Scientific publications of the Saarland University
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Heat Preconditioning of Nanofat Does Not Improve Its Vascularization Properties
Get PDFHeat preconditioning has been shown to promote nutritive perfusion and tissue survival in autologous fat grafting as well as in flap and breast surgery. However,
its impact on the vascularization properties of nanofat has not been investigated so far.
Therefore, we exposed nanofat from donor mice to a temperature of 43 ◦C for 1 h and
assessed the effects of this heat stress on cell viability and the expression of heat shock
proteins (HSPs) and angiogenesis-related factors. Moreover, dermal substitutes seeded with
heat-preconditioned and non-preconditioned control nanofat were implanted into dorsal
skinfold chambers of recipient mice to study their vascularization and tissue integration
in vivo by means of repeated intravital fluorescence microscopy, histology and immunohistochemistry. Heat preconditioning upregulated the expression of HSPs in nanofat without
affecting cell viability. Moreover, it resulted in the downregulation of many pro-angiogenic
factors and the increased expression of anti-angiogenic factors, indicating a shift towards
an anti-angiogenic phenotype. Accordingly, implanted dermal substitutes seeded with
heat-preconditioned nanofat exhibited a reduced vascularization and were not better integrated into the host tissue when compared to controls. These findings indicate that
heat preconditioning cannot be recommended for enhancing the vascularization capacity
of nanofat
Revitalizing the Epigenome of Adult Jaw Periosteal Cells: Enhancing Diversity in iPSC-Derived Mesenchymal Stem Cells (iMSCs)
Get PDFInduced pluripotent stem cells (iPSCs) are rapidly emerging as a transformative
resource in regenerative medicine. In a previous study, our laboratory achieved a significant
milestone by successfully reprograming jaw periosteal cells (JPCs) into iPSCs, which were
then differentiated into iPSC-derived mesenchymal stem cells (iMSCs). Using an optimized
protocol, we generated iMSCs with a remarkable osteogenic potential while exhibiting
lower expression levels of the senescence markers p16 and p21 compared to the original
JPCs. This study aimed to explore the epigenetic landscape by comparing the DNA methylation and transcription profiles of iMSCs with their JPC precursors, seeking to uncover key
differences. Additionally, this analysis provided an opportunity for us to investigate the
potential rejuvenation effects associated with cellular reprogramming. To assess the safety
of the generated cells, we evaluated their ability to form teratomas through subcutaneous
injection into immunodeficient mice. Our findings revealed that, while the methylation
profile of iMSCs closely mirrored that of JPCs, distinct iMSC-specific methylation patterns
were evident. Strikingly, the application of DNA methylation (DNAm) clocks for biological age estimation showed a dramatic reduction in DNAm age to approximately zero in
iPSCs—a rejuvenation effect that persisted in the derived iMSCs. This profound reset in
biological age, together with our transcriptome data, indicate that iMSCs could possess an
enhanced regenerative potential compared to adult MSCs. Future in vivo studies should
validate this hypothesis
Correction: Hosseinikha et al. Nanomaterials for the Diagnosis and Treatment of Inflammatory Arthritis. Int. J. Mol. Sci. 2021, 22, 3092
Get PDFIn the original publication [...
