Publications by authors named "Christopher Chen"

687 Publications

Retinal imaging in Alzheimer's disease.

J Neurol Neurosurg Psychiatry 2021 Jun 9. Epub 2021 Jun 9.

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

Identifying biomarkers of Alzheimer's disease (AD) will accelerate the understanding of its pathophysiology, facilitate screening and risk stratification, and aid in developing new therapies. Developments in non-invasive retinal imaging technologies, including optical coherence tomography (OCT), OCT angiography and digital retinal photography, have provided a means to study neuronal and vascular structures in the retina in people with AD. Both qualitative and quantitative measurements from these retinal imaging technologies (eg, thinning of peripapillary retinal nerve fibre layer, inner retinal layer, and choroidal layer, reduced capillary density, abnormal vasodilatory response) have been shown to be associated with cognitive function impairment and risk of AD. The development of computer algorithms for respective retinal imaging methods has further enhanced the potential of retinal imaging as a viable tool for rapid, early detection and screening of AD. In this review, we present an update of current retinal imaging techniques and their potential applications in AD research. We also discuss the newer retinal imaging techniques and future directions in this expanding field.
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http://dx.doi.org/10.1136/jnnp-2020-325347DOI Listing
June 2021

High burden of cerebral white matter lesion in 9 Asian cities.

Sci Rep 2021 Jun 2;11(1):11587. Epub 2021 Jun 2.

Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.

Age-related white matter lesion (WML) is considered a manifestation of sporadic cerebral small vessel disease and an important pathological substrate for dementia. Asia is notable for its large population with a looming dementia epidemic. Yet, the burden of WML and its associated risk factors across different Asian societies are unknown. Subjects from 9 Asian cities (Bangkok, Bandung, Beijing, Bengaluru, Hong Kong, Kaohsiung, Manila, Seoul, and Singapore) were recruited (n = 5701) and classified into (i) stroke/transient ischemic attack (TIA), (ii) Alzheimer's disease (AD)/mild cognitive impairment (MCI), or (iii) control groups. Data on vascular risk factors and cognitive performance were collected. The severity of WML was visually rated on MRI or CT. The prevalence of moderate-to-severe WML was the highest in subjects with stroke/TIA (43.3%). Bandung Indonesia showed the highest prevalence of WML, adjusted for age, sex, education, disease groups, and imaging modality. Hypertension and hyperlipidemia were significant risk factors for WML, and WML was negatively associated with MMSE in all groups. WML is highly prevalent in Asia and is associated with increasing age, hypertension, hyperlipidemia, and worse cognitive performance. Concerted efforts to prevent WML will alleviate the huge dementia burden in the rapidly aging Asian societies.
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http://dx.doi.org/10.1038/s41598-021-90746-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172636PMC
June 2021

Hippocampal transcriptome profiling reveals common disease pathways in chronic hypoperfusion and aging.

Aging (Albany NY) 2021 Jun 1;13. Epub 2021 Jun 1.

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Vascular dementia (VaD) is a progressive cognitive impairment of vascular etiology. VaD is characterized by cerebral hypoperfusion, increased blood-brain barrier permeability and white matter lesions. An increased burden of VaD is expected in rapidly aging populations. The hippocampus is particularly susceptible to hypoperfusion, and the resulting memory impairment may play a crucial role in VaD. Here we have investigated the hippocampal gene expression profile of young and old mice subjected to cerebral hypoperfusion by bilateral common carotid artery stenosis (BCAS). Our data in sham-operated young and aged mice reveal an age-associated decline in cerebral blood flow and differential gene expression. In fact, BCAS and aging caused broadly similar effects. However, BCAS-induced changes in hippocampal gene expression differed between young and aged mice. Specifically, transcriptomic analysis indicated that in comparison to young sham mice, many pathways altered by BCAS in young mice resembled those already present in sham aged mice. Over 30 days, BCAS in aged mice had minimal effect on either cerebral blood flow or hippocampal gene expression. Immunoblot analyses confirmed these findings. Finally, relative to young sham mice the cell type-specific profile of genes in both young BCAS and old sham animals further revealed common cell-specific genes. Our data provide a genetic-based molecular framework for hypoperfusion-induced hippocampal damage and reveal common cellular signaling pathways likely to be important in the pathophysiology of VaD.
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http://dx.doi.org/10.18632/aging.203123DOI Listing
June 2021

The Effects of Mean of Visit-to-Visit Blood Pressure on Incident Brain Vascular Lesions and Functional-Cognitive Decline.

J Alzheimers Dis 2021 May 26. Epub 2021 May 26.

Memory Aging and Cognition Centre, National University Health System, Singapore.

Background: Cerebrovascular disease (CeVD) is an underlying cause of cognitive impairment and dementia. Hypertension is a known risk factor of CeVD, but the effects of mean of visit-to-visit blood pressure (BP) on incident CeVD and functional-cognitive decline remains unclear.

Objective: To determine the association between mean of visit-to-visit BP with the incidence and progression of CeVD [white matter hyperintensities (WMH), infarcts (cortical infarcts and lacunes), cerebral microbleeds (CMBs), intracranial stenosis, and hippocampal volume] as well as functional-cognitive decline over 2 years of follow-up.

