro-inflammatory agents in stroke (Fig.  17 A) [ 127 ]. The nanobuffer cleared inflammatory factors and ROS in cell experiments and preferentially accumulated in the infarct core in rat models (Fig.  17 B). It neutralized harmful agents in the penumbra and modulated neuronal vitality with controlled CBD release (Fig.  17 C). In vivo studies showed a reduction in harmful factors in the core and penumbra, decreased infarct size, and improved neurological outcomes. The nanobuffer strategy was first proposed in this study to remodel the hostile environment of the core and protect the salvageable penumbra for the treatment of IS. LA-NM-NP/CBD indeed played a comprehensive therapeutic role via remodeling the microenvironment of the ischemic core and simultaneously protecting the penumbra by neutralizing detrimental factors from the core and slowly releasing CBD. The nanobuffer provided a promising strategy for treating IS by modulating the core as well as the penumbra.

Copyright © 2022, American Chemical Society

Neutrophil-bomimetic “nanobuffer” for remodeling the microenvironment in the infarct core and protecting neurons in the penumbra via neutralization of detrimental factors to treat IS. A Schematic illustration of LA-NM-NP/CBD preparation and its nanobuffer effect. B Nanobuffer effect of LA-NM-NP/CBDs against the core and neuroprotective effect for the penumbra in vitro. C Nanobuffer formed at the infarct core by the accumulation of LA-NM-NPs and buffering detrimental erosions in vivo.

In summary, IS involves the occurrence and development of multiple pathophysiologies, and single-functional NPs exhibit limited efficacy in addressing the intricate and interconnected cascade reactions. Multi-functional targeted neuroprotective NPs have great potential for the treatment of IS ischemia and reperfusion. This approach signifies the direction for future advancements in the field.

Conclusions and perspectives

IS pathogenesis is marked by a complex interplay of pathophysiological processes, including excitotoxicity, oxidative stress, inflammation, and cellular death. The distinctive properties of the BBB present a significant challenge, as they impede the delivery of many potent therapeutic agents to areas affected by cerebral ischemia. This barrier has been a primary factor contributing to suboptimal clinical outcomes due to the inability to target ischemic zones with specific treatments effectively. In response to this challenge, the remarkable brain-targeting capabilities and BBB permeability of NPs have sparked innovative research. Scientists have developed an array of NP-based strategies for targeted therapeutic delivery to ischemic brain regions. These strategies primarily utilize NPs designed for neuroprotection and those optimized for combination therapy. These advancements in NP-mediated treatment modalities have demonstrated promising results in enhancing the efficacy of IS treatment during preclinical studies.

In addition, the drug delivery pathway is a crucial factor that influences the ability of NPs to target the brain. In the context of IS therapy, intravenous injection stands out as the preferred method for delivering NPs, offering operational convenience, the ability to administer high dosages, and minimal invasiveness. Following intravenous administration, the fate of NPs within the body is determined by factors such as their particle size, surface targeting groups, and surface charges. Notably, NPs tend to interact with plasma proteins, giving rise to a “protein corona” on their surfaces, which hinders their ability to target the brain effectively and permeate the BBB [ 128 ]. While an alternative, non-invasive approach via the intranasal route has been documented to bypass the BBB and swiftly achieve therapeutic drug concentrations, the drawback lies in the limited delivery dosage associated with intranasal administration [ 129 ]. Additionally, the motion of cilia and the presence of mucus present further obstacles by obstructing the delivery of medications to the brain. Alternative methods, including retro-orbital and intrathecal injections, provide a direct pathway for delivering therapeutic agents to the brain, circumventing the BBB. Nonetheless, these approaches are limited by the requirement for advanced injection skills and the significant discomfort they cause to patients. In an attempt to preserve the vitality of stem cells and boost the efficiency of RNA or DNA transfection, certain NPs tailored for stem cell or gene therapy have been utilized for highly invasive intracranial administration. Considering the varied mechanisms of action and targeting strategies of NPs, the achievement of optimal therapeutic results can be facilitated by the choice of suitable administration routes.

In conclusion, the advancements in NPs-mediated approaches for treating IS are evident in several key areas: (i) improving the stability of therapeutic substances in the blood and extending their circulation time; (ii) enhancing the targeting of the brain and permeability of the BBB for therapeutic agents; (iii) reducing the toxicity of therapeutic agents; (iv) enhancing the viability of stem cells and improving the efficiency of delivering therapeutic genes; (v) combining therapeutic agents targeting different aspects into a single nano-formulation for synergistic therapy. This suggests a promising future for the clinical application of NPs in IS treatment.