Untersuchung der S100A8/S100A9-CD147 Achse in Peniskarzinomen und beteiligten infiltrierenden Immunzellen
Get PDFÜbersicht: Das penile Plattenepithelkarzinom (PeCa) ist eine seltene Tumorentität in den Industriestaaten Europas und Nordamerikas, macht aber bis zu 10% der Malignome bei Männern in Entwicklungsländern wie Uganda aus. Neben der aktuellen WHO-Klassifikation, die zwischen HPV-positiven und -negativen Tumoren unterscheidet, etabliert sich immer mehr das Konzept die Subtypen stärker in Diagnostik, Therapie und Prognose einzubeziehen. Das Plattenepithelkarzinom macht 95% aller penilen Malignome aus, seltener sind andere Tumorentitäten wie Adenokarzinome, Melanome oder Sarkome. Als „orphan disease“ besteht ein Defizit bezüglich groß angelegter Studien zu potenziellen diagnostischen und möglicherweise therapeutisch verwendbaren Biomarkern zur Therapieplanung, Prognosekalkulation und Verlaufskontrolle. Bisher hat sich neben p16, als Surrogatmarker für eine HPV-getriebene Karzinogenese, in den Leitlinien und außerhalb von Studien kein histopathologischer Biomarker etabliert. Aufgrund von Vorarbeiten in der Arbeitsgruppe untersucht diese Arbeit mittels IHC-Färbung die S100A8/A9-, CD15- und CD147-Expression in PeCa-Proben aus Invasionsfront, Tumorzentrum und Lymphknotenmetastasen im Zusammenhang zu den klinischen Patientendaten sowie dem Vorhandensein von Immunzellinfiltraten in den untersuchten Proben. Material und Methodik: Insgesamt wurden TMA-Proben von 92 Patienten aus Deutschland und Russland zwischen 1992 und 2015, jeweils für Invasionsfront (IF), Tumorzentrum (TZ) und Lymphknotenmetastasen (LKM) untersucht. Zusätzlich wurden auch Normalgewebe (NO) und reguläre Tumorschnitte verwendet. Nach dem Ausschluss nicht auswertbarer Proben und solchen mit fehlenden Daten, verblieben 74 Patienten in der untersuchten Kohorte. Die TMAs wurden von 2 erfahrenen Uropathologen histopathologisch nach der WHO-Klassifikation von 2016 und der 8. Edition der TNM-Klassifikation maligner Tumore eingeteilt. Der HPV-Status wurde durch PCR DNA-Nachweis und die immunhistochemische p16-Expression definiert. Die S100A8-, S100A9-, CD15 und CD147-Expression wurden mittels IHC nachgewiesen. Ergänzend erfolgten auch Versuche an einem in vitro PeCa-Zelllinienmodell zur S100A8/A9-Färbung der 3D-organotypischen Kulturen.
Ergebnisse: Das mittlere Alter der Patienten betrug 61 Jahre, die meisten zeigen ein Grading von 2 (55,4%), 46 (62,2%) wiesen invasives und 22 (29,8%) metastasierendes Tumorwachstum auf. 29 Patienten (39,2%) sind HPV+, 45 (60,8%) sind HPV-. Im untersuchten Kollektiv sind neun verschiedene histologische Subtypen identifiziert worden. Alle LKM zeigten sich S100A8+/A9+ und CD147+, das TZ war signifikant stärker positiv als die IF. HPV+-Proben mit positiver S100A8/A9- und CD147-Färbung waren häufiger mit Metastasen assoziiert. Die CD147-Färbung war im Tumorgewebe signifikant stärker als im Normalgewebe. Neutrophile Immunzellinfiltrate fanden sich als S100A8+/A9+/CD15+-Zellen in vielen Tumorproben, dort assoziiert mit einer schlechteren Differenzierung und Auftreten von LKM. In vitro Färbungen für S100A8/A9 zeigten eine positive Färbung, jedoch insbesondere hinsichtlich der LKM weniger ausgeprägt als in der TMA-Färbung.
