Beyond a Transmission Cable-New Technologies to Reveal the Richness in Axonal Electrophysiology.

The axon is a neuronal structure capable of processing, encoding, and transmitting information. This assessment contrasts with a limiting, but deeply rooted, perspective where the axon functions solely as a transmission cable of somatodendritic activity, sending signals in the form of stereotypical action potentials. This perspective arose, at least partially, because of the technical difficulties in probing axons: their extreme length-to-diameter ratio and intricate growth paths preclude the study of their dynamics through traditional techniques. Recent findings are challenging this view and revealing a much larger repertoire of axonal computations. Axons display complex signaling processes and structure-function relationships, which can be modulated via diverse activity-dependent mechanisms. Additionally, axons can exhibit patterns of activity that are dramatically different from those of their corresponding soma. Not surprisingly, many of these recent discoveries have been driven by novel technology developments, which allow for in vitro axon electrophysiology with unprecedented spatiotemporal resolution and signal-to-noise ratio. In this review, we outline the state-of-the-art in vitro toolset for axonal electrophysiology and summarize the recent discoveries in axon function it has enabled. We also review the increasing repertoire of microtechnologies for controlling axon guidance which, in combination with the available cutting-edge electrophysiology and imaging approaches, have the potential for more controlled and high-throughput in vitro studies. We anticipate that a larger adoption of these new technologies by the neuroscience community will drive a new era of experimental opportunities in the study of axon physiology and consequently, neuronal function.

Impact of sociodemographic and economic determinants of health on COVID-19 infection: incidence variation between reference periods.

OBJECTIVES: The COVID-19 pandemic hit Portugal in March 2020, causing widespread disruption to various aspects of society. While extensive research has been conducted on the significance of socio-economic disparities in infection risk, this study aims to enhance our understanding of their evolving relationship over time by analysing four distinct periods in 2020. STUDY DESIGN AND METHODS: This retrospective observational ecological study included individuals residing in the Primary Healthcare Cluster areas of Almada-Seixal and Western Lisbon and Oeiras, who tested positive for SARS-CoV-2 through a polymerase chain reaction (PCR) test between the 2nd of March and the 8th of November of 2020. Using incidence rates for each specific neighbourhood (n = 29) and period, we explored the relationship between neighbourhood-level socio-economic variables and the risk of infection using negative-binomial regression models. RESULTS: In the analysed period, a total of 8562 confirmed COVID-19 cases were identified. Overall incidence rates for each period were sequentially 2.74, 5.03, 3.99 and 14.29 COVID-19 cases per 100,000 person-days. Housing overcrowding, illiteracy rate and place of birth were associated with increased risk of infection, while age, congregate living, and employment in the secondary sector exhibited the opposite association. No association was consistent across all time periods. CONCLUSIONS: Our findings support the idea that the influence of socio-economic determinants of health is not immutable throughout time. In a pandemic context where information, knowledge, beliefs, and behaviours are ever-changing and evolving, a dynamic, inclusive, and adaptable approach to disease control can lead to a more equitable distribution of improved outcomes, benefiting all strata of society.

Lung cancer survival and sex-specific patterns in Portugal: A population-based analysis.

