Building confidence and trust in Ireland's National Maternity Services Workforce -What matters most and how?

National surveys on care experiences are increasingly adopted as regulatory mechanisms for improving care quality and increasing public trust in healthcare services. Based on data collected as part of Ireland's 2020 National Maternity Experience Survey, this study investigates care-related factors that contribute most to confidence and trust in the professional workforce (or carers) within Irish maternity services. The survey covered the full spectrum of maternity care and received 3,206 responses which were analysed using structural equation modelling. Results show that trust in carers may be enhanced through greater attention to the quality of interpersonal aspects of maternity care in a few core areas. We found that factors related to dignity and respect (ß=0.270), involvement in decision-making (ß=0.186), pain management (ß=0.172), and communication (ß=0.151) are core determinants of confidence and trust in the professional workforce of maternity services. Perceived quality of care in these four aspects increased on average, with the women's age. Women under 29 rated their experiences in these areas as significantly lower than the average. Women with a disability also rated their experiences significantly lower than average in three core areas. Our results suggest that trustworthy, equitable, and high-quality maternity care requires ongoing development of interpersonal skills within the maternity services professional workforce particularly in caring for younger women (under 29 years) and those with a disability.

Biological sex is associated with heterogeneous responses to IL-6 receptor inhibitor treatment in COVID-19-A retrospective cohort study.

COVID-19 is associated with higher inflammatory markers, illness severity and mortality in males compared to females. Differences in immune responses to COVID-19 may underpin sex- specific outcome differences. We hypothesised that anti-IL-6 receptor monoclonal antibodies are associated with heterogenous treatment effects between male and female patients. We conducted a retrospective cohort study assessing the interaction between biological sex and anti-IL-6 receptor antibody treatment with respect to hospital mortality or progression of respiratory failure. We used a Cox proportional hazards regression model to adjust for age, ethnicity, steroid use, baseline C-reactive protein, and COVID-19 variant. We included 1274 patients, of which 58% were male and 15% received anti-IL-6 receptor antibodies. There was a significant interaction between sex and anti-IL-6 receptor antibody use on progression to respiratory failure or death (p = 0.05). For patients who did not receive anti-IL-6 receptor antibodies, the risk of death was slightly higher in males (HR = 1.13 (0.72-1.79)), whereas in patients who did receive anti-IL-6 receptor antibodies, the risk was lower in males (HR = 0.65 (0.32-1.33)). There was a heterogenous treatment effect with anti-IL-6 receptor antibodies between males and females; with anti-IL-6 receptor antibody use having a greater benefit in preventing progression to respiratory failure or death in males (p = 0.05).

Experiences of shared decision making in acute hospitals: A mixed methods secondary analysis of the Irish National Inpatient Experience Survey.

INTRODUCTION: This study explored patient experiences of shared decision making (SDM) in public acute hospitals in Ireland. METHODS: Quantitative and qualitative data from three years of the Irish National Inpatient Experience Survey were analysed. Survey questions were mapped to definitions of SDM and subjected to principal components analysis. Three SDM subscales (care on the ward; treatments; discharge) and one overall SDM scale were created. Differences in experiences of SDM by aspects of care and patient group were assessed. Thematic analysis of qualitative responses was undertaken. RESULTS: 39,453 patients participated in the survey. The mean SDM experience score was 7.60 ± 2.43. Experience scores were highest on the treatments sub-scale, and lowest during discharge. Patients who had a non-emergency admission, those aged 51-80 years and men had more positive experiences than other groups. Patient comments highlighted that opportunities to clarify information and facilitation of families/caregivers in SDM were found to be lacking. CONCLUSION: There were differences in experiences of SDM by aspects of care and patient group. PRACTICE IMPLICATIONS: Efforts to improve SDM in acute hospitals are required, particularly at the time of discharge. SDM may be improved by facilitation of more time for discussion between clinicians and patients and/or their families/caregivers.

Dying, death and bereavement: developing a national survey of bereaved relatives.