Schlussfolgerung: Es sind weitere Analysen größerer retrospektiver Auswertungen oder zukünftige prospektive Studien nötig, um diese Daten zu verifizieren, insbesondere im Hinblick auf die Korrelationen zum HPV-Status und den dazu assoziierten Subtypen. So könnten unter anderem weitere Hinweise für ein erhöhtes oder frühes Metastasierungspotential in die inguinalen Lymphknoten durch S100A8/A9+CD15 positive Infiltrate und eine entsprechende Tumorfärbung gefunden werden. Weiter könnte S100 und CD147 so als möglicher Marker im Tumormikromilieu dazu dienen Neutrophile zu erkennen, die eine prämetastatische Loge in Lymphknoten und Organen für eine Metastasierung schaffen und so zur Risikokalkulation und Therapieplanung dienen. Auf Grund der hier gezeigten Subgruppen-Analyse mit verstärktem Auftreten von Lymphknotenmetastasen in HPV+-S100A8+/A9+-CD147+-Proben kann pauschal keine bessere Prognose bei HPV-positivem Status analog anderer Tumorentitäten quittiert werden. Es ist wichtig einheitliche diagnostische Methodiken und Definitionen zum HPV-Status zu etablieren, um Studien besser vergleichbar zu machen.Investigation of the S100A8/S100A9-CD147 axis in penile carcinomas and involved infiltrating immune cells
Purpose: Penile squamous cell carcinoma (PeCa) is a rare tumor entity in the industrialized countries of Europe and North America, but accounts for up to 10% of malignancies in men in developing countries such as Uganda. In addition to the current WHO classification, which distinguishes between HPV-positive and negative tumors, the concept of including subtypes more strongly in diagnostics, therapy and prognosis is becoming increasingly established. Squamous cell carcinoma accounts for 95% of all penile malignancies; other tumor entities such as adenocarcinomas, melanomas or sarcomas are less common. As an "orphan disease", there is a lack of large-scale studies on potential diagnostic and possibly therapeutically applicable biomarkers for therapy planning, prognosis calculation and follow-up. To date, apart from p16, as an HPV surrogate marker, no histopathological biomarker has been established in the guidelines or outside of studies. Therefore, this study uses IHC staining to investigate S100A8/A9, CD15 and CD147 expression in PeCa samples from the invasion front, tumor center and lymph node metastases in relation to clinical patient data and the presence of immune infiltrates in the samples examined.
Materials and Methods: In total, TMA samples from 92 patients from Germany and Russia between 1992 and 2015 were analyzed for invasion front (IF), tumor center (TZ) and lymph node metastases. Normal tissue (NO) and regular tumor sections were also used. After excluding non-evaluable samples and those with missing data, 74 patients remained in the cohort under investigation. The TMAs were histopathologically classified by 2 experienced uropathologists according to the WHO classification of 2016 and the 8th edition of the TNM classification of malignant tumors. HPV status was defined by PCR DNA detection and immunohistochemical p16 expression. S100A8, S100A9, CD15 and CD147 expression was detected by IHC. In addition, experiments were also performed on an in vitro PeCa cell line model for S100A8/A9 staining of the 3D organotypic cultures.
Results: The median age of patients was 61 years, most showed a grading of 2 (55.4%), 46 (62.2%) showed invasive and 22 (29.8%) metastatic tumor growth. 29 patients (39.2%) were HPV+, 45 (60.8%) were HPV-. Nine different histologic subtypes were identified in the investigated collective. All LKM were S100A8+/A9+ and CD147+, the TZ was significantly more positive than the IF. HPV+ samples with positive S100A8/A9 and CD147 staining were more frequently associated with metastases. CD147 staining was significantly stronger in tumor
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tissue than in normal tissue. Neutrophil immune infiltrates were present as S100A8+/A9+/CD15+ cells in many tumor samples, where they are associated with poor differentiation and occurrence of LKM. In vitro staining for S100A8/A9 showed positive staining, but less pronounced than in TMA staining, particularly regarding LKM.
Conclusion: Further analyses of larger retrospective evaluations and future prospective studies are required to verify these data, particularly with regard to the correlations with HPV status and the associated subtypes. For example, further evidence for an increased or early metastatic potential to the inguinal lymph nodes could be found through S100A8/A9+CD15 positive infiltrates and tumor staining. Furthermore, S100 and CD147 as a possible marker in the tumor microenvironment could be used to detect neutrophils that create a pre-metastatic niche in lymph nodes and organs for metastasis and thus serve for risk calculation and therapy planning. Due to the subgroup analysis shown here with an increased occurrence of lymph node metastases in HPV+-S100A8+/A9+-CD147+ samples, a better prognosis cannot be generally confirmed for HPV-positive status analogous to other tumor entities. It is important to establish uniform diagnostic methods and definitions of HPV status to make studies more comparable