INTRODUCTION: In Portugal, lung cancer (LC) is the first cause of cancer-related death and of death and disability combined. This study aims to analyze the overall survival (OS) and relative survival (RS) of patients diagnosed with LC in 2009-2011 by socio-demographic and tumor characteristics, and analyze sex-specific patterns. METHODS: We estimated 5-year OS using the Kaplan-Meier method and 5-year net survival through the RS framework. Cox regression modeling was used to determine the hazard ratio (HR) of death associated with each independent variable. FINDINGS: For the 11,523 cases analyzed, median 5-year OS was 264 days (95% confidence interval [CI]: 254.8-273.2), the cumulative OS was 13.6% and RS was 15.1%. Males had a lower median survival (237 days; 95% CI: 228.2-245.7) compared to females (416 days; 95% CI: 384.4-447.6) (p < 0.0001) and lower 5-year RS proportions (12.1% vs. 24.9%). RS progressively decreased with age (41.7% for age-group <40 to 7.2% for ≥80) and stage (66.6% for stage I to 2.4% for stage IV). As predictors of decreased survival, we identified male gender, increasing age >50, histologic types (squamous cell carcinoma, non-small cell lung cancer not otherwise specified, other unspecified and small cell lung cancer), and increasing stage. Compared to women, the risk of death in men was 37.7% higher (HR = 1.386; 95% CI: 1.295-1.484). CONCLUSIONS: The differences between OS and RS were small, reflecting the high lethality of LC. Male gender and older age are factors related to poor prognosis. Histology also plays a role in survival prognosis and varies with gender, but the factor related to the worst survival is stage. Although the study reflects data from a decade ago, and major changes occurred in diagnosis, staging and treatment, particularly for advanced disease, as LC mortality is strongly correlated with late stage diagnosis, all efforts should be made to secure early diagnosis and improve survival prospects.

National trends in the use of oral chemotherapy over 13 years.

Background: Systemic cancer therapy has traditionally been administered using an intravenous (IV) route, implying patients' frequent visits to hospitals to access to their therapy. If we consider the actual pipeline in oncology, oral chemotherapy will be the main component of cancer treatment in the next few years. This shift in the administration route requires different care models in order to guarantee treatment efficacy and safety. Objective: To analyze time trends in oral chemotherapy consumption in Portugal. Method: Oral chemotherapy consumption over a 13-year period (2008-2020) was analyzed, considering dispensed units by the administration route with respective costs, resorting to the drug regulatory agency (INFARMED I.P.) database. Oral consumption patterns were further explored using common daily doses (CDD) for three conditions, including chronic myeloid leukemia (CML), non-small-cell lung cancer (NSCLC), and breast cancer (BC), to adjust for the effect of varying doses. Data were analyzed descriptively resorting to Microsoft Office Excel 2010. Results: Overall chemotherapy consumption increased +Δ54.7%, with the highest contribution in units observed in oral forms (+Δ58.8%). The total expenditure increased +Δ96.5%, and despite the increase in oral forms (+Δ221.6%), intravenous forms continued to be the major cost driver, with an important contribution from immunotherapy. Much of the increase was led by the approval of 40 new IV and 48 new oral cancer medications with higher costs introduced in the market. Using CDD as an alternative metric to units had varying impacts by indication. The observed increases seemed to focus on specific cancer sites with varying effect; in CML, there was a 2.39-fold increase, compared to 4.41 for NSCLC and 1.86 for BC. However, for BC, two distinct sub-patterns were observed for hormone therapy (increasing 1.83) and for the novel tyrosine kinase inhibitors (increasing 40.8). Conclusion: The growing use of oral chemotherapy is obvious and calls for investments in supporting patients in managing medication adherence and adverse events. The shifts in the healthcare system are complex and need to be prioritized. Our data suggest that priority could be attributed to cancer sites driving innovation, namely, advanced breast cancer.

Bidirectional flow of action potentials in axons drives activity dynamics in neuronal cultures.

Objective. Recent technological advances are revealing the complex physiology of the axon and challenging long-standing assumptions. Namely, while most action potential (AP) initiation occurs at the axon initial segment in central nervous system neurons, initiation in distal parts of the axon has been reported to occur in both physiological and pathological conditions. The functional role of these ectopic APs, if exists, is still not clear, nor its impact on network activity dynamics.Approach. Using an electrophysiology platform specifically designed for assessing axonal conduction we show here for the first time regular and effective bidirectional axonal conduction in hippocampal and dorsal root ganglia cultures. We investigate and characterize this bidirectional propagation both in physiological conditions and after distal axotomy.Main results.A significant fraction of APs are not coming from the canonical synapse-dendrite-soma signal flow, but instead from signals originating at the distal axon. Importantly, antidromic APs may carry information and can have a functional impact on the neuron, as they consistently depolarize the soma. Thus, plasticity or gene transduction mechanisms triggered by soma depolarization can also be affected by these antidromic APs. Conduction velocity is asymmetrical, with antidromic conduction being slower than orthodromic.Significance.Altogether these findings have important implications for the study of neuronal functionin vitro, reshaping our understanding on how information flows in neuronal cultures.