BACKGROUND: Assessing and measuring the experience and quality of care provided is central to the improvement of care delivery of all healthcare systems. This paper reports on the development of a survey instrument to capture the experiences of care at end of life from the perspective of bereaved relatives in the Republic of Ireland. METHODS: A multi-method, multi-stakeholder, sequential approach was adopted for this study. Items for inclusion in the survey instrument bank were identified through (1) a feasibility study and scoping literature review, (2) expert panel programme board review, (3) focus groups and (4) gap analysis. The following steps were undertaken to prioritise the items for inclusion in the final survey instrument: (1) a Delphi study (2) technical expert panel review (3) cognitive interviews with bereaved relatives and an (4) expert panel programme board review. RESULTS: Following an iterative process with key stakeholders, a survey instrument was developed with sections focusing on the provision of care at home, in the last nursing home / residential care facility, hospice and hospital, as well as care experience in the last 2 days of life, the relative's experiences of care and support, the circumstances of care surrounding death and demographic information. In total, a bank of 123 questions were prioritised to be included in the National End of Life Survey instrument. CONCLUSION: The survey will provide a standardised national approach to capturing the experience of care of those who have died, from the perspective of bereaved relatives in the Republic of Ireland. This will allow health service providers, policy makers and regulators to gather important insights into the experiences of care at end of life and will help fulfil the requirement of healthcare services to ensure they are providing high-quality care.

Women's experiences of initiating feeding shortly after birth in Ireland: A secondary analysis of quantitative and qualitative data from the National Maternity Experience Survey.

OBJECTIVE: To explore women's experiences of initiating and continuing breast or formula feeding shortly after birth in Ireland's maternity hospitals and units, as well as at home after birth. DESIGN: Mixed methods secondary analysis of qualitative and quantitative data from the Irish National Maternity Experience Survey 2020. SETTING: All 19 maternity hospitals and units in the Republic of Ireland and the national home births service. Women were asked about their maternity care experiences, including antenatal care, care during labour and birth, feeding, and care at home after birth. PARTICIPANTS: A total of 3,205 women who gave birth in October or November 2019 participated in the study (50% response rate). MEASUREMENTS: Free-text comments related to women's experiences of initiating and continuing breast or formula feeding were analysed using thematic analysis. Quantitative data were described using means (SD) and frequencies and percentages. FINDINGS: In the first few days after birth, 41.9% of women breastfed exclusively, 29.0% used formula and breast milk, and 29.1% bottle-fed only. Seven-hundred and twenty women (22.5%) made 824 comments related to feeding. Four themes were identified: (1) support and encouragement from healthcare professionals, (2) information and advice regarding feeding, (3) Pressure to feed in a particular way and (lack of) respect for personal preferences, and (4) hospital environment and resources. KEY CONCLUSIONS: Some women experienced a lack of support with feeding their babies, regardless of feeding method. Clear and concise information on feeding practices and home supports could help to support mothers with breast or formula feeding. IMPLICATIONS FOR PRACTICE: It is important that healthcare professionals provide evidence-based information and support, while respecting women's choices. Lactation consultants could offer training and consistent information to healthcare professionals as well as providing specialist support to mothers who experience problems with breastfeeding during their hospital stay and in the postnatal period.

Generating actionable insights from free-text care experience survey data using qualitative and computational text analysis: A study protocol.

Introduction:The National Care Experience Programme (NCEP) conducts national surveys that ask people about their experiences of care in order to improve the quality of health and social care services in Ireland. Each survey contains open-ended questions, which allow respondents to comment on their experiences. While these comments provide important and valuable information about what matters most to service users, there is to date no unified approach to the analysis and integration of this detailed feedback. The objectives of this study are to analyse qualitative responses to NCEP surveys to determine the key care activities, resources and contextual factors related to positive and negative experiences; to identify key areas for improvement, policy development, healthcare regulation and monitoring; and to provide a tool to access the results of qualitative analyses on an ongoing basis to provide actionable insights and drive targeted improvements. Methods:Computational text analytics methods will be used to analyse 93,135 comments received in response to the National Inpatient Experience Survey and National Maternity Experience Survey. A comprehensive analytical framework grounded in both service management literature and the NCEP data will be employed as a coding framework to underpin automated analyses of the data using text analytics and deep learning techniques. Scenario-based designs will be adopted to determine effective ways of presenting insights to knowledge users to address their key information and decision-making needs. Conclusion:This study aims to use the qualitative data collected as part of routine care experience surveys to their full potential, making this information easier to access and use by those involved in developing quality improvement initiatives. The study will include the development of a tool to facilitate more efficient and standardised analysis of care experience data on an ongoing basis, enhancing and accelerating the translation of patient experience data into quality improvement initiatives.

Care Experiences of Older People in the Emergency Department: A Concurrent Mixed-Methods Study.