Positive Impact Product Engineering - Produktentstehungsmodell für Produktsysteme mit netto-positiver Nachhaltigkeitswirkung
Get PDFDas Überschreiten planetarer Grenzen und die zunehmende soziale Ungleichheit erfordern eine nachhaltige Entwicklung und eine Transformation der Entstehung und Nutzung von Produkten. Diese Dissertation präsentiert folglich das Positive Impact Product Engineering (PIPE)-Modell, ein ganzheitliches Modell zur nachhaltigen Produktentstehung, das die Vision von Produktsystemen mit netto-positiven Nachhaltigkeitswirkungen verfolgt. Ziel ist es, positive Effekte in den Bereichen Ökologie, Soziales, Ökonomie und Kreislaufwirtschaft gezielt zu verstärken, negative Auswirkungen zu minimieren und durch überkompensierende Maßnahmen in eine netto-positive Bilanz zu überführen. Die Arbeit identifiziert Defizite im Forschungsstand der „Nachhaltigen Produktentstehung“ in Analyse, Synthese und Integration positiver Wirkungen. Diese Lücken werden durch ein Entstehungsmodell für technische Produktsysteme geschlossen. Im vierphasigen Produktentstehungsprozess werden durch iterative Kombination von Analyse- und Synthesemethoden die Nachhaltigkeitswirkungen optimiert, um die Vision des netto-positiven Produktsystems systematisch zu realisieren. Zwei Fallstudien – die Entwicklung eines Kinderlaufrads und eines e-Bikes – validieren das Modell. Die Ergebnisse unterstreichen dessen Potenzial bei der Entstehung nachhaltiger Produkte, zeigen jedoch auch derzeitige Limitationen bei komplexen Systemen auf. PIPE leistet damit einen wertvollen Beitrag zur notwendigen Transformation der Produktentstehung.The transgression of planetary boundaries and growing social inequality necessitate sustainable development and a transformation in how products are developed and used. In response, this dissertation introduces Positive Impact Product Engineering (PIPE), a holistic model for sustainable product development (SPD), aiming for product systems with net-positive impacts. The model seeks to enhance positive effects in ecological, social, and economic dimensions, as well as in the context of a circular economy, while minimizing negative impacts and compensating for unavoidable ones through additional measures that generate positive impacts, ensuring a net-positive outcome. This work identifies gaps in the research on SPD in analysis, synthesis, and integration of positive impacts. These gaps are addressed by an engineering model for technical product systems. The four-phase development process combines analysis and synthesis methods iteratively, optimizing sustainability impacts and systematically realizing the vision of a net-positive product system. Validation is provided through two case studies—the development of a children's balance bike and an e-bike. The findings highlight the model’s potential for SPD, while also emphasizing limitations in dealing with complex systems. Overall, PIPE makes a valuable contribution to the necessary transformation of product development processes, advancing them towards sustainable development
SURWEY real-world study of solriamfetol: initiation, titration, safety, efficacy, and follow-up experience for patients with obstructive sleep apnea in Germany
Get PDFPurpose Solriamfetol is approved for use in the European Union to treat excessive daytime sleepiness (EDS) associated
with obstructive sleep apnea (OSA). SURWEY characterized real-world evidence regarding physician initiation and titration
strategies and patient experiences with solriamfetol. We report SURWEY data for patients with OSA and EDS in Germany
(N=83).
Methods SURWEY was a retrospective chart review conducted among physicians in Germany. Eligible patients were
age ≥ 18 years who reached a stable solriamfetol dose and completed ≥ 6 weeks of treatment. Patients were grouped by solri amfetol initiation strategy: changeover, add-on, new-to-therapy.
Results Patients’ mean (SD) age was 49 (14) years. New-to-therapy was the most common initiation strategy. Solriamfetol
was initiated at 37.5 mg/day in most patients (n=57, 69%) and titrated in 53 patients (64%); 30 (57%) completed titra tion within 2 weeks. In a post-hoc analysis, mean (SD) Epworth Sleepiness Scale (ESS) score was 16.0 (3.2) at baseline
and decreased by 5.4 (3.6) at final follow-up (~ 16 weeks; p<.001). Improvement in patient- and physician-rated EDS was
reported by ~ 90% of patients. Most patients (55%) reported effects of solriamfetol lasting ≥ 8 h; 91% of patients reported
no change in nighttime sleep quality. The most frequent adverse events were headache (8%), decreased appetite (7%), and
insomnia (6%).
Conclusion Most patients in this study were new to therapy. Solriamfetol was typically initiated at 37.5 mg/day; titration was
common. ESS scores improved with solriamfetol treatment, and most patients self-reported improvement in EDS symptoms.