Rapid detection of biofilm-producing Candida species via MALDI-TOF mass spectrometry.

AIMS: The aim of this study was to evaluate the formation of biofilm by Candida spp. isolated from the bloodstream, using traditional spectrophotometric methodologies. In addition, the goal was to compare the results with those obtained through MALDI-TOF/MS, as well as to verify its use as a potential tool for the detection of biofilm-forming strains. METHODS AND RESULTS: Hundred and thirteen isolates of Candida spp. were studied: 41 were Candida albicans, 27 C. tropicalis, 18 C. glabrata, 17 C. parapsilosis and 10 C. krusei. Metabolic activity was determined through the tetrazolium salt (XTT) reduction assay and biomass by staining with Crystal Violet. All isolates were able to form biofilm, 94% of which were strong producers, with high biomass quantification (95%; 107/113) and high metabolic activity (99%; 112/113). Mass spectra of the biofilm-producing isolates showed differences in the intensity of mass peaks when compared with the spectra of the nonproducing strains. CONCLUSIONS: It was demonstrated that MALDI-TOF/MS was able to detect specific biofilm proteins, as the mass spectra of the isolates presented differences when compared with nonproducing strains. SIGNIFICANCE AND IMPACT OF THE STUDY: MALDI-TOF/MS can become a valuable tool for biofilm detection at the moment of the identification of the microorganism, thus contributing greatly to the management of patients with Candidemia.

Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Relevance of quantification in brain PET studies with 18F-FDG. / Relevancia de la cuantificación en los estudios PET cerebrales con 18F-FDG.

The inclusion of 18F-FDG PET as a biomarker in the diagnostic criteria of neurodegenerative diseases and its indication in the presurgical assessment for drug-resistant epilepsies allow to improve specificity of these diagnosis. The traditional interpretation of neurological PET studies has been performed qualitatively, although in the last decade, several quantitative evaluation methods have emerged. This technical development has become relevant in clinical practice, improving specificity, reproducibility and reducing the interrater reliability derived from visual analysis. In this article we update/review the main imaging processing techniques currently used. This may allow the Nuclear Medicine physician to know their advantages and disadvantages when including these procedures in daily clinical practice.

Quality of Life and Characterization of Patients With Atopic Dermatitis in Portugal: The QUADEP Study.

BACKGROUND AND OBJECTIVE: To investigate the quality of life (QOL) of and to characterize patients with atopic dermatitis (AD) in Portugal. METHODS: This was a cross-sectional study of patients with AD and other eczemas. Skindex-29, Skindex-teen, and the Childhood Atopic Dermatitis Impact Scale (CADIS) were the instruments used to assess QOL in adults, teenagers, and children, respectively. The SF-12 was also used, and disease severity was evaluated using the Patient-Oriented SCORAD (PO-SCORAD) instrument. Associations with QOL were assessed based on the odds ratio (OR). P values <.05 and 95%CIs were considered statistically significant. RESULTS: The study population comprised 162 participants aged 0.5-74 years. We found that 37.3% of AD patients consider their disease disabling and that more than half of the patients feel stigmatized by society. The mean Skindex score for AD was 39.68, and the impact on QOL was severe in 44%. "Symptoms" was the most affected category in adults. AD was moderate to severe in 87% of the sample. One of the factors that most influenced poorer QOL in AD was age: with increasing age, the Skindex is likely to increase (OR, 1.03; 95%CI, 1.00-1.06). "Considering the disease a disability" was also associated (OR, 6.72; 95%CI, 2.56-17.63). QOL worsens with increasingly affected body area (OR, 1.07; 95%CI, 1.03-1.11) and the presence of edema (OR, 2.0; 95%CI, 1.23-3.40). CONCLUSIONS: This is the first study to provide data on QOL in patients with AD in Portugal. Our data show an expected negative impact. More awareness-raising activities are needed to increase knowledge, decrease stigmatization, and, consequently, address the factors involved in the QOL of patients with AD.