Methods: 373 patients from a memory-clinic underwent BP measurements at baseline, year 1, and year 2. The mean of visit-to-visit systolic BP, diastolic BP, pulse pressure, and mean arterial pressure were calculated. Baseline and year 2 MRI scans were graded for WMH, infarcts, CMBs, intracranial stenosis, and hippocampal volume. Functional-cognitive decline was assessed using locally validated protocol. Logistic and linear regression models with odds ratios, mean difference, and 95%confidence interval were constructed to analyze associations of visit-to-visit BP on CeVD incidence and progression as well as functional-cognitive decline.

Results: Higher mean of visit-to-visit diastolic BP was associated with WMH progression. Higher tertiles of diastolic BP was associated with WMH progression and incident CMBs. There was no association between mean of visit-to-visit BP measures with incident cerebral infarcts, intracranial stenosis, change in hippocampal volume, and functional-cognitive decline.

Conclusion: These findings suggest the possibility of hypertension-related vascular brain damage. Careful monitoring and management of BP in elderly patients is essential to reduce the incidence and progression of CeVD.
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http://dx.doi.org/10.3233/JAD-210188DOI Listing
May 2021

Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer.

Nat Commun 2021 05 27;12(1):3199. Epub 2021 May 27.

Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Boston, MA, USA.

In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.
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http://dx.doi.org/10.1038/s41467-021-23394-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160338PMC
May 2021

State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease.

Alzheimers Dement 2021 May 27. Epub 2021 May 27.

Eisai Inc., Neurology Business Group, Woodcliff Lake, New Jersey, USA.

Recent advances in developing disease-modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health-care systems toward biomarker-guided early detection, diagnosis, and therapeutic decision-making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs-once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state-of-the-art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP-associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD.
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http://dx.doi.org/10.1002/alz.12372DOI Listing
May 2021

Management of Recalcitrant Cubital Tunnel Syndrome.

J Am Acad Orthop Surg 2021 May 17. Epub 2021 May 17.

From the Denver Health Medical Center, Denver, CO (Lauder), the University of Colorado School of Medicine, Aurora, CO (Lauder, Bolson, Leversedge), the TriHealth Hand Surgery Specialists, Cincinnati, OH (Chen), and the Rocky Mountain Regional VA Medical Center, Aurora, CO (Bolson).

Cubital tunnel syndrome is a common upper extremity compressive neuropathy. Recalcitrant cubital tunnel syndrome poses diagnostic and treatment challenges. Potential etiologies of persistent or recurrent symptoms after surgical treatment include an inaccurate preoperative diagnosis, incomplete nerve decompression, iatrogenic injury, postsurgical perineural adhesions, irreversible nerve pathology, or conditions associated with secondary nerve compression. Confirmation of recalcitrant ulnar nerve pathology relies on a thorough history to consider symptoms and chronology, careful examination to quantify nerve function and to assess for focal nerve provocation, and objective testing to highlight a possible nerve lesion such as ultrasonography and electrodiagnostic testing. Conservative treatment may provide symptomatic relief; however, surgical management such as revision neuroplasty, neurolysis, nerve reconstruction, and/or anterior transposition may be indicated. Optimizing the biology of the local nerve environment is critical. No surgical treatment procedure has shown superiority over another; however, individualized treatment is emphasized to improve symptoms and maximize nerve recovery potential.
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http://dx.doi.org/10.5435/JAAOS-D-20-01381DOI Listing
May 2021

Extracellular Matrix Alignment Directs Provisional Matrix Assembly and Three Dimensional Fibrous Tissue Closure.

Tissue Eng Part A 2021 May 12. Epub 2021 May 12.

Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.

Gap closure is a dynamic process in wound healing, in which a wound contracts and a provisional matrix is laid down, to restore structural integrity to injured tissues. The efficiency of wound closure has been found to depend on the shape of a wound, and this shape dependence has been echoed in various studies. While wound shape itself appears to contribute to this effect, it remains unclear whether the alignment of the surrounding extracellular matrix (ECM) may also contribute. In this study, we investigate the role both wound curvature and ECM alignment have on gap closure in a 3D culture model of fibrous tissue. Using microfabricated flexible micropillars positioned in rectangular and octagonal arrangements, seeded 3T3 fibroblasts embedded in a collagen matrix formed microtissues with different ECM alignments. Wounding these microtissues with a microsurgical knife resulted in wounds with different shapes and curvatures that closed at different rates. Observing different regions around the wounds, we noted local wound curvature did not impact the rate of production of provisional fibronectin matrix assembled by the fibroblasts. Instead, the rate of provisional matrix assembly was lowest emerging from regions of high fibronectin alignment and highest in the areas of low matrix alignment. Our data suggest that the underlying ECM structure affects the shape of the wound as well as the ability of fibroblasts to build provisional matrix, an important step in the process of tissue closure and restoration of tissue architecture. The study highlights an important interplay between ECM alignment, wound shape, and tissue healing that has not been previously recognized and may inform approaches to engineer tissues.
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http://dx.doi.org/10.1089/ten.tea.2020.0332DOI Listing
May 2021

Blood-Based Cardiac Biomarkers and the Risk of Cognitive Decline, Cerebrovascular Disease, and Clinical Events.