Common adverse events were consistent with those reported in previous clinical trials
The Clinical Impact of Somatic Copy Number Variations in Patients With Stage IV Wilms Tumor Enrolled in the SIOP 2001 Trial and Study
Get PDFBackground: Recent research elucidated the prognostic significance of molecular biology in Wilms tumor (WT) by linking
somatic genomic variants (such as gain of chromosome 1q) to unfavorable patient outcomes. This analysis describes the clinical
impact of copy number variations (CNV) in tumor samples of WT patients with stage IV disease.
Methods: Tumor samples of 55 WT patients with stage IV disease from the United Kingdom, France, and Germany enrolled in the
SIOP 2001 study and treated with preoperative chemotherapy (pCHT) were examined for their CNVs of chromosome 1q and other
regions of interest using multiplex ligation-dependent probe amplification (MLPA). The identified CNV were analyzed regarding
their prognostic impact.
Results: Chromosome 1q gain (1q+) and TP53 loss occurred in 38.2% and 16.4% of tumors and were associated with older patient
age at diagnosis (median [months]: 65 and 64 vs. 49 each, p = 0.03 and 0.02, respectively) and poorer 5-year event-free survival
(40.0% and 11.1% vs. 67.7% and 82.6%, p = 0.04 and <0.01, respectively) compared to their specific control group of tumors without
the respective CNV. In patients with pulmonary-only metastasis, 1q+ was an adverse prognostic marker irrespective of remission
status after pCHT with or without metastasectomy. A simultaneous MYCN gain occurred more frequently in tumors with 1q+
than in tumors without 1q+ (p = 0.03). TP53 loss was linked to high-risk histology and inferior 5-year overall survival (p < 0.001). Conclusions
We confirm the prognostic relevance of 1q+ and TP53 loss in stage IV WTs and emphasize their potential utility for future treatment stratification
Prävalenz und Risikofaktoren der Leberfibrose mit Hilfe der Elastographie im hausärztlichen Bereich
Get PDFDie Leberzirrhose ist weltweit für 1,2 Millionen Todesfälle jährlich verantwortlich und ist die zehnthäufigste Todesursache in den westlichen Industrienationen. Zu der Lebensprävalenz finden sich in der Literatur Angaben zwischen 6 % und 26 %. Des Weiteren ist ein Rückgang der Häufigkeit nicht absehbar, da die Rate der Nicht-alkoholassoziierten Leberverfettungen (NAFLD) weiter zunimmt. Die von uns durchgeführte Studie konnte Risikofaktoren für die Ausbildung einer erhöhten Lebersteifigkeit zeigen. Es zeigte sich, dass Patient*innen mit arterieller Hypertonie, erhöhtem Controlled Attenuation Parameter (CAP-Wert), zunehmendem Alter und männlichem Geschlecht ein erhöhtes Risiko für eine erhöhte Lebersteifigkeitsmessung (LSM) in der Elastographie hatten. Einen hohen Einfluss auf die LSM hat das Vorliegen einer arteriellen Hypertonie. So ist das Risiko für Patient*innen mit arterieller Hypertonie im Vergleich zu Patient*innen ohne arterielle Hypertonie um 140 % erhöht. Es konnte gezeigt werden, dass schon das Ansteigen des CAP-Wertes um einen Punkt in dB/m einem um 1,6 % höherem relativen Risiko entspricht. Der CAP-Wert ist ein Parameter für das Ausmaß einer potentiellen Leberverfettung und wird mit Hilfe der Elastographie bestimmt. Zudem stieg das Risiko für eine Leberfibrose mit jedem Lebensalter um 2,8 % an. Weibliches Geschlecht zeigte sich als protektiver Faktor: Männer haben im Vergleich zu Frauen ein um 181 % höheres Risiko zu erkranken. Zwar tranken Männer signifikant mehr Alkohol als Frauen (5,9 vs. 2,2 Getränke pro Woche), jedoch hatte der Alkoholkonsum in der keinen Einfluss auf das Vorliegen einer Fibrose.