The growing population of older people has increased demand to meet their complex healthcare needs, including in emergency departments (EDs). This study explored the experiences of people aged 65+ in Irish EDs, involving secondary analysis of quantitative and qualitative data from the 2019 National Inpatient Experience Survey (NIES). Experiences in the ED and overall hospital experiences were dichotomized as poor to fair or good to very good. Logistic regression was used to model quantitative data. Free text comments relating to EDs were thematically analyzed. Of 12,343 survey participants, 4,442 (39.9%) were aged 65+ years and used the ED. Longer waiting times, completion of the questionnaire by another person either with or on behalf of the patient, and having both a medical card and private health insurance were predictors of poor to fair ED experiences. Patients aged 85+ years were more likely to report good to very good ED experiences. Poor experiences in the ED were associated with poorer overall hospital experiences (odds ratio [OR]: 2.19, 95% confidence interval [CI]: 1.76 to 2.73, p < .001). Thematic analysis revealed that long waiting times and unpleasant waiting conditions, including lack of communication, privacy, and personal care were important challenges encountered in the ED, with some older patients noting their preference for separate ED services. There is a need to reduce waiting times and integrate user perspectives in the planning, organization, and delivery of ED care to improve experiences and quality of care for a growing older population.

Development of a survey instrument to evaluate women's experiences of their maternity care.

BACKGROUND: The process of developing a survey instrument to evaluate women's experiences of their maternity care is complex given that maternity care encapsulates various contexts, services, professions and professionals across the antenatal, intranatal and postnatal periods. AIM: To identify and prioritise items for inclusion in the National Maternity Experience Survey, a survey instrument to evaluate women's experiences of their maternity care in the Republic of Ireland. METHODS: This study used an adapted two-phase exploratory sequential mixed methods design. Phase one identified items for possible inclusion and developed an exhaustive item pool through a systematic review, focus groups and one to one interviews, and a gap analysis. Phase two prioritised the items for inclusion in the final item bank through a Delphi study and consensus review. FINDINGS: Following iterative consultation with key stakeholder groups, a bank of 95 items have been prioritised and grouped within eight distinct care sections; care during your pregnancy, care during your labour and birth, care in hospital after the birth of your baby, specialised care for your baby, feeding your baby, care at home after the birth of your baby, overall care and you and your household. CONCLUSION: Robust and rigorous methods have been used to develop a bank of 95 suitable items for inclusion in the National Maternity Experience Survey.

Variation in resource allocation in urgent and emergency Care Systems in Ireland.

BACKGROUND: A key challenge for most systems is how to provide effective access to urgent and emergency care across rural and urban populations. Tensions about the placement and scope of hospital emergency services are longstanding in Irish political life and there has been recent reform to centralise hospital services in some regions. The focus of this paper is a system approach to examine the geographic variation in resourcing and utilisation of such care across GP practices, out-of-hours care, ambulance services, Emergency Departments and Local Injury Units in Ireland. METHODS: We used a cross-sectional study design to evaluate variation in resource allocation by aggregating geographic funding to various elements of the urgent and emergency care system and assessing patterns in hospital resource utilisation across the population. Expenditure, staffing, access and activity data were gathered from government sources, individual facilities and service providers, health professional bodies, private firms and central statistics. Data on costs and activity in 2014 are collated and presented at both county and regional levels. Analyses focus on resources spent on urgent and emergency care across geographic areas, the role of population concentration in allocation, the relationship between pre-hospital spending and in-hospital spending, and the utilisation of hospital-based emergency care resources by residents of each county. RESULTS: An array of funding mechanisms exists, resulting in a fragmented approach to the resourcing of urgent and emergency care. There are large differences in spending per capita at the county-level, ranging from between €50 and €200 per capita; however, these are less pronounced regionally. Distribution of hospital emergency care resources is highly skewed to the North East of the country, and away from the recently reconfigured South and Mid-West regions. CONCLUSIONS: This analysis advances the traditional approach of evaluating individual services or hospital resourcing. There are notable differences in utilisation of hospital-based emergency care resources at the regional level, indicating that populations within those regions which have been reconfigured have lower utilisation of hospital resources. There is a clear case for more integration in decision-making around funding and consideration of key principles, such as equity, to guide that process.

Understanding the impetus for major systems change: A multiple case study of decisions and non-decisions to reconfigure emergency and urgent care services.