Stroke 2021 May 11:STROKEAHA120032571. Epub 2021 May 11.

Department of Pharmacology, National University of Singapore. (M.K.P.L., C.C., S.H.).

Background And Purpose: Cardiac biomarkers, NT-proBNP (N-terminal probrain natriuretic peptide), hs-cTnT (high-sensitivity-cardiac troponin T), and GDF-15 (growth differentiation factor-15) have been proposed as important biomarkers of early vascular pathology. However, little is known of the longitudinal associations of these cardiac biomarkers with cerebrovascular disease and clinical events. We examine the association of blood-based cardiac biomarkers (NT-proBNP, hs-cTnT, and GDF-15) with cognitive decline, incident cerebrovascular disease, vascular events, and mortality.

Methods: Four hundred thirty-four memory-clinic patients provided blood samples at baseline, underwent 3 annual neuropsychological assessments and brain magnetic resonance imaging scans at baseline and follow-up. NT-proBNP and hs-cTnT concentrations were measured by electrochemiluminescence immunoassay and GDF-15 by quantitative sandwich immunoassay. Baseline and follow-up magnetic resonance imagings were graded for white matter hyperintensities, lacunes, cerebral microbleeds, cortical infarcts, and intracranial stenosis. Data on incident vascular events and mortality were obtained.

Results: Patients with higher levels of NT-proBNP, hs-cTnT, and GDF-15 showed greater decline in memory domain. Additionally, hs-cTnT was associated with decline in global cognition, executive function, and visuomotor speed. Higher levels of NT-proBNP were associated with incident cerebral microbleeds and hs-cTnT with incident cortical infarcts. During a mean follow-up of 3 years, 26 (5.9%) patients died and 35 (8.1%) developed vascular events. Patients with higher levels of NTpro-BNP and hs-cTnT were at increased risk of vascular events whereas those with higher levels of NT-proBNP and GDF-15 were at risk of mortality.

Conclusions: Higher levels of blood-based cardiac biomarkers were associated with decline in memory and risk of vascular events and mortality. Moreover, NT-proBNP and hs-cTnT were associated with incident cerebral microbleeds and cortical infarcts. Thus, these biomarkers are potentially useful in identifying patients at risk of adverse vascular events and death.
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http://dx.doi.org/10.1161/STROKEAHA.120.032571DOI Listing
May 2021

Direct laser writing for cardiac tissue engineering: a microfluidic heart on a chip with integrated transducers.

Lab Chip 2021 05;21(9):1724-1737

Department of Mechanical Engineering, Boston University, Boston, MA 02215, USA. and Photonics Center, Boston University, Boston, MA 02215, USA and Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA and Division of Materials Science and Engineering, Boston University, Boston, Massachusetts 02215, USA and Department of Physics, Boston University, Boston, MA 02215, USA.

We have developed a microfluidic platform for engineering cardiac microtissues in highly-controlled microenvironments. The platform is fabricated using direct laser writing (DLW) lithography and soft lithography, and contains four separate devices. Each individual device houses a cardiac microtissue and is equipped with an integrated strain actuator and a force sensor. Application of external pressure waves to the platform results in controllable time-dependent forces on the microtissues. Conversely, oscillatory forces generated by the microtissues are transduced into measurable electrical outputs. We demonstrate the capabilities of this platform by studying the response of cardiac microtissues derived from human induced pluripotent stem cells (hiPSC) under prescribed mechanical loading and pacing. This platform will be used for fundamental studies and drug screening on cardiac microtissues.
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http://dx.doi.org/10.1039/d0lc01078bDOI Listing
May 2021

Strategic infarct locations for post-stroke cognitive impairment: a pooled analysis of individual patient data from 12 acute ischaemic stroke cohorts.

Lancet Neurol 2021 06 23;20(6):448-459. Epub 2021 Apr 23.

Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

Background: Post-stroke cognitive impairment (PSCI) occurs in approximately half of people in the first year after stroke. Infarct location is a potential determinant of PSCI, but a comprehensive map of strategic infarct locations predictive of PSCI is unavailable. We aimed to identify infarct locations most strongly predictive of PSCI after acute ischaemic stroke and use this information to develop a prediction model.

Methods: In this large-scale multicohort lesion-symptom mapping study, we pooled and harmonised individual patient data from 12 cohorts through the Meta-analyses on Strategic Lesion Locations for Vascular Cognitive Impairment using Lesion-Symptom Mapping (Meta VCI Map) consortium. The identified cohorts (as of Jan 1, 2019) comprised patients with acute symptomatic infarcts on CT or MRI (with available infarct segmentations) and a cognitive assessment up to 15 months after acute ischaemic stroke onset. PSCI was defined as performance lower than the fifth percentile of local normative data, on at least one cognitive domain on a multidomain neuropsychological assessment or on the Montreal Cognitive Assessment. Voxel-based lesion-symptom mapping (VLSM) was used to calculate voxel-wise odds ratios (ORs) for PSCI that were mapped onto a three-dimensional brain template to visualise PSCI risk per location. For the prediction model of PSCI risk, a location impact score on a 5-point scale was derived from the VLSM results on the basis of the mean voxel-wise coefficient (ln[OR]) within each patient's infarct. We did combined internal-external validation by leave-one-cohort-out cross-validation for all 12 cohorts using logistic regression. Predictive performance of a univariable model with only the location impact score was compared with a multivariable model with addition of other clinical PSCI predictors (age, sex, education, time interval between stroke onset and cognitive assessment, history of stroke, and total infarct volume). Testing of visual ratings was done by three clinicians, and accuracy, inter-rater reliability, and intra-rater reliability were assessed with Cohen's weighted kappa.