Comprehensive analysis of meningioma in the first two decades of life: A systematic review.

PURPOSE: To evaluate the relationship between meningioma histological subtype and tumor site in under-20 year-olds. METHODS: A review of the literature on meningioma during the first 2 decades of life was carried out through a Medline search up to February 2019. To evaluate the adult population, a cross-sectional study was conducted on patients operated on between 2000 and 2014 in a single institution. Exclusion criteria comprised: series reports and papers that lacked detailed description of clinical findings, neuroimaging confirmation of tumor location, and/or at least 5 years' follow-up. RESULTS: One hundred and seven manuscripts were included, for 365 under-20 year-old patients: 200 male, and 164 female. Histopathology found 197 cases (53.9%) of WHO grade I meningioma, with predominance of meningothelial (41.1%) and transitional (30.9%) subtypes; 123 (33.7%) grade II, and 45 (12.3%) grade III. For 65 (18.25%) of the 356 cases, recurrence was documented, with only 24 deaths (6.7%). CONCLUSION: Meningioma in this population presented 2 differences compared to the adult population: male predominance, and high incidence of atypical meningioma. Surgery was the primary treatment. Adjuvant radiotherapy is controversial in the literature.

Neuro-oncological features of spinal meningiomas: Systematic review.

PURPOSE: Review the published data on spinal meningioma (SM) to create a more comprehensive picture of its natural history. METHODS: A review of the published SM literature was carried out through a Medline search up to December 2018. The search using the keyword "spinal meningiomas" returned 248 papers and the parameters analyzed in our present study were examined in those publications. Papers without a detailed description of clinical findings, neuroimaging confirmation of the spinal tumor, minimum follow-up of 5 years, or a clear description of the clinical findings were excluded. RESULTS: In the 24 manuscripts reviewed, 1811 (1450 females/361 males) patients with SM were analyzed. The thoracic spine (1181-64.6%) and cervical spine (394-22.7%) were the more prevalent levels. The psammomatous (27.8%) and meningothelial variants (25.2%) were the most prevalent histopathological subtypes. Gross total resection (Simpson I and II) was achieved in 94.5% of cases and subtotal resection (Simpson III or more) in 5.5%. The tumor recurrence rate was 4.4%, and the mortality rate related to surgery or disease progression was 3%. CONCLUSION: WHO grade I predominance was observed among spinal meningiomas, analogous to intracranial meningiomas. SMs predominated in the thoracic spine. Surgery with gross total resection was achieved in the vast majority of cases, resulting in low recurrence and mortality rates.

Late Onset Graft Plasmacytoma-Like PTLD Presenting as Acute Hyperglycemia in a Kidney-Pancreas Transplant Recipient.

Allograft infiltration has been described in up to 20% of all patients with posttransplant lymphoproliferative disorder (PTLD), most representing EBV-positive B-cell lymphomas. Plasma cells are often observed in humoral rejection biopsies, but graft infiltration by plasmacytoma-like PTLD is rare. We report the case of a 54-year-old simultaneous pancreas-kidney transplant recipient (immunosuppression: OKT3, methylprednisolone, cyclosporine, and azathioprine), diagnosed with an IgG-kappa monoclonal gammopathy of undetermined significance eighteen years after transplant. Nine months later, pancreas allograft biopsy performed due to new-onset hyperglycemia (HgA1C 8.6%, C-peptide 6.15ng/mL and anti-GAD 0.9UI/mL) revealed a monotypic plasma cell infiltrate, CD19, CD79a, CD138 positive, with IgG-kappa light chain restriction, and EBV negative. PET-scan FDG uptake was limited to pancreas allograft. Tumor origin could not be established (using DNA microsatellite analysis). Despite treatment with bortezomib and dexamethasone, patient eventually died one month later. This is the first report of a late onset extramedullary plasmacytoma involving a pancreas allograft.