OBJECTIVE: The optimal organisation of emergency and urgent care services (EUCS) is a perennial problem internationally. Similar to other countries, the Health Service Executive in Ireland pursued EUCS reconfiguration in response to quality and safety concerns, unsustainable costs and workforce issues. However, the implementation of reconfiguration has been inconsistent at a regional level. Our aim was to identify the factors that led to this inconsistency. METHODS: Using a multiple case study design, six case study regions represented full, partial and little/no reconfiguration at emergency departments (EDs). Data from documents and key stakeholder interviews were analysed using a framework approach with cross-case analysis. RESULTS: The impetus to reconfigure ED services was triggered by patient safety events, and to a lesser extent by having a region-specific plan and an obvious starting point for changes. However, the complexity of the next steps and political influence impeded reconfiguration in several regions. Implementation was more strategic in regions that reconfigured later, facilitated by clinical leadership and "lead-in time" to plan and sell changes. CONCLUSION: While the global shift towards centralisation of EUCS is driven by universal challenges, decisions about when, where and how much to implement are influenced by local drivers including context, people and politics. This can contribute to a public perception of inequity and distrust in proposals for major systems change.

Case fatality ratios for serious emergency conditions in the Republic of Ireland: a longitudinal investigation of trends over the period 2002-2014 using joinpoint analysis.

BACKGROUND: In the past decade, the Republic of Ireland has undertaken significant reconfiguration programmes to improve emergency services. During this time the public healthcare system experienced a large real decrease in resources. This study assesses national and regional population outcomes over the period 2002-2014, and whether changes coincide with system reconfiguration and the financial restrictions imposed by the 2008 recession. METHODS: Case fatality ratios (CFRs) were constructed for emergency conditions for 2002-2014. Total emergency conditions and individual condition trends were analysed nationally using joinpoint analysis. National results informed the investigation of trends at a regional and county level using an inverse standard error weighted generalised linear model with a log link to construct funnel plots. County-level CFRs were compared for the first and last 3 years of the period to further investigate the changes to county results over the 13 year period, specifically in comparison to the national-level CFR. RESULTS: Nationally, there was an annual fall in CFRs (2.1%). The decline was faster from 2002 to 2007 (annual percentage change = - 3.4; 95% CI-4.4, - 2.4), compared to 2007-2014 (annual percentage change = - 1.2; 95% CI -1.9, - 0.5). The South-East had a lower rate of decrease and the West had a higher rate. Cross sectional analysis of two periods (2002-2004 and 2012-2014) showed high consistency in the counties performance relative to the national CFR in both periods. CONCLUSION: Change in the national trend coincided with the onset of economic stress on the public health system. Attributing the decline in CFR improvement to economic factors is weakened by the uneven nature of the trend change. No distinct pattern of change was identified among regions which underwent substantial reconfiguration of emergency services.

Understanding perspectives on major system change: A comparative case study of public engagement and the implementation of urgent and emergency care system reconfiguration.

OBJECTIVES: Major changes have been made to how emergency care services are configured in several regions in the Republic of Ireland. This study investigated the hypothesis that engagement activities undertaken prior to these changes influenced stakeholder perspectives on the proposed changes and impacted on the success of implementation. METHODS: A comparative case-study approach was used to explore the changes in three regions. These regions were chosen for the case study as the nature of the proposals to reconfigure care provision were broadly similar but implementation outcomes varied considerably. Documentary analysis of reconfiguration planning reports was used to identify planned public engagement activities. Semi-structured interviews with 74 purposively-sampled stakeholders explored their perspectives on reconfiguration, engagement activities and public responses to reconfiguration. Framework analysis was used, integrating inductive and deductive approaches. RESULTS: Approaches to public engagement and success of implementation differed considerably across the three cases. Regions that presented the public with the reconfiguration plan alone reported greater public opposition and difficulty in implementing changes. Engagement activities that included a range of stakeholders and continued throughout the reconfiguration process appeared to largely address public concerns, contributing to smoother implementation. CONCLUSIONS: The presentation of reconfiguration reports alone is not enough to convince communities of the case for change. Genuine, ongoing and inclusive engagement offers the best opportunity to address community concerns about reconfiguration.

Patient experience of different regional models of urgent and emergency care: a cross-sectional survey study.