Findings: In our sample of 2950 patients (mean age 66·8 years [SD 11·6]; 1157 [39·2%] women), 1286 (43·6%) had PSCI. We achieved high lesion coverage of the brain in our analyses (86·9%). Infarcts in the left frontotemporal lobes, left thalamus, and right parietal lobe were strongly associated with PSCI (after false discovery rate correction, q<0·01; voxel-wise ORs >20). On cross-validation, the location impact score showed good correspondence, based on visual assessment of goodness of fit, between predicted and observed risk of PSCI across cohorts after adjusting for cohort-specific PSCI occurrence. Cross-validations showed that the location impact score by itself had similar performance to the combined model with other PSCI predictors, while allowing for easy visual assessment. Therefore the univariable model with only the location impact score was selected as the final model. Correspondence between visual ratings and actual location impact score (Cohen's weighted kappa: range 0·88-0·92), inter-rater agreement (0·85-0·87), and intra-rater agreement (for a single rater, 0·95) were all high.

Interpretation: To the best of our knowledge, this study provides the first comprehensive map of strategic infarct locations associated with risk of PSCI. A location impact score was derived from this map that robustly predicted PSCI across cohorts. Furthermore, we developed a quick and reliable visual rating scale that might in the future be applied by clinicians to identify individual patients at risk of PSCI.

Funding: The Netherlands Organisation for Health Research and Development.
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http://dx.doi.org/10.1016/S1474-4422(21)00060-0DOI Listing
June 2021

Force-FAK signaling coupling at individual focal adhesions coordinates mechanosensing and microtissue repair.

Nat Commun 2021 04 21;12(1):2359. Epub 2021 Apr 21.

Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.

How adhesive forces are transduced and integrated into biochemical signals at focal adhesions (FAs) is poorly understood. Using cells adhering to deformable micropillar arrays, we demonstrate that traction force and FAK localization as well as traction force and Y397-FAK phosphorylation are linearly coupled at individual FAs on stiff, but not soft, substrates. Similarly, FAK phosphorylation increases linearly with external forces applied to FAs using magnetic beads. This mechanosignaling coupling requires actomyosin contractility, talin-FAK binding, and full-length vinculin that binds talin and actin. Using an in vitro 3D biomimetic wound healing model, we show that force-FAK signaling coupling coordinates cell migration and tissue-scale forces to promote microtissue repair. A simple kinetic binding model of talin-FAK interactions under force can recapitulate the experimental observations. This study provides insights on how talin and vinculin convert forces into FAK signaling events regulating cell migration and tissue repair.
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http://dx.doi.org/10.1038/s41467-021-22602-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060400PMC
April 2021

Methods for tuning plasmonic and photonic optical resonances in high surface area porous electrodes.

Sci Rep 2021 Apr 7;11(1):7656. Epub 2021 Apr 7.

The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, USA.

Surface plasmons have found a wide range of applications in plasmonic and nanophotonic devices. The combination of plasmonics with three-dimensional photonic crystals has enormous potential for the efficient localization of light in high surface area photoelectrodes. However, the metals traditionally used for plasmonics are difficult to form into three-dimensional periodic structures and have limited optical penetration depth at operational frequencies, which limits their use in nanofabricated photonic crystal devices. The recent decade has seen an expansion of the plasmonic material portfolio into conducting ceramics, driven by their potential for improved stability, and their conformal growth via atomic layer deposition has been established. In this work, we have created three-dimensional photonic crystals with an ultrathin plasmonic titanium nitride coating that preserves photonic activity. Plasmonic titanium nitride enhances optical fields within the photonic electrode while maintaining sufficient light penetration. Additionally, we show that post-growth annealing can tune the plasmonic resonance of titanium nitride to overlap with the photonic resonance, potentially enabling coupled-phenomena applications for these three-dimensional nanophotonic systems. Through characterization of the tuning knobs of bead size, deposition temperature and cycle count, and annealing conditions, we can create an electrically- and plasmonically-active photonic crystal as-desired for a particular application of choice.
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http://dx.doi.org/10.1038/s41598-021-86813-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027385PMC
April 2021

Caregiving, care burden and awareness of caregivers and patients with dementia in Asian locations: a secondary analysis.

BMC Geriatr 2021 04 7;21(1):230. Epub 2021 Apr 7.

Department of Neurology, Seoul National University College of Medicine & Clinical Neuroscience Center, Seoul National University Bundang Hospital, 582, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Seoul, Republic of Korea.

Background: This study investigated the differences in caregiver activity, caregiver burden, and awareness of both caregivers and patients with Alzheimer's disease (AD) across different Asian locations.