Despite the substantial progress in NP development, certain challenges impede their clinical translation. Initially, NPs frequently focus on individual pathological processes associated with IS, thereby neglecting to offer a holistic shield for the central nervous system. Additionally, the intricacy of integrating various therapeutic agents within a single nanocarrier system may impede their translation into clinical practice. Secondly, animal models of cerebral ischemia may not fully replicate the pathogenesis seen in human patients. Thirdly, while efforts to enhance brain targeting through modifications and biomimetic strategies have shown promise, the BBB remains a significant obstacle for NPs to overcome, resulting in many NPs failing to reach the ischemic regions in the brain. Utilizing the body's endogenous components or physiological mechanisms may represent a viable approach to facilitate the transport of NPs across the BBB. Lastly, understanding the intracerebral fate of NPs is crucial for improving the treatment effect of IS and ensuring their long-term safety in clinical settings. Further research and development are needed to address these challenges and optimize the efficacy and safety of NP-based therapies for IS treatment.

A substantial disparity persists between the preclinical trials and the practical utilization of NPs in treating IS. Given the unique brain structural characteristics and intricate injury mechanisms associated with this condition, NPs necessitate a thoughtful design approach that integrates their ability to penetrate the BBB with the specific microenvironment of ischemic regions. This strategic design aims to enhance targeted delivery to the lesion site. Furthermore, there is a crucial need for an in-depth exploration of the pathological mechanisms of IS and effective therapeutic drugs to restore impaired neurological functions, ultimately mitigating disability and mortality among patients. As nanomedicine advances and our understanding of IS's pathophysiology deepens, it becomes imperative to enhance the biological functionalities of NPs to facilitate their clinical translation for more effective treatment of IS.

Data availability

Data will be made available on request. No datasets were generated or analysed during the current study.

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Acknowledgements

W. Liu and L. Liu contributed equally to this work. This study was supported by the National Nature Science Foundation of China (No. 52103170), National Key Research and Development Project of China (No. 2018YFC1315200), the National Research and Development Program of China (No. 2017YFC1307701) and the traditional Chinese Medicine Science and Technology Project of Qingdao (No. 2022-zyyz07).

The National Nature Science Foundation of China, 52103170, National Key Research and Development Project of China, 2018YFC1315200, the National Research and Development Program of China, 2017YFC1307701, the traditional Chinese Medicine Science and Technology Project of Qingdao,2022-zyyz07

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Wei Liu, Lubin Liu contributed equally to this work.

Authors and Affiliations

Department of Emergency Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China

Wei Liu, Ju Bai, Jialiang Guan & Jinping Sun

Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China

Wei Liu & Hongzhao Qi

Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China

Lubin Liu & Yutong Xie

Clinical Laboratory, Qingdao Traditional Chinese Medicine Hospital (Qingdao Hiser Hospital), Qingdao Hiser Hospital Affiliated of Qingdao University, Qingdao, 266033, China

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J.S. and H.Q. supervised and organized the review. W.L., L.L., H.L. and Y.X. wrote the main manuscript text. J.B. and J.G. prepared Figs.  1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 . All authors reviewed the manuscript.

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Correspondence to Hongzhao Qi or Jinping Sun .

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Liu, W., Liu, L., Li, H. et al. Targeted pathophysiological treatment of ischemic stroke using nanoparticle-based drug delivery system. J Nanobiotechnol 22 , 499 (2024). https://doi.org/10.1186/s12951-024-02772-2

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Association among VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs11676382 polymorphisms and acute ischemic stroke

Affiliations.

• 1 Department of Neurosciences, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
• 2 Department of Pharmacology, Toxicology and Clinical Pharmacology, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
• 3 Department of Internal Medicine, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
• 4 Department of Geriatrics-Gerontology, "Iuliu Haţieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
• 5 Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
• PMID: 37653796
• PMCID: PMC10470791
• DOI: 10.1097/MD.0000000000034836

Acute ischemic stroke is a major cause of morbidity and mortality worldwide, and genetic factors play a role in the risk of stroke. Single nucleotide polymorphisms (SNPs) in the VKORC1, CYP4F2, and GGCX genes have been linked to clinical outcomes, such as bleeding and cardiovascular diseases. This study aimed to investigate the association between specific polymorphisms in these genes and the risk of developing the first episode of acute ischemic stroke in patients without a known embolic source. This retrospective, cross-sectional, observational, analytical, case-control study included adult patients diagnosed with acute ischemic stroke. The SNPs in VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs11676382 genes were genotyped and analyzed together with the demographic and clinical factors of the 2 groups of patients. The presence of SNPs in VKORC1 or CYP4F2 genes significantly increased the risk of ischemic stroke in the context of smoking, arterial hypertension, and carotid plaque burden. The multivariate logistic model revealed that smoking (odds ratio [OR] = 3.920; P < .001), the presence of carotid plaques (OR = 2.661; P < .001) and low-density lipoprotein cholesterol values >77 mg/dL (OR = 2.574; P < .001) were independently associated with stroke. Polymorphisms in the VKORC1 and CYP4F2 genes may increase the risk of ischemic stroke in patients without a determined embolic source. Smoking, the presence of carotid plaques, and high low-density lipoprotein cholesterol levels were reconfirmed as important factors associated with ischemic stroke.