In einem explorativen Ansatz wurden der Einfluss der übrigen Variablen (Kaffeekonsum pro Woche, Diabetes mellitus, Body Mass Index (BMI), Hyperlipidämie und AOK-versichert) mit der LSM errechnet. Hierbei ergab sich eine positive Korrelation von r = 0,257 (p < 0,05) zwischen der LSM und dem BMI. Im Weiteren wurde der CAP-Wert als abhängige Variable verwendet. In der multiplen linearen Regression zeigten der BMI mit r = 1,335, die LSM mit r = 2,054, das Alter mit r = 0,454 und die arterielle Hypertonie mit r = 20,879 eine signifikante Korrelation mit der Leberverfettung. Explorativ konnten signifikante Ergebnisse für die Korrelationen zwischen CAP, LSM (r = 0,230), BMI (r = 0,275) und Alter (r = 0,236) erreicht werden.
Aus den oben gezeigten Daten schlussfolgern wir, dass die Entstehung einer Leberfibrose durch zwei veränderbare Faktoren beeinflusst werden kann. Arterielle Hypertonie und Leberverfettung, gemessen durch den CAP-Wert, sollten somit deutlich mehr in den Fokus von Hausärzt*innen genommen werden, um das Risiko einer Leberfibrose so gering wie möglich zu halten. Besonders bei männlichen und älteren Patienten sollten Hausärzt*innen auf die Optimierung der arteriellen Hypertonie und der Reduktion einer Leberverfettung hinwirken.Liver cirrhosis is the cause of 1.2 million deaths worldwide every year which makes it the number 10 cause of death in Western countries. In a literature research you can find a lifetime prevalence reaching from 5.6 % to 25.6 %. Additionally, a decrease of prevalence is highly unlikely because the number of patients with Non-alcoholic fatty liver disease (NAFLD) has risen in recent years. This study was able to show risk factors for the development of higher liver stiffness. Patients with arterial hypertension, elevated controlled attenuation parameter (CAP), higher age and men had a higher risk of elevated liver stiffness measurement (LSM). Arterial hypertension had a high impact on LSM. The risk of a patient with arterial hypertension to present with higher LSM is elevated by 140 % in comparison to a patient without arterial hypertension. Another important factor is an elevated CAP. This study shows that with every extra CAP point in dB/m the relative risk cirrhosis rises by 1.6 %. Higher age also appears to be a risk factor: With every additional year the risk increases by 2.8 %. Female sex seems to be a protective factor: In comparison men had a 181 % higher risk of cirrhosis. Men drank more alcoholic beverages than women (5.92 drinks vs. 2.24 drinks per week) but there was no association between alcohol consumption and cirrhosis in our study.
In exploratory testing the remaining variants (coffee consumption per week, diabetes mellitus type 2, hyperlipidemia and social health insurance were evaluated regarding the effect on LSM. There was a positive correlation (r = 0.257, p < 0.05) between LSM and Body Mass Index (BMI).
In a secondary analysis, CAP was used as dependent variable. In multiple linear regression, BMI showed r = 1.335, LSM r = 2.054, age r = 0.454 and arterial hypertension r = 20.879. All these variants had a significant impact on CAP and therefore on the manifestation of NAFLD. From an exploratory perspective there was a significant correlation between CAP, LSM (r = 0.230), BMI (r = 0.275) and age (r = 0.236).