Methods: This was a secondary analysis of a multi-national cohort study that aimed to assess caregiver activity and caregiver burden using the Caregiver Activity Scale (CAS) and Zarit Burden Interview (ZBI), respectively. Patients' awareness of their dementia diagnosis was assessed by asking the following yes/no question: "Do you have dementia?" Caregivers' awareness of the patient's dementia diagnosis was assessed by asking the following yes/no question: "Does your patient have dementia?"

Results: In total, 524 caregivers of patients with AD from China, Hong Kong, South Korea, the Philippines, Singapore, Thailand, and Taiwan participated. The CAS and ZBI score were significantly different across most locations (p < 0.001 and p = 0.033, respectively). Overall, 56.6% of caregivers and 37.5% of patients had awareness of the dementia diagnosis, and the proportion of patients and caregivers with awareness were also different between each location (all, p < 0.001).

Conclusions: Caregiving, caregiver burden, and the awareness of caregivers and patients were different across many Asian locations. With understanding of cultural differences, further public education on dementia could help increase the awareness of patients and caregivers and reduce caregiver burden.

Trial Registration: ClinicalTrials.gov , NCT02262975 . Registered 13 October 2014.
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http://dx.doi.org/10.1186/s12877-021-02178-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028783PMC
April 2021

NEURoaid II (MLC901) in cognitively Impaired not demenTEd patientS (NEURITES): A pilot double blind, placebo-controlled randomized trial.

Alzheimers Dement (N Y) 2021 31;7(1):e12161. Epub 2021 Mar 31.

Neurology Raffles Neuroscience Centre Singapore Republic of Singapore.

Objective: To investigate the efficacy and safety of MLC901 in vascular cognitive impairment no dementia (VCIND) patients.

Design: This was a multi-center, double-blind, randomized, placebo-controlled pilot study.

Setting And Participant: VCIND patients from hospitals in Singapore (67), Vietnam (19), and the Philippines (17) were recruited and followed-up from March 2013 to April 2018.

Methods: The primary outcome was executive function as measured by the Verbal Fluency (VF) and 2-part Color Trails Test (CTT). The mean difference in the scores between baseline and week 12, and baseline and week 24, was compared between MLC901 and placebo using a two-sample t-test.

Results: The trial randomized 103 subjects: MLC901 (n = 57) and placebo (n = 46). The mean age of participants was 68.3 ± 8.4 years and 38.8% were female. Improvement in executive function with MLC901 was not significantly better than placebo at week 12 (CTT1 mean difference [md] 3.8 seconds, 95% confidence interval [CI]: -9.0 to 16.5, CTT2 md 10.9 seconds, 95% CI: -0.2 to 22.0), and at week 24 (CTT1 md 2.8 seconds, 95% CI: -8.4 to 14.0, CTT2 md = 4.4 seconds, 95% CI: -8.2 to 16.9). Improvement in VF from baseline was not significantly different between MLC901 and placebo at weeks 12 and 24. There were no significant differences in adverse events (43.5% vs. 56.1%) or serious adverse events (13% vs. 22.8%) in placebo versus MLC901 groups. In post hoc exploratory analysis, the treatment effect of MLC901 on cognitive function appears more apparent in subjects with existing impairment in executive function: CTT2 (md 14.4 seconds [ = .05] and 9.9 seconds [ = .3] at week 12 and week 24, respectively).

Conclusions: Whilst MLC901 appears to be safe, there was no significant cognitive benefit from MLC901 in the study population. Post hoc hypotheses generating analyses suggest that VCIND patients with existing impairment in executive function may show benefit.
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http://dx.doi.org/10.1002/trc2.12161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010368PMC
March 2021

Fast, multiplane line-scan confocal microscopy using axially distributed slits.

Biomed Opt Express 2021 Mar 9;12(3):1339-1350. Epub 2021 Feb 9.

Department of Biomedical Engineering, Boston University, 44 Cummington Mall, Boston, MA 02215, USA.

The inherent constraints on resolution, speed and field of view have hindered the development of high-speed, three-dimensional microscopy techniques over large scales. Here, we present a multiplane line-scan imaging strategy, which uses a series of axially distributed reflecting slits to probe different depths within a sample volume. Our technique enables the simultaneous imaging of an optically sectioned image stack with a single camera at frame rates of hundreds of hertz, without the need for axial scanning. We demonstrate the applicability of our system to monitor fast dynamics in biological samples by performing calcium imaging of neuronal activity in mouse brains and voltage imaging of cardiomyocytes in cardiac samples.
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http://dx.doi.org/10.1364/BOE.417286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984773PMC
March 2021

Plasma P-tau181 to Aβ42 ratio is associated with brain amyloid burden and hippocampal atrophy in an Asian cohort of Alzheimer's disease patients with concomitant cerebrovascular disease.

Alzheimers Dement 2021 Mar 31. Epub 2021 Mar 31.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore.

Introduction: There is increasing evidence that phosphorylated tau (P-tau181) is a specific biomarker for Alzheimer's disease (AD) pathology, but its potential utility in non-White patient cohorts and patients with concomitant cerebrovascular disease (CeVD) is unknown.

Methods: Single molecule array (Simoa) measurements of plasma P-tau181, total tau, amyloid beta (Aβ)40 and Aβ42, as well as derived ratios were correlated with neuroimaging modalities indicating brain amyloid (Aβ+), hippocampal atrophy, and CeVD in a Singapore-based cohort of non-cognitively impaired (NCI; n = 43), cognitively impaired no dementia (CIND; n = 91), AD (n = 44), and vascular dementia (VaD; n = 22) subjects.