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PBL - Stroke Case Study

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• Describe the blood supply of the brain.
• Explore the epidemiology of strokes.
• Explain the value of CT with and without contrast in this PBL scenario.
• Consider the treatment and prognosis of the patient.
• Amlodipine : A calcium channel blocker. It works by blocking calcium influx into smooth muscles cells of the wall
• Aphasia [2] : Difficulty in using language. It is categorised into four main types:
• Expressive aphasia – patients know what to say, but are having trouble saying what they mean.
• Receptive aphasia – patients are having difficulty making sense of the words or diagrams.
• Anomic aphasia – patients are facing problems recalling words, names or numbers. (“speaking in a
• Global aphasia – patients cannot speak, understand speech, read, or write. It is the combination of
• Pack year : unit for measuring the smoking history of a person as to be used in risk factor estimation.

• Equivocal plantar response : normal and consistent plantar reflex of both legs. Plantar reflex is a reflex elicited

• Haemorrhagic stroke : Aneurism of blood vessels in the brain that burst.
• Ischemic stroke : Blood vessels in the brain are either clog by local atherosclerosis or thromboembolism.
• Transient ischemic attack (TIA) : Same pathophysiology as ischemic stroke, but occurrence last less than 24 hours. Therefore, it is always a retrospective diagnosis.

• Explain the basic principle of CT with and without contrast in this PBL scenario.
• Thrombolytic (within golden 3-4.5 hours): Tissues plasminogen activator (tPA); Alteplase; Urokinase
• Intravenous fibrinolytic therapy
• Surgery: carotid endoterectomy/ angioplasty
• Ultrasound-enhanced thrombolysis
• Speech & language therapy helps people who have problems producing or understanding speech.
• Physiotherapy helps with relearning movement and co-ordination of muscles.
• Psychological care helps with common mental health problems such as depression.
• Occupational therapy helps with assessing patients’ home and improving their abilities to carry out daily activities such as dressing and eating.
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Global trends and hotspots in the study of the effects of PM2.5 on ischemic stroke

• Qian Liu 1 , 2 ,
• Shijie Yang 3 &
• HeCheng Chen 1 , 2  

Journal of Health, Population and Nutrition volume  43 , Article number:  133 ( 2024 ) Cite this article

Metrics details

The objective of this study was to visually analyse global research trends and hotspots regarding the role of PM2.5 in ischemic stroke.

The Web of Science core collection database was used to search the literature on PM2.5 and ischemic stroke from 2006 to 2024. Visualization analysis was conducted using CiteSpace, VOSviewer, and an online bibliometric platform.

The analysis comprises 190 articles published between 2006 and 2024 by 1229 authors from 435 institutions in 39 countries, across 78 journals. Wellenius GA has the highest number of published and cited papers. China has the highest number of papers, while Canada has the highest citation frequency. Capital Medical University published the highest number of papers, and Harvard University had the highest citation frequency for a single paper. The study investigated the impact of PM2.5 on ischemic stroke in three phases. The first phase analysed hospitalisation rates for correlations. The second phase utilised large-scale multi-cohort data from around the world. The third phase involved studying global exposure risk through machine learning and model construction. Currently, there is limited research on the mechanisms involved, and further in-depth investigation is required.

This paper presents a bibliometric analysis of the research framework and hotspots concerning the effect of PM2.5 on ischemic stroke. The analysis aims to provide a comprehensive understanding of this field for researchers. It is expected that research on the effect of PM2.5 on ischemic stroke will remain an important research topic in the future.

Introduction

Ischemic stroke is the leading cause of death and disability worldwide, posing a great threat to human health [ 1 ]. Air pollution is an individual risk factor for ischemic stroke independent of smoking, poor diet, and physical inactivity in the United States. Air pollution accounts for more than a quarter of the stroke burden. [ 2 ]. Airborne fine particulate matter (PM2.5, aerodynamic diameter < 2.5 μm) is the main component of air pollution. At present, a large number of studies have shown that air pollution are highly associated with an increased risk of ischemic stroke, especially PM2.5 [ 3 , 4 , 5 ]. Gu et al. found that for every 10 µg/ m 3 increase in the PM2.5 level in China, hospitalizations for acute cerebrovascular disease and Transient Ischemic Attacks increased by 0.20% and 0.33%, respectively [ 6 ]. Therefore, reducing air pollution and improving air quality are of great significance for reducing the incidence of ischemic stroke.

Bibliometric analysis is a widely used method for evaluating the quality and impact of academic research in various fields [ 7 , 8 , 9 , 10 ]. It presents the knowledge structure and research status of a field more intuitively through quantitative analysis of published literature, making it a faster and more accurate way to study trends and hotspots compared to systematic and wide-ranging reviews and other types of literature research. [ 11 , 12 , 13 ].

Research on the impact of global air pollution on human health has led to a gradual deepening of our understanding of the effect of air pollution on stroke. Specifically, research on the impact of PM2.5 on ischemic stroke has been ongoing for decades, resulting in significant developments and high-quality research results. To date, no bibliometric study has been conducted on the impact of PM2.5 on ischemic stroke to explore the distribution characteristics and trends in this research field. Therefore, this study aims to bibliometrically the relevant literature on the effect of PM2.5 on ischemic stroke, explore the current hotspots and possible future trends in this research field, identify potential research gaps, and provide an important reference for researchers and institutions in this field.