Eczema and Urticaria in the Adult Population in Portugal: A Prevalence Study. / Eccema y urticaria en la población adulta en Portugal: un estudio de prevalencia.

BACKGROUND AND AIMS: Eczema and urticaria are both inflammatory skin diseases. The prevalence of both diseases varies worldwide and the reasons are unknown. We aimed to investigate the eczema and urticaria prevalence in the Portuguese adult (≥16 years-old) population. MATERIALS AND METHODS: A telephone interview survey was performed in the last quarter of 2017. To calculate the prevalences, subjects should have been previously diagnosed with eczema/urticaria by a health professional, be aged ≥16 years-old, and reside in Portugal. The sample had a proportion that was approximately representative by population, region, gender, and age group. Odds ratios were performed to measure associations with prevalences. SPSS statistics and values of p<0.05 with 95% confidence intervals were considered statistically significant. RESULTS: 5,000 phone calls were analysed. The prevalence of eczema and urticaria in Portugal is 4.4% and 3.4%, respectively. Algarve is the region with the highest prevalence for both diseases. Being a female is the factor that most influenced these diseases with an OR=1.99 (p<0.001; CI 1.49-2.66) for eczema and 1.73 (p=0.001; CI 1.25 - 2.40) for urticaria, with also higher prevalences (5.7% and 4.2%, respectively). CONCLUSIONS: The prevalences found are higher than in previous studies in Portugal and comparable to results from other countries. Comparisons among prevalence of eczema are affected by several obstacles. Regarding urticaria, our results seem to be in the same line as others. Being female with eczema and urticaria is more common and represents a higher risk factor than male subjects. According to Harrop et al., 2007, in Europe, atopic eczema is 0.14-0.60% of general eczema. In this way, we can estimate that prevalence of atopic eczema in Portugal is around 0.61-2.64%.

In the Era of Cost-Effectiveness Analysis, Affordability Is a Limiting Factor for Patients' Access to Innovative Cancer Treatments.

BACKGROUND: Over the past 5 years, 55 new anticancer drugs have been launched worldwide. Considering the increasing costs of innovative treatments, both the number and the relevance of cost-effectiveness analyses have increased, meaningfully supporting decision making by stakeholders and policy makers. Notably, cost-effective treatments remain unavailable to patients because they are still unaffordable for a multitude of payers. OBJECTIVES: To discuss the differences between cost-effectiveness and affordability. METHODS: We reviewed the most relevant data on the divergences between cost-effectiveness and affordability. In addition, we included our recommendations to improve patients' access to innovative cancer therapies. RESULTS: The increasing costs of recently launched antineoplastic drugs, as high as $150 000 per year, represent a major barrier to patients' access to treatments globally. In Brazil, for example, patients' access to innovative treatments depends greatly on whether the individual has private health insurance. In the public health sector, patients' access to cost-effective innovative treatments varies according to the financial capacity of the facility, leading to inequalities within the same healthcare system. CONCLUSIONS: We conclude that because of the socioeconomic inequality mostly seen in lower and middle-income countries, it is difficult to define a cost-effectiveness threshold by region or a willingness-to-pay threshold affordable to the entire population. We consider that benchmark interventions might help to find an affordable willingness-to-pay threshold, and league table interventions might help policy makers, physicians, and the society to share the decision making.

Pyomyositis in a Patient with IgA Nephropathy and Kidney Transplant.

Infections are among the most common complications transplant physicians face when dealing with solid organ transplant recipients. We present a case of pyomyositis caused by Staphylococcus aureus in a patient with IgA nephropathy and a kidney transplant, under treatment with mTOR inhibitors and prednisone. This entity is a rare intramuscular infection, given the resistance of healthy muscle to colonization. We review the most frequent agents, the diagnostic algorithm, and therapeutic alternatives. We also comment on the role of mTOR inhibitors in this case as possible predisposing factor for the infection.

Predictive and Comparative Study Between Clinic Consensus Document for Pancreas Acceptance and Predictive Value of Preprocurement Pancreas Allocation Suitability Score (P-PASS).