Results: P-tau181/Aβ42 ratio showed the highest area under the curve (AUC) for Aβ+ (AUC = 0.889) and for discriminating between AD Aβ+ and VaD Aβ- subjects (AUC = 0.903). In addition, P-tau181/Aβ42 ratio was associated with hippocampal atrophy. None of the biomarkers was associated with CeVD.

Discussion: Plasma P-tau181/Aβ42 ratio may be a noninvasive means of identifying AD with elevated brain amyloid in populations with concomitant CeVD.
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http://dx.doi.org/10.1002/alz.12332DOI Listing
March 2021

Controlled Apoptosis of Stromal Cells to Engineer Human Microlivers.

Adv Funct Mater 2020 Nov 8;30(48). Epub 2020 Jun 8.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Engineered tissue models comprise a variety of multiplexed ensembles in which combinations of epithelial, stromal, and immune cells give rise to physiologic function. Engineering spatiotemporal control of cell-cell and cell-matrix interactions within these 3D multicellular tissues would represent a significant advance for tissue engineering. In this work, a new method, entitled CAMEO (Controlled Apoptosis in Multicellular tissues for Engineered Organogenesis) enables the non-invasive triggering of controlled apoptosis to eliminate genetically-engineered cells from a pre-established culture. Using this approach, the contribution of stromal cells to the phenotypic stability of primary human hepatocytes is examined. 3D hepatic microtissues, in which fibroblasts can enhance phenotypic stability and accelerate aggregation into spheroids, were found to rely only transiently on fibroblast interaction to support multiple axes of liver function, such as protein secretion and drug detoxification. Due to its modularity, CAMEO has the promise to be readily extendable to other applications that are tied to the complexity of 3D tissue biology, from understanding organoid models to building artificial tissue grafts.
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http://dx.doi.org/10.1002/adfm.201910442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996305PMC
November 2020

SINgapore GERiatric intervention study to reduce physical frailty and cognitive decline (SINGER)-pilot: A feasibility study.

Alzheimers Dement (N Y) 2021 15;7(1):e12141. Epub 2021 Mar 15.

Memory, Ageing and Cognition Centre (MACC), Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore.

Introduction: The SINGER pilot randomized controlled trial aims to examine the feasibility and acceptability of the Finnish Geriatric Intervention Study (FINGER) multi-domain lifestyle interventions compared to Singaporean adaptations.

Methods: Seventy elderly participants were recruited and randomized into FINGER (n = 36) or SINGER (n = 34) interventions; involving physical exercise, cognitive training, diet, and vascular risk factors management, for 6 months.

Results: Both intervention groups were equally feasible and acceptable with participants completing at least 80% of the interventions. Body strength improved in both groups ( = .04, = .06, = .05). More participants in the SINGER group attained good blood pressure control at month-6 compared to FINGER (41% vs 19%; = .06).

Discussion: This study is the first to compare the feasibility of multi-domain interventions adapted to local culture with the FINGER interventions. The findings will be utilized for a larger study to provide evidence for the efficacy of multi-domain lifestyle interventions in preventing cognitive decline.
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http://dx.doi.org/10.1002/trc2.12141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958306PMC
March 2021

Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.

Lancet Neurol 2021 04 17;20(4):294-303. Epub 2021 Mar 17.

Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk.

Methods: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602.

Findings: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models.

Interpretation: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted.

Funding: British Heart Foundation and Stroke Association.
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http://dx.doi.org/10.1016/S1474-4422(21)00024-7DOI Listing
April 2021

Controlled Cell Alignment Using Two-Photon Direct Laser Writing-Patterned Hydrogels in 2D and 3D.

Macromol Biosci 2021 May 19;21(5):e2100051. Epub 2021 Mar 19.

Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA.

Direct laser writing (DLW) via two-photon polymerization is an emerging highly precise technique for the fabrication of intricate cellular scaffolds. Despite recent progress in using two-photon-polymerized scaffolds to probe fundamental cell behaviors, new methods to direct and modulate microscale cell alignment and selective cell adhesion using two-photon-polymerized microstructures are of keen interest. Here, a DLW-fabricated 2D and 3D hydrogel microstructures, with alternating soft and stiff regions, for precisely controlled cell alignment are reported. The use of both cell-adhesive and cell-repellent hydrogels allows selective adhesion and alignment of human mesenchymal stem cells within the printed structure. Importantly, DLW patterning enables cell alignment on flat surfaces as well as irregular and curved 3D microstructures, which are otherwise challenging to pattern with cells.
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http://dx.doi.org/10.1002/mabi.202100051DOI Listing
May 2021

Case 8-2021: A 34-Year-Old Woman with Cholangiocarcinoma.

N Engl J Med 2021 03;384(11):1054-1064

From the Departments of Medicine (L.G., C.T.C.), Radiology (T.T.P.), and Pathology (V.D.), Massachusetts General Hospital, and the Departments of Medicine (L.G., C.T.C.), Radiology (T.T.P.), and Pathology (V.D.), Harvard Medical School - both in Boston.