Materials and methods

Data sources and search strategy.

The Web of Science (WOS) is an extensive, multidisciplinary database encompassing all high-impact scientific journals and distinguished indexes [ 14 , 15 , 16 ]. In comparison with Scopus or MEDLINE/PubMed, the literature measurement analysis facilitated by the WOS database can retrieve more comprehensive information [ 17 ]. A literature search using the Web Science Core (WoSCC) database on February 18, 2024. The articles were retrieved from January 1, 2000, to February 18, 2024.The search strategy employed was as follows:

(((((((((((((((((((((((TS=(Ischemic Strokes)) OR TS=(Stroke, Ischemic)) OR TS=(Ischaemic Stroke)) OR TS=(Ischaemic Strokes)) OR TS=(Stroke, Ischaemic)) OR TS=(Cryptogenic Ischemic Stroke)) OR TS=(Cryptogenic Ischemic Strokes)) OR TS=(Ischemic Stroke, Cryptogenic)) OR TS=(Stroke, Cryptogenic Ischemic)) OR TS=(Cryptogenic Stroke)) OR TS=(Cryptogenic Strokes)) OR TS=(Stroke, Cryptogenic)) OR TS=(Cryptogenic Embolism Stroke)) OR TS=(Cryptogenic Embolism Strokes))OR TS=(Embolism Stroke, Cryptogenic)) OR TS=(Stroke, Cryptogenic Embolism)) OR TS=(Wake-up Stroke)) OR TS=(Stroke, Wake-up)) OR TS=(Wake up Stroke)) OR TS=(Wake-up Strokes)) OR TS=(Acute Ischemic Stroke)) OR TS=(Acute Ischemic Strokes)) OR TS=(Ischemic Stroke, Acute)) OR TS=(Stroke, Acute Ischemic)

Step 1 AND Step 2, NOT TI = (“guideline” or “recommendation” or “consensus” or “case report” or “meta” or “review”), AND Language = English. A total of 308 relevant articles were searched.

After conducting an initial data search, two authors screened all manuscripts. Any discrepancies identified by the authors were then independently screened by a third author to ensure their relevance to the topic of this study. A total of 190 documents were retrieved and exported as ‘full records and citation references’ and ‘tabs separate files’ for further analysis.

Data analysis

The bibliometrics used in this study mainly include evaluation techniques and relational techniques [ 18 ]. Evaluation techniques are employed to assess the productivity and impact of scientific papers. These include the number of publications, which is used to assess productivity [ 19 ]; the number of citations, which is used to measure the impact of publications [ 20 ]; the h-index [ 21 ], which is used to measure the number of citations to “h” papers; the g-index, which is used to identify the largest number such that the top g articles receive at least g2 citations [ 22 ]; and the m-index, which takes into account the number of years since the article was published [ 23 ]. These techniques have been employed in the analysis of the PM2.5 effect on ischemic stroke, which has been conducted in collaboration with the most prolific authors and journals in this field. Concurrently, relational techniques are employed to investigate the co-occurrence of keywords and the co-citation of journals, with the generation of a visual graph. The term “co-citation” is used to describe the practice of multiple articles being cited jointly. The outcome of a keyword co-occurrence analysis is a network of topics and their interconnections. The content of a document is examined through the lens of a specific word, which can shed light on the relationship between concepts within a given field [ 24 ]. The higher the frequency of words, the stronger the conceptual connections [ 25 ].

The data in “tabs separate files” were imported into the bibliometric online analysis platform ( http://bibliometric.com ) to analyze the relationship between the collaborating countries/regions. CiteSpace [ 26 ] and VOSviewer [ 27 ], the two most commonly used visual tools analysis software in bibliometrics are mainly used to observe research hotspots and trends in a certain field and visualize them in graphical form [ 27 , 28 ]. We applied CiteSpace (version 6.2.R4) and VOSviewer (version 1.6.20) software to visualize bibliometric data. Imported in “full record and citation reference” format and collaborated on the filtered literature between countries/regions, co-authored and co-citation, co-occurrence, clustering and burst analysis. The PRISMA flowchart illustrates the methodology employed in this study, delineating the procedures undertaken for data acquisition, cleaning, and inclusion (Fig.  1 ) [ 23 , 29 ].

PRISMA flowchart

Following a rigorous process of literature cleaning, inclusion, and exclusion, a total of 308 literature sources were downloaded. These sources were then filtered to exclude early access literature, correction literature, editorial materials, conference abstracts, and conference proceedings. The final number of literature sources included for analysis was 190. The literature spanned the period from 2006 to 2024 and included 78 journals, 1229 authors, 435 institutions, and 39 countries. There were 5775 references cited.

Publication review

Publication numbers.