OBJECTIVES: To compare user experiences of 8 regional urgent and emergency care systems in the Republic of Ireland, and explore potential avenues for improvement. DESIGN: A cross-sectional survey. SETTING: Several distinct models of urgent and emergency care operate in Ireland, as system reconfiguration has been implemented in some regions but not others. The Urgent Care System Questionnaire was used to explore service users' experiences with urgent and emergency care. Linear regression and logistic regression were used to detect regional variation in each of the 3 domains and overall ratings of care. PARTICIPANTS: A nationally representative sample (N=8002) of the general population was contacted by telephone, yielding 1205 participants who self-identified as having used urgent and emergency care services in the previous 3 months. MAIN OUTCOME MEASURES: Patient experience was assessed across 3 domains: entry into the system, progress through the system and patient convenience of the system. Participants were also asked to provide an overall rating of the care they received. RESULTS: Service users in Dublin North East gave lower ratings on the entry into the system scale than those in Dublin South (adjusted mean difference=-0.18; 95% CI -0.35 to -0.10; p=0.038). For overall ratings of care, service users in the Mid-West were less likely than those in Dublin North East to give an excellent rating (adjusted OR 0.57; 95% CI 0.35 to 0.92; p=0.022). Survey items relating to communication, and consideration of patients' needs were comparatively poorly rated. The use of public emergency departments and out-of-hours general practice care was associated with poorer patient experiences. CONCLUSIONS: No consistent relationship was found between the type of urgent and emergency care model in different regions and patient experience. Scale-level data may not offer a useful metric for exploring the impact of system-level service change.

Intra-arterial delivery of AAV vectors to the mouse brain after mannitol mediated blood brain barrier disruption.

The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption that we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single administration.

Cannulation of the internal carotid artery in mice: a novel technique for intra-arterial delivery of therapeutics.

We have developed a novel minimally invasive technique for the intra-arterial delivery of therapeutics to the mouse brain. CD-1 mice were anesthetized and placed in a lateral decubitus position. A 10mm midline longitudinal incision was made over the thyroid bone. The omohyoid and sternomastoid muscles were retracted to expose the common carotid artery and external carotid artery (ECA). To maximize delivery of administered agents, the superior thyroid artery was ligated or coagulated, and the occipital artery and the pterygopalatine artery (PPA) were temporarily occluded with 6-0 prolene suture. The ECA was carefully dissected and a permanent ligature was placed on its distal segment while a temporary 6-0 prolene ligature was placed on the proximal segment in order to obtain a flow-free segment of vessel. A sterilized 169 µm outer diameter polyimide microcatheter was introduced into the ECA and advanced in retrograde fashion toward the carotid bifurcation. The catheter was then secured and manually rotated so that the microcatheter tip was oriented cephalad in the internal carotid artery (ICA). We were able to achieve reproducible results for selective ipsilateral hemispheric carotid injections of mannitol mediated therapeutics and/or gadolinium-based MRI contrast agent. Survival rates were dependent on the administered agent and ranged from 78 to 90%. This technique allows for reproducible delivery of agents to the ipsilateral cerebral hemisphere by utilizing anterograde catheter placement and temporary ligation of the PPA. This method is cost-effective and associated with a low rate of morbimortality.

Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra-arterial delivery of bevacizumab: from bedside to bench.

Bevacizumab (BV), a humanized monocolonal antibody directed against vascular endothelial growth factor (VEGF), is a standard intravenous (IV) treatment for recurrent glioblastoma multiforme (GBM), that has been introduced recently as an intra-arterial (IA) treatment modality in humans. Since preclinical models have not been reported, we sought to develop a tumor stem cell (TSC) xenograft model to investigate IA BV delivery in vivo. Firefly luciferase transduced patient TSC were injected into the cortex of 35 nude mice. Tumor growth was monitored weekly using bioluminescence imaging. Mice were treated with either intraperitoneal (IP) or IA BV, with or without blood-brain barrier disruption (BBBD), or with IP saline injection (controls). Tumor tissue was analyzed using immunohistochemistry and western blot techniques. Tumor formation occurred in 31 of 35 (89%) mice with a significant signal increase over time (p=0.018). Post mortem histology revealed an infiltrative growth of TSC xenografts in a similar pattern compared to the primary human GBM. Tumor tissue analyzed at 24 hours after treatment revealed that IA BV treatment with BBBD led to a significantly higher intratumoral BV concentration compared to IA BV alone, IP BV or controls (p<0.05). Thus, we have developed a TSC-based xenograft mouse model that allows us to study IA chemotherapy. However, further studies are needed to analyze the treatment effects after IA BV to assess tumor progression and overall animal survival.

Intra-arterial bevacizumab with blood brain barrier disruption in a glioblastoma xenograft model.