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http://dx.doi.org/10.1056/NEJMcpc2027092DOI Listing
March 2021

The effect of intracranial stenosis on cognitive decline in a memory clinic cohort.

Eur J Neurol 2021 Jun 18;28(6):1829-1839. Epub 2021 Mar 18.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore City, Singapore.

Background And Purpose: Intracranial stenosis (ICS) is a risk factor for cognitive impairment and dementia in cross-sectional studies. However, data examining the effect of ICS on cognitive decline are limited. We investigated the effect of ICS on cognition over a period of 3 years in a memory clinic cohort.

Methods: Patients were recruited from the National University Hospital in Singapore. Data were collected using a standardised questionnaire, physical examination, and 3-T magnetic resonance imaging (MRI) at baseline. ICS was defined as arterial narrowing that exceeded 50% of the luminal diameter in any intracranial vessel. Cognition was measured at baseline and annually for 3 years using the Mini-Mental State Examination, the Montreal Cognitive Assessment, and a detailed neuropsychological test battery. The association between ICS and cognitive decline was analysed using generalised estimating equations.

Results: A total of 364 patients were included in the analysis. The mean (±SD) age was 71.9 (±8.0) years, and 164 (45.1%) patients were male. A total of 66 (18.1%) patients had ICS. ICS was associated with worse executive function (β = -0.37, 95% confidence interval = -0.68 to -0.05, p = 0.022) and modified the effect of follow-up time on memory (p = 0.005) and visuomotor speed (p = 0.047). These results remained significant after controlling for demographics, overall diagnosis, cardiovascular risk factors, and MRI markers of cerebrovascular disease.

Conclusions: Intracranial stenosis was independently associated with worse executive function across all time points, and cognitive decline in memory and visuomotor speed over 3 years of follow-up. This suggests that ICS may be a useful indicator of vascular brain damage leading to cognitive decline and may warrant consideration of antiatherosclerotic treatment in clinical trials.
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http://dx.doi.org/10.1111/ene.14788DOI Listing
June 2021

Optogenetic current in myofibroblasts acutely alters electrophysiology and conduction of co-cultured cardiomyocytes.

Sci Rep 2021 Feb 24;11(1):4430. Epub 2021 Feb 24.

Department of Biomedical Engineering, Johns Hopkins University, 720 Rutland Ave., Baltimore, MD, 21205, USA.

Interactions between cardiac myofibroblasts and myocytes may slow conduction and generate spontaneous beating in fibrosis, increasing the chance of life-threatening arrhythmia. While co-culture studies have shown that myofibroblasts can affect cardiomyocyte electrophysiology in vitro, the extent of myofibroblast-myocyte electrical conductance in a syncytium is unknown. In this neonatal rat study, cardiac myofibroblasts were transduced with Channelrhodopsin-2, which allowed acute and selective increase of myofibroblast current, and plated on top of cardiomyocytes. Optical mapping revealed significantly decreased conduction velocity (- 27 ± 6%, p < 10), upstroke rate (- 13 ± 4%, p = 0.002), and action potential duration (- 14 ± 7%, p = 0.004) in co-cultures when 0.017 mW/mm light was applied, as well as focal spontaneous beating in 6/7 samples and a decreased cycle length (- 36 ± 18%, p = 0.002) at 0.057 mW/mm light. In silico modeling of the experiments reproduced the experimental findings and suggested the light levels used in experiments produced excess current similar in magnitude to endogenous myofibroblast current. Fitting the model to experimental data predicted a tissue-level electrical conductance across the 3-D interface between myofibroblasts and cardiomyocytes of ~ 5 nS/cardiomyocyte, and showed how increased myofibroblast-myocyte conductance, increased myofibroblast/myocyte capacitance ratio, and increased myofibroblast current, which occur in fibrosis, can work in tandem to produce pro-arrhythmic increases in conduction and spontaneous beating.
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http://dx.doi.org/10.1038/s41598-021-83398-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904933PMC
February 2021

Transient Support from Fibroblasts is Sufficient to Drive Functional Vascularization in Engineered Tissues.

Adv Funct Mater 2020 Nov 25;30(48). Epub 2020 Jun 25.

Biological Design Center, Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.

Formation of capillary blood vasculature is a critical requirement for native as well as engineered organs and can be induced in vitro by co-culturing endothelial cells with fibroblasts. However, whether these fibroblasts are required only in the initial morphogenesis of endothelial cells or needed throughout is unknown, and the ability to remove these stromal cells after assembly could be useful for clinical translation. In this study, we introduce a technique termed CAMEO (Controlled Apoptosis in Multicellular Tissues for Engineered Organogenesis), whereby fibroblasts are selectively ablated on demand, and utilize it to probe the dispensability of fibroblasts in vascular morphogenesis. The presence of fibroblasts is shown to be necessary only during the first few days of endothelial cell morphogenesis, after which they can be ablated without significantly affecting the structural and functional features of the developed vasculature. Furthermore, we demonstrate the use of CAMEO to vascularize a construct containing primary human hepatocytes that improved tissue function. In conclusion, this study suggests that transient, initial support from fibroblasts is sufficient to drive vascular morphogenesis in engineered tissues, and this strategy of engineering-via-elimination may provide a new general approach for achieving desired functions and cell compositions in engineered organs.
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http://dx.doi.org/10.1002/adfm.202003777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891457PMC
November 2020

Plasma osteopontin as a biomarker of Alzheimer's disease and vascular cognitive impairment.