The top 5 by number of publications by author, country, institution and journal, as well as by citations, are summarised in Table  1 . The top author by the number of publications and citations was Wellenius GA, with 8 publications and an average annual citation number of 88.875; this author focuses on the effect of duration of PM2.5 exposure on ischemic stroke and the relationship between air pollution exposure and ischemic stroke risk in women. The country with the most published studies was China with 106 publications and an average annual citation number of 37.831. Articles from the United States had the highest total number of citations and articles from Canada had the highest average number of citations at 106.077. Capital Medical University published the most articles, with a total of 16 articles, and the average citation of each article was 14.062. Harvard University had the highest average citations per article, which was 282.714. The Table  2 shows that the United States Department of Health and Human Services sponsored the highest number of articles in terms of funding sources. SCIENCE OF THE TOTAL ENVIRONMENT published the most articles, but the average single citation of ENVIRONMENTAL POLLUTION was the highest, which was 54.818.

Number of publications varies by year

By analyzing the number of papers published in a particular research field over the years and the countries in which they were published, we can determine the past development history of this field and the global attention to this field, and also predict the development prospects of this field.

The earliest study of PM2.5 on ischemic stroke was published by Paul J Villeneuve et al. in 2006 [ 30 ], and the number of publications has not increased significantly since then. A clear cut-off point was observed in 2014, and the number of published papers increased significantly thereafter (Fig.  2 ). The participation of countries and regions was an important factor affecting the number of papers published, and much of the contribution during this period was high-quality case-crossover analysis. In 2014, scholars in Taiwan published the first study on the effect of regional PM2.5 levels on ischemic stroke. Since then, the number of regional cooperation and broader studies has increased significantly. Subsequently, the length of PM2.5 exposure period, source methods, and different production scenarios were studied from multiple perspectives. The number of publications peaked in 2022. Therefore, the increase of multi-regional, multi-angle, multi-level research ideas and cooperation and exchange has greatly promoted the development of this research field.

Number of national publications per year

Inter-state cooperation

The United States had a large contribution to PM2.5 research. Four of the top five funding agencies were from the United States. Although the number of articles published in the United States was not the largest, the single cited number was the highest. Since 2013, China’s contribution to this field has become increasingly prominent, with the largest number of articles published in this field, and the National Natural Science Foundation of China has also funded the largest number of research projects in this field (Table  2 ). As a country with a large population and deeply affected by PM2.5, China has an extremely high prevalence of ischemic stroke. It has invested huge in this field and made outstanding contributions. It is believed that China will make greater contributions in this field in the future. China and the United States also have the most cooperation and exchanges in this field (Figure 3 ). The latest research results published by Wellenius GA in 2024 are cooperated with Chinese scholars [ 31 ], and there are many more such cooperation and exchanges.

Cooperation between countries

Distribution of citations between journals

The Dual-Map Overlay shows the distribution of citation relationships between journals (Fig.  4 ). The citing literature is on the left side of the graph, and the cited literature is on the right side of the graph. The colored path between the two represents the citation relationship. Two main citation pathways were found, indicating that studies published in veterinary, animal and natural sciences were mainly cited by studies published in environmental sciences, toxicology and nutrition. Studies published in neurology, kinesiology, and ophthalmology journals are primarily cited by studies published in health, nursing, and medical journals.

Dual-Map Overlay

Top 5 cited articles

The top 5 cited articles included 1 Meta-analysis articles and 4 clinical articles (Table  3 ). Publication dates ranged from 2011 to 2020. The article with the highest number of citations, entitled “An Integrated Risk Function for Estimating the Global Burden of Disease Attributable to Ambient Fine Particulate Matter Exposure”, was published by Burnett, Richard T et al. in 2014 in ENVIRONMENTAL HEALTH PERSPECTIVES , with a total of 1272 citations. Available relative risk information from studies of ambient air pollution (AAP), second-hand tobacco smoke, household solid cooking fuels and active smoking (AS) was integrated to fitted the integrated exposure response (IER) model, which estimated the combined risks of exposure to multi-source PM2.5 [ 32 ]. The second and fifth cited articles are the studies on the risk of PM2.5 exposure published by Shah AS et al. and Lipsett MJ et al. These studies elucidate the risk of PM2.5 exposure in two distinct aspects: short-term exposure and long-term exposure, respectively [ 33 , 34 ]. Air pollution in China remains a significant concern, with a considerable body of scholarship dedicated to understanding the impact of PM2.5 on public health. A review of the literature reveals that the third and fourth most-cited articles pertain to the disease burden associated with PM2.5 in China [ 35 , 36 ].

Co-citation analysis

Author co-citation network analysis.

Lotka’s law was used to determine the minimum number of co-citations. [ 37 ]. Fifty-seven authors met the criteria, with Pope Ca, Wellenius GA, and Tian YH being the top three co-cited authors. The authors were divided into three clusters (Fig.  5 ).