Taken together our data indicates that the risk of liver fibrosis is strongly related to arterial hypertension and fatty liver, measured via CAP. Primary physicians should be determined to optimize arterial hypertension and fatty liver, especially in male and older patients who have a higher risk of liver fibrosis
Re-Designing Business Process Models for Enhancing Sustainability in Spinach Production Through Lean Tools with Digital Transformation
Get PDFThis study addresses rising sustainability demands in the agro-industry by examining how
data-driven approaches can reduce inefficiencies, waste, and poor resource use in spinach
production. It investigates the impact of Total Productive Maintenance (TPM), First-In–First Out (FIFO), process standardization, and circular economy practices—enhanced through
digital transformation—on operational efficiency in a Peruvian agro-industrial firm. An
exploratory case study was conducted using pilot implementations, direct observation, and
quantitative analysis. Statistical tools, including Holt–Winters forecasting, were applied to
assess the effectiveness of the interventions. Digital technologies supported data collection,
traceability, and decision-making. An exploratory case study was conducted using pilot
implementations, direct observation, and quantitative analysis. The integration of digital
tools with lean and circular practices supports sustainable agro-industrial supply chains,
contributing to food security and socio-economic resilience. This research offers a holistic,
data-driven framework that aligns operational excellence with sustainability and digital
innovation. Findings are based on a single case, limiting their generalizability. Broader
applications and long-term effects warrant further study. Practitioners should adopt system thinking approaches integrating digital, lean, and circular strategies. Future research should
explore scalability, cost-efficiency, and policy support mechanisms
Scalable polymeric nanoparticles for potential nose-to-brain delivery applications
No full textNose-to-brain (N2B) delivery offers a non-invasive route to treat central nervous system (CNS) diseases via bypassing the blood-brain barrier (BBB). Polymeric nanoparticles (NPs) such as poly(lactic-co-glycolic acid) (PLGA) NPs are biodegradable, making them promising carriers. Incorporating hydrophobic and hydrophilic small and large molecular weight (Mw) substances with innovative methods could enhance bioavailability. However, scalable manufacturing of these NPs remains a challenge. Therefore, this study investigates encapsulating model substances with different Mw into these PLGA NPs using two continuous manufacturing technologies: the spinning disc system (SDS) and the micro-spray-reactor (MSR). By employing the modified-nanoprecipitation method with the SDS, a small Mw hydrophobic substance (curcumin), and by the double emulsion method and MSR, small and large Mw drugs (Ciprofloxacin HCl and albumin-FITC) were successfully encapsulated with high encapsulation efficiencies. Blank and model-substance-loaded (albumin-FITC and wheat germ agglutinin-488 (WGA488)) fluorescent PLGA NPs were prepared using the MSR system to assess their potential for future N2B delivery applications. The NPs showed biocompatibility and sustained drug release profiles and were not internalized in test cells, which is ideal for N2B delivery. Overall, these proof-of-concept studies show scalable NP manufacturing and flexible drug loading for future applications such as N2B deliveryDas Delivery von Wirkstoffen über die Nase zum Gehirn (N2B) bietet einen nicht-invasiven Weg zur Behandlung von Erkrankungen des zentralen Nervensystems durch Umgehung der Blut-Hirn-Schranke. Polymere Nanopartikel (NP) wie PLGA NP sind bioabbaubar und daher vielversprechende Träger. Die Einbindung hydrophober und hydrophiler Substanzen mit kleinen und großen Molekulargewichten (Mw) mittels innovativer Technologien könnte die Bioverfügbarkeit verbessern. Die skalierbare Produktion dieser NPs bleibt jedoch eine Herausforderung. Diese Studie untersucht die kontinuierliche Herstellung von PLGA NPs mit Modellsubstanzen unterschiedlichen Mw mittels Spinning-Disc-System (SDS) und Micro-Spray-Reactor (MSR). Mit der modifizierten Nanopräzipitationsmethode mit SDS und einer hydrophoben Substanz mit kleinem Mw (Curcumin) sowie der Doppelemulsionsmethode und dem MSR wurden Substanzen mit kleinem und großem Mw (Ciprofloxacin HCl und Albumin-FITC) erfolgreich mit hoher Verkapselungseffizienz verkapselt. Leere und mit Albumin-FITC und WGA488 beladene fluoreszierende PLGA NP wurden mit dem MSR-System hergestellt, um ihr Potenzial für künftige N2B-Transportanwendungen zu bewerten. Die NPs wiesen Biokompatibilitäts- und anhaltende Wirkstofffreisetzungsprofile auf und wurden nicht zellular internalisiert, was für die N2B-Verabreichung ideal ist. Insgesamt zeigen diese Studien, dass die Herstellung von NPs mit verschiedenen Wirkstoffmolekülen für zukünftige Anwendungen skalierbar machbar ist.This work was carried out as part of the Bio2Brain project which has received funding
from the European Union’s Horizon 2020 research and innovation programme under
the Marie Skłodowska-Curie grant agreement No 956977