Sci Rep 2021 Feb 17;11(1):4010. Epub 2021 Feb 17.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Unit 09-01, Centre for Translational Medicine (MD6), 14 Medical Drive, Singapore, 117599, Singapore.

Cerebrovascular disease (CeVD) and neurodegenerative dementia such as Alzheimer's disease (AD) are frequently associated comorbidities in the elderly, sharing common risk factors and pathophysiological mechanisms including neuroinflammation. Osteopontin (OPN) is an inflammatory marker found upregulated in vascular diseases as well as in AD. However, its involvement in vascular dementia (VaD) and pre-dementia stages, namely cognitive impairment no dementia (CIND), both of which fall under the spectrum of vascular cognitive impairment (VCI), has yet to be examined. Its correlations with inflammatory cytokines in cognitive impairment also await investigation. 80 subjects with no cognitive impairment (NCI), 160 with CIND and 144 with dementia were included in a cross-sectional study on a Singapore-based memory clinic cohort. All subjects underwent comprehensive clinical, neuropsychological and brain neuroimaging assessments, together with clinical diagnoses based on established criteria. Blood samples were collected and OPN as well as inflammatory cytokines interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF) were measured using immunoassays. Multivariate regression analyses showed significant associations between increased OPN and VCI groups, namely CIND with CeVD, AD with CeVD and VaD. Interestingly, higher OPN was also significantly associated with AD even in the absence of CeVD. We further showed that increased OPN significantly associated with neuroimaging markers of CeVD and neurodegeneration, including cortical infarcts, lacunes, white matter hyperintensities and brain atrophy. OPN also correlated with elevated levels of IL-6, IL-8 and TNF. Our findings suggest that OPN may play a role in both VCI and neurodegenerative dementias. Further longitudinal analyses are needed to assess the prognostic utility of OPN in disease prediction and monitoring.
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http://dx.doi.org/10.1038/s41598-021-83601-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889621PMC
February 2021

White matter network damage mediates association between cerebrovascular disease and cognition.

J Cereb Blood Flow Metab 2021 Feb 2:271678X21990980. Epub 2021 Feb 2.

Department of Medicine, Center for Sleep and Cognition, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

To determine whether white matter network disruption mediates the association between MRI markers of cerebrovascular disease (CeVD) and cognitive impairment. Participants (n = 253, aged ≥60 years) from the Epidemiology of Dementia in Singapore study underwent neuropsychological assessments and MRI. CeVD markers were defined as lacunes, white matter hyperintensities (WMH), microbleeds, cortical microinfarcts, cortical infarcts and intracranial stenosis (ICS). White matter microstructure damage was measured as fractional anisotropy and mean diffusivity by tract based spatial statistics from diffusion tensor imaging. Cognitive function was summarized as domain-specific Z-scores.Lacunar counts, WMH volume and ICS were associated with worse performance in executive function, attention, language, verbal and visual memory. These three CeVD markers were also associated with white matter microstructural damage in the projection, commissural, association, and limbic fibers. Path analyses showed that lacunar counts, higher WMH volume and ICS were associated with executive and verbal memory impairment via white matter disruption in commissural fibers whereas impairment in the attention, visual memory and language were mediated through projection fibers.Our study shows that the abnormalities in white matter connectivity may underlie the relationship between CeVD and cognition. Further longitudinal studies are needed to understand the cause-effect relationship between CeVD, white matter damage and cognition.
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http://dx.doi.org/10.1177/0271678X21990980DOI Listing
February 2021

Reconstituting the dynamics of endothelial cells and fibroblasts in wound closure.

APL Bioeng 2021 Mar 19;5(1):016102. Epub 2021 Jan 19.

The Biological Design Center and Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA.

The formation of healthy vascularized granulation tissue is essential for rapid wound closure and the prevention of chronic wounds in humans, yet how endothelial cells and fibroblasts coordinate during this process has been difficult to study. Here, we have developed an system that reveals how human endothelial and stromal cells in a 3D matrix respond during wound healing and granulation tissue formation. By creating incisions in engineered cultures composed of human umbilical vein endothelial cells and human lung fibroblasts embedded within a 3D matrix, we observed that these tissues are able to close the wound within approximately 4 days. Live tracking of cells during wound closure revealed that the process is mediated primarily by fibroblasts. The fibroblasts migrate circumferentially around the wound edge during early phases of healing, while contracting the wound. The fibroblast-derived matrix is, then, deposited into the void, facilitating fibroblast migration toward the wound center and filling of the void. Interestingly, the endothelial cells remain at the periphery of the wound rather than actively sprouting into the healing region to restore the vascular network. This study captures the dynamics of endothelial and fibroblast-mediated closure of three-dimensional wounds, which results in the repopulation of the wound with the cell-derived extracellular matrix representative of early granulation tissue, thus presenting a model for future studies to investigate factors regulating vascularized granulation tissue formation.
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http://dx.doi.org/10.1063/5.0028651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817247PMC
March 2021