Co-citation author analysis Red : cluster1; Green : cluster2; Blue : cluster3

Professor Pope Ca from Brigham Young University has conducted comprehensive research on the multifaceted, multi-regional, and multi-level impact of PM2.5 on disease. His team has made a substantial contribution to the assessment of the global burden of disease caused by fine particulate matter. Wellenius, a professor at Boston University, has been engaged in research in the field of environmental and health sciences for an extended period. His contributions to the field include a significant impact on the understanding of the influence of PM2.5 on cardiovascular and cerebrovascular disease. His research has been based on a thorough examination of the local area of PM2.5, the duration of exposure, and the factors influencing the PM2.5 exposure. Professor Tian YH of Beijing University has conducted extensive research on the impact of PM2.5 in China. His studies have covered a vast area, encompassing up to 184 cities, and have focused on the effects of PM2.5 on ischemic cerebral apoplexy. The findings have been used to inform national policy.

Journals co-citation network analysis

If at least one article from both journals is cited in the cited article, two journals are considered to be cited simultaneously [ 38 ]. Seventy journals met the criteria, with ENVIRONMENTAL HEALTH PERSPECTIVES , STROKE , and ENVIRONMENT INTERNATIONAL being the top three cited journals (Fig.  6 ). The total number of citations for ENVIRONMENTAL HEALTH PERSPECTIVES was high, and the average number of citations per article was as high as 211.14.

Co-citation Jour analysis Red : cluster1; Green : cluster2; Blue : cluster3

Literature co-citation network analysis

Literature were cited analysis is a widely used to study the knowledge in certain areas framework method [ 39 ]. Figure  7 shows the literature co-citation network in the field of PM2.5 effect on ischemic stroke. In the figure, a node represents a document/article, while the connecting line between the two nodes represents the co-cited association between the two articles. The larger the node, the more citations an article has. The smaller the distance between two nodes, the higher the citation frequency of the literature.

Co-citation reference analysis Red : cluster1; Green : cluster2; Blue : cluster3

There were 24 literatures that met the criteria (Fig.  7 ), and the top 3 cited references were Brook Robert D et al. 2010, Wellenius GA et al. 2012, and Wellenius GA et al. 2005. Brook Robert D et al. conducted a review of the effects of particulate air pollution on cardiovascular disease and concluded that the longer the exposure to PM2.5, the greater the risk of cardiovascular mortality and that lower levels of PM2.5 were associated with lower cardiovascular mortality [ 40 ]. Wellenius GA et al. found that exposure to PM2.5, a level considered generally safe by the US Environmental Protection Agency’s, increased the risk of ischemic stroke within hours of exposure. This means that lower levels of PM2.5 are not safe [ 41 ]. Wellenius GA et al. in 2005 found that PM2.5 levels increased the risk of ischemic but not hemorrhagic stroke [ 42 ]. The above three articles reached the same conclusion from different perspectives: exposure to PM2.5 may increase the risk of ischemic stroke. This provides a solid basis for further research.

Co-occurrence network and analysis of keywords

According to Lotka’s law, 88 keywords were included in the co-occurrence network analysis (Fig.  8 ). The co-occurrence network was divided into 6 clusters. A total of 10 bursts were identified, with the highest intensity being ‘hospital admissions’ (strength, 4.27), followed by ‘global burden’ (strength, 4.14). The last burst was “PM2.5” (strength, 3.89; Fig.  9 ). In order to better analyse the annual research hotspots and the overall trend of change in the research area, citespace was used to perform a timezone analysis of the keywords (Fig.  10 ). The whole graph was divided into several vertical blocks from 2006 to 2024, with an interval of one year. Each block had several nodes, and each node represented a keyword. The nodes are composed of one or more colours, and each colour represents a year. The colour in the outer circle of the node represents the closest to the present, and the width of the colour represents the popularity of the year. If the node is all red, it represents the central hot word. The connection between the nodes represents the connection between two keywords. As you can see from the figure, the study of PM2.5 and ischemic stroke only started in 2006, less than 20 years ago. From 2006 to 2008, a large number of studies on air pollution, ischemic stroke, cardiovascular disease, hospital admissions and exposure were carried out in this area and continue to this day. In 2022, PM2.5 became a central buzzword in the field. From 2011 to 2014, this field focused on the global health burden of PM2.5, using a large number of case-crossover analysis methods, and a large number of Chinese scholars began to pay attention to this field. From 2016 to 2018, this field began to focus on national and regional research, and there were a large number of studies on the effect of PM2.5 on ischemic stroke in China. At the same time, since 2016, this area has received more and more attention, reaching a peak in 2023. From 2018, more in-depth research will be conducted on PM2.5 as a risk factor, and attention to this area will become more popular. By 28 February 2024, the number of research articles in 2024 will have reached the level of the whole year 2014. Research on the effect of PM2.5 on ischemic stroke is expected to show an increasing trend in the future.