PURPOSE: In this study we investigated the treatment response and survival of intra-arterial (IA) compared to intra-peritoneal (IP) delivery of bevacizumab (BV) in a glioblastoma (GBM) xenograft mouse model. METHODS: 3x10(5) U87-Luc cells were stereotactically implanted into the cortex of 35 nude mice and grouped for treatment (n = 7 in each group): IP saline (group 1), single IP BV (group 2), biweekly IP BV for 3 weeks (group 3), single intra-arterial (IA) BV alone (group 4) and single IA BV with blood brain barrier disruption (BBBD) (group 5). Tumor growth was monitored every 3 to 4 days using bioluminescence imaging (BLI) and survival was analyzed by the Kaplan Meier method. Tumor tissue was analyzed using H&E staining and immunohistochemistry. RESULTS: Based on BLI, BV treated mice showed a delayed tumor growth over time compared to control. Kaplan Meier analysis demonstrated a median survival time of 28 days for group 1,31 days for group 2, 34 days for group 3, 36 days for group 4 and 36 days for group 5 (p < 0.0001). Mice treated with repeated IP BV (p = 0.003) or single IA BV with (p = 0.015) or without (p = 0.005) BBBD showed a significant survival benefit compared to single IP BV treated mice. Post mortem analysis revealed a histological pattern with a more discontinuous border between tumor and mouse brain in the repeated IP BV and single IA BV with or without BBBD treated mice compared to the sharply defined edges of single IP BV treated and control mice. CONCLUSIONS: In this study we showed a significant survival benefit of repeated IP BV and single IA BV with or without BBBD treated mice compared to single IP BV treated and control mice in a U87 xenograft model.

Real-time imaging of perivascular transport of nanoparticles during convection-enhanced delivery in the rat cortex.

Convection-enhanced delivery (CED) is a promising technique for administering large therapeutics that do not readily cross the blood brain barrier to neural tissue. It is of vital importance to understand how large drug constructs move through neural tissue during CED to optimize construct and delivery parameters so that drugs are concentrated in the targeted tissue, with minimal leakage outside the targeted zone. Experiments have shown that liposomes, viral vectors, high molecular weight tracers, and nanoparticles infused into neural tissue localize in the perivascular spaces of blood vessels within the brain parenchyma. In this work, we used two-photon excited fluorescence microscopy to monitor the real-time distribution of nanoparticles infused in the cortex of live, anesthetized rats via CED. Fluorescent nanoparticles of 24 and 100 nm nominal diameters were infused into rat cortex through microfluidic probes. We found that perivascular spaces provide a high permeability path for rapid convective transport of large nanoparticles through tissue, and that the effects of perivascular spaces on transport are more significant for larger particles that undergo hindered transport through the extracellular matrix. This suggests that the vascular topology of the target tissue volume must be considered when delivering large therapeutic constructs via CED.

Microfluidic probes in the treatment of brain-related diseases.

Many new therapeutic compounds have been developed that target malignancies and other disorders of the brain. However, delivering these compounds to diseased tissue remains a difficult challenge. One option for local drug delivery in the brain is direct infusion of the compounds through a catheter into the brain parenchyma. Over the last decade, new infusion catheters have been developed to improve this delivery method. Some of these catheters are needles or cannulas that have been modified specifically to increase the infusion rate that can be achieved without leakage of the infusate out of the brain. Other new catheters have been fabricated using micromachining techniques adapted from electronics manufacturing. These microfabricated catheters can achieve comparable infusion rates as standard needles, but they also can incorporate features that would be difficult to build into needles or cannulas to improve drug delivery. This article reviews the development of these devices, their performance in preclinical studies and their potential benefits to neural drug delivery.

Flexible microfluidic devices supported by biodegradable insertion scaffolds for convection-enhanced neural drug delivery.

Convection enhanced delivery (CED) can improve the spatial distribution of drugs delivered directly to the brain. In CED, drugs are infused locally into tissue through a needle or catheter inserted into brain parenchyma. Transport of the infused material is dominated by convection, which enhances drug penetration into tissue compared with diffusion mediated delivery. We have fabricated and characterized an implantable microfluidic device for chronic convection enhanced delivery protocols. The device consists of a flexible parylene-C microfluidic channel that is supported during its insertion into tissue by a biodegradable poly(DL-lactide-co-glycolide) scaffold. The scaffold is designed to enable tissue penetration and then erode over time, leaving only the flexible channel implanted in the tissue. The device was able to reproducibly inject fluid into neural tissue in acute experiments with final infusate distributions that closely approximate delivery from an ideal point source. This system shows promise as a tool for chronic CED protocols.