The strict selection of pancreas for transplant has forced the development of different documents to select the suitable organ in order to minimize the risks and complications of the transplant. In 2008, Eurotransplant published the Preprocurement Pancreas Allocation Suitability Score (P-PASS) for pretransplant selection. In 2001 the Hospital Clinic of Barcelona developed a Clinical Consensus Document (CCD). OBJECTIVES: We aimed to analyze the predictive decision of the pancreas acceptance to offers received in the hospital, according to the CCD criteria and compare it with the recommended value of suitability for accepting the pancreas according to the P-PASS value. MATERIAL AND METHODS: We performed a retrospective comparative study between the criteria of selection of the CCD for pancreas from 2016-2017 in comparison with the values obtained if the P-PASS had been used: ≤ 17, acceptance criteria and P-PASS; > 17, risk criteria. We defined the organ reported as rejected or accepted. The accepted organ could be procured and transplanted or discarded. RESULTS: With the CCD criteria, 7 more organs were transplanted than if we only applied the potential P-PASS criteria. In contrast, P-PASS would have ruled out an additional 9% of pancreases in relation to CCD criteria. CONCLUSIONS: According our experience, it is difficult to find an adequate prediction model to select pancreas for transplantation. The application of the DCC criteria increases the number of organs valid for transplantation. At present, new criteria should be re-evaluated within multicenter studies.

Monopolar 250-500 Hz language mapping: Results of 41 patients.

OBJECTIVES: To determine whether high-frequency 250-500 Hz monopolar stimulation is effective for mapping cortical and subcortical language structures during brain tumor resection. METHODS: Using high-frequency monopolar stimulation, we mapped the speech areas of 41 awake patients undergoing brain tumor resection in the dominant hemisphere, subject to risk of lesions in the cortical and subcortical speech tracts. Patients were tested for object naming, semantic and other language tasks. RESULTS: Mapping was positive in 22 out of 41 patients. Nine patients presented clinical worsening immediately after surgery. Only one patient did not recover after the 30-day follow-up. Nineteen patients showed negative mapping for language tracts, none of whom exhibited worsening of symptoms at the final evaluation. The applied method showed 89% sensitivity and 56% specificity rates. CONCLUSIONS: The applied method was effective in identifying cortical and subcortical speech areas during the surgical resection of brain tumors. SIGNIFICANCE: Determining whether monopolar high-frequency stimulation is effective for language mapping is important, since it may be very effective in infiltrating tumor areas and nearby edema region.

Guiding morphogenesis in cell-instructive microgels for therapeutic angiogenesis.

Efficient cell delivery strategies are urgently needed to improve the outcome of cell-based pro-angiogenic therapies. This study describes the design of an injectable cell delivery platform, based on biomaterial-guided morphogenesis principles. Soft high-mannuronic acid alginate microgels, oxidized and functionalized with integrin-binding peptides, provided adequate biochemical/biomechanical cues for the co-assembly of mesenchymal stem cells and outgrowth endothelial cells (OEC) into pre-vascularized microtissues. In vitro priming conditions regulated OEC tubulogenesis, which only occurred under normoxia (+O2) in the presence of angiogenic factors (+GF) and, importantly, did not revert in an ischemic-like environment. Primed (+O2+GF) microgel-entrapped cells secreted a large variety of angiogenesis-related proteins and produced endogenous extracellular-matrix, rich in fibronectin and collagen type I, fostering cell-cell/cell-matrix interactions and establishing a stable angiogenic niche. Extending the pre-culture time resulted in higher cell outward migration and in vivo angiogenic potential. Microgels partially disintegrated upon implantation in chick embryos, promoting interaction between pre-vascularized microtissues and the host. Preserved human vascular structures were still detected in vivo, and human cells showed the ability to migrate and integrate with the chick vasculature. Our results suggest that an integrated approach combining pro-angiogenic cells, cell-instructive microgels and adequate in vitro priming may provide the basis for successful therapeutic angiogenesis.