Co-Occurrence of key words Red : cluster1; Green : cluster2; Blue : cluster3; Yellow : cluster4; Purple: cluster5; Light blue: cluster6

Key words with the strongest citation bursts

Timezone of key words

Bibliometrics can help people understand the research focus, framework and trend of a certain field intuitively and comprehensively. PM2.5 has been widely studied as a risk factor for ischemic stroke, and reducing the level of PM2.5 can effectively reduce the occurrence of ischemic stroke. A summary of previous studies in this field has occasionally been reported, but there has been no bibliometric description of the literature in this field.

A bibliometric analysis of the study found that the most published author was Wellenius GA, who is affiliated with the Department of Environmental Health at the Boston University School of Public Health. The most cited article is a study by Burnett, Richard T et al., on risk estimation models for PM2.5 exposure. The research integrates the relative risk (RR) information of PM2.5 from different global scenarios and sources of different combustion types to construct and fit a sustainable and updated comprehensive exposure-response model, which can provide important reference for the regulation of PM2.5 32 . Air pollution from PM2.5 is a global problem that has caused a global health burden. In the early stage, almost all the studies on PM2.5 came from developed countries such as Europe and the United States. However, the worst affected areas of PM2.5 pollution are mainly in developing countries. However, the research in this field from developing countries starts very late, and there is a lack of primary epidemiological investigation. From Fig.  2 , we can find that the first study on China was reported in 2013, which was a study published by scholars in Taiwan on the relationship between PM2.5 level and hospitalization rate of ischemic stroke in Taipei City, Taiwan Province [ 43 ]. The initial study in this field was published in mainland China in 2014, although it was a Meta analysis [ 44 ]. This indicated that mainland China was also beginning to focus on the field. In India, another large developing country, the first study on PM2.5 within the country was not published until 2016 [ 45 ]. Furthermore, Burnett et al. not only included global PM2.5 data from various areas but also considered different sources of PM2.5 production, such as smoking, second-hand smoke, and household fuels. These sources are prevalent in daily life, which enhances the generalisation and wide application of the study’s conclusions. This also better illustrates the global PM2.5 exposure risk worldwide. At that time, the study by Burnett, Richard T et al. made a significant contribution to the global PM2.5 exposure problem and was undoubtedly a major achievement. A global integrated exposure-response risk assessment has been applied similarly, providing a crucial reference for policymakers in the field of global climate policy [ 46 , 47 , 48 ].

Co-citation analysis offers valuable insights into the structural characteristics of a research area. The authors were divided into three clusters based on their citations. Cluster 1 authors focused on studying the impact of PM2.5 levels on the risk of ischemic stroke in various regions of the world. Cluster 2 authors conducted a study on the relationship between PM2.5 levels and ischemic stroke risk in various regions of China. These researches included multiple perspectives on different exposure periods, surrounding environments, and different subtypes of ischemic stroke. Chen Gongbo et al. [ 49 ], Liang, Ruiming et al. [ 50 ] and Zhang, Yi et al. [ 51 ] conducted studies on the effects of long-term and short-term exposure to PM2.5 on the risk of ischemic stroke. They concluded that PM2.5 is associated with a high risk of ischemic stroke, regardless of the duration of exposure. Furthermore, studies have been conducted on the various components of PM2.5. Zhang et al. [ 51 ] discovered that exposure to NH4 + was linked to the highest risk of ischemic stroke, while polycyclic aromatic hydrocarbons (PHS) were primarily associated with ischemic stroke. NH4 + originated mainly from residential and agricultural emissions, while PHS mainly came from automobiles and other related fuel combustion [ 52 , 53 ]. Many of these studies are based on large, multi-city samples, Tian Y et al. conducted a study based on data from the National Urban Workers’ Basic Medical Insurance database, which recorded 8,834,533 patients hospitalized for cardiovascular reasons in 184 cities in China from 1 January 2014 to 31 December 2017. The study found that short-term exposure to PM2.5 was associated with increased hospital admissions for all major cardiovascular diseases except hemorrhagic stroke in China. This association was observed even when exposure levels did not exceed current regulatory limit [ 54 ], Cai M et al. found that exposure to PM2.5 was highly associated with a high risk of ischemic stroke recurrence in China, based on data from more than 1 million stroke patients [ 55 ]. The authors of Cluster 3 focus on risk assessment and model construction related to PM2.5. This provides a reference for preventing and treating PM2.5 exposure in the future.

The top 3 cited references were Brook Robert D et al. 2010 [ 40 ], Wellenius GA et al. 2012 [ 41 ], and Wellenius GA et al. 2005 [ 42 ]. The papers represent early and pioneering research in the field, providing a solid theoretical foundation for subsequent studies. The journals in which they were published are of high quality and widely accepted by researchers. The authors are also leading scientists in the field, and their research results are significantly forward-looking and instructive. The co-cited articles were divided into three categories. Cluster 1 was constructed around Wellenius GA et al. 2012 and Wellenius GA et al. 2005. These studies mainly demonstrated that PM2.5 contributes to the risk of ischemic stroke. Cluster 2 was constructed around Brook Robert D et al. In 2010, multiple cohorts and large sample data further confirmed that PM2.5 increases the risk of ischemic stroke. Cluster 3, as analysed by Tian Yh et al. in 2018, provides insight into the development trend and pattern of ischemic stroke caused by PM2.5 from a time series perspective.

To gain a better understanding of the dynamic developmental changes and patterns in the field, this study utilized Citespace for burst word analysis and Timezone analysis. The findings indicate that between 2006–2016, the field primarily focused on the relationship between air pollution and hospital admissions. The study found that air pollution significantly affected cardiovascular disease admissions, and when ischemic stroke was included in the study of cardiovascular disease. Between 2013 and 2017, researchers increasingly focused on the significant role of particulate matter in air pollution, including the effect of PM2.5 levels on ischemic stroke. The buzzwords during this period were ‘hospital admissions’ and ‘cardiovascular disease’. Between 2017 and 2020, scholars in the field shifted their focus towards the worldwide impact of air pollution. This period also saw a significant increase in the number of articles published in the field, with many developing countries joining the research efforts. The term ‘global burden’ was coined to describe this phenomenon. Since then, researchers have subdivided air pollution into different types, with PM2.5 receiving significant attention as a risk factor. This focus began with the explosion in 2022, which saw a peak in publications on the topic. In recent years, advancements in research methods have enabled researchers to conduct large-scale exposure risk assessments around the world regarding PM2.5 as a risk factor. This has provided valuable insights for the development of global climate policies. Therefore, the key terms for 2020–2024 are “PM2.5”, “risk factor”, and “modelling”.

This bibliometric study examines the impact of PM2.5 on ischemic stroke and serves as a valuable reference for those interested in this field. However, there are some limitations to consider. Firstly, the study only includes research articles, excluding conferences, letters, and articles in non-English languages, which limits the scope of the articles included. Secondly, the search was restricted to the WoSCC database. The WoSCC database covers most research articles, but it is challenging to guarantee the inclusion of all articles in the field. Despite these limitations, they do not affect the broad applicability of the findings of this study. The analyses are based on real-world data, and the results are reliable. They reflect the structural characteristics and dynamics of the field and are valuable for a comprehensive understanding of the field. Additionally, they are highly informative for the study of future trends in the field. There is a significant amount of high-quality evidence from clinical studies, epidemiological investigations, and large-sample model construction regarding the effect of PM2.5 on ischemic stroke. However, the mechanism behind this effect remains unclear and requires further research in the future.

The study of the effects of PM2.5 on ischemic stroke is a relevant and attractive field. Environmentalists, neurologists, and other professionals will continue to advance this field. In recent years, the addition of computationalists and meteorologists has led to the development of models and the use of meteorological satellite remote sensing. Bibliometrics analyses the research framework and hotspots of PM2.5’s impact on ischemic stroke, which is a significant driver of ischemic stroke. The model construction, based on large samples and multiple cohorts, effectively assessed the global exposure risk of PM2.5. This provides an important reference for the development of global climate change response strategies and helps researchers to have a more comprehensive understanding of the field, providing ideas for future research.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Airborne fine particulate matter aerodynamic diameter < 2.5 μm

Web Science Core

Polycyclic aromatic hydrocarbons

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Acknowledgements

We thank all study participants and data collectors for their participation and. cooperation. We also thank the Cerebrovascular Disease Center of Gansu Provincial. Hospital for their comprehensive cooperation and data support. We would like to. Thank the Key Laboratory of Cerebrovascular Disease of Gansu Province, China. (20JR10RA431), the Scientific Research Foundation of Gansu Provincial Hospital, China (Key Discipline Project) (2019 − 395), and Inhalable fine particulate matter. Promotes the activation of DAPKI/ERK pathway in brain tissue and its effect on. Ischemic stroke /ZX-62000001-2023-457.

This study was funded by the Key Laboratory of Cerebrovascular Disease of Gansu Province, China (20JR10RA431),the Scientific Research Foundation of Gansu Provincial Hospital, China (Key Discipline Project) (2019 − 395) and Inhalable fine particulate matter promotes the activation of DAPKI/ERK pathway in brain tissue and its effect on ischemic stroke /ZX-62000001-2023-457. There were no roles in study design, data collection, analysis, decision to publish, or manuscript preparation.

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Key Laboratory of Cerebrovascular Disease of Gansu Province, Gansu Provincial Hospital, Lanzhou, Gansu, China

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Qian Liu: conception, methodology, software, data collection, writing - original manuscript. Shijie Yang: methodology, software, data collection. Chen He Cheng: writing - revision, editing and financial support.

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Liu, Q., Yang, S. & Chen, H. Global trends and hotspots in the study of the effects of PM2.5 on ischemic stroke. J Health Popul Nutr 43 , 133 (2024). https://doi.org/10.1186/s41043-024-00622-3

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Received : 16 June 2024

Accepted : 14 August 2024

Published : 28 August 2024

DOI : https://doi.org/10.1186/s41043-024-00622-3

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