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From Organoids to Bioprinting: Advancing the Building Blocks of Breast Tissue Engineering
No full textBreast tissue is essential for milk production and has significant health implications due to the high prevalence of breast cancer. Despite advances in understanding breast biology and cancer treatment, challenges remain. Current treatment development is hindered by inefficiencies, high costs, and ethical concerns over animal models, which poorly mimic human breast biology. Improving and humanizing preclinical models is crucial for better insights into breast function and disease. The mammary gland’s three-dimensional structure is vital to its function, making 3D organoid models central to breast tissue engineering. While organoids improve on traditional 2D cell cultures in complexity, no fully functional, lactating mammary organoid model exists. Key limitations include a lack of spatial control, hormonal cues, stromal tissue, and vasculature. Advances in tissue engineering, biofabrication, and microfluidics offer potential solutions, with 3D bioprinting enabling precise deposition of cells and matrix components. Light-based methods, especially volumetric bioprinting, show promise due to their high resolution and layer-free printing. Additionally, bioreactors and organ-on-a-chip systems provide dynamic control over cell environments, guiding self-organization and maturation. This thesis, From Organoids to Bioprinting: Advancing the Building Blocks of Breast Tissue Engineering, aimed to develop an advanced in vitro mammary gland model bridging gaps between simplified cell cultures, non-human animal models, and complex human biology. Key Findings: Chapter 2: Identified research priorities, including integrating biofabrication with organoid technology, improving multicellularity, scalability, and post-printing maturation. Human breast milk was highlighted as a valuable cell source for tissue engineering. Chapter 3: Established breast milk as a non-invasive source for mammary organoids (MBOs), encompassing all major epithelial cell types and forming TDLU-like structures—the milk-producing units of the breast. Chapter 4: Used MBOs to assess breast cancer treatment safety. Given the abundance of milk, MBOs could serve as a biobank for population-wide tissue variations, identifying rare side effects and screening immunotherapy targets. Chapter 5: Developed a biofabrication pipeline integrating volumetric bioprinting, cell seeding, perfusion, and imaging-based validation. Findings suggest future enhancements should include hormonal stimulation, stromal cells, and MBO integration. Chapter 6: Introduced AnyBio, an affordable (€350) open-source mSLA-based bioprinter, demonstrating its versatility in biomaterial printing and cellular viability. Chapter 7 & Annex 1: Explored two biomaterials—supramolecular GelMA for vascularization, organoid culture, and T-cell migration within a 3D-printed breast cancer model, and gel-norbonene for light-induced porosity, supporting vascularization in a vessel-on-a-chip model. Conclusion: This thesis approached breast tissue engineering from multiple angles, emphasizing the need for improved multicellularity, multi-material composition, and architectural complexity. The integration of diverse fabrication techniques and a deeper understanding of the mammary extracellular matrix and stem cell organization will be crucial for future progress. Dynamic post-fabrication culture conditions have shown promise in functional maturation. Core Principles: Open Science & Accessibility: Open-source equipment and workflows promote democratization of knowledge in biofabrication. Sustainability: Computational data analysis and resource-efficient lab practices minimize waste. Future work could lead to a fully functional human mammary gland model, advancing research on lactation, breast cancer, and treatment development in an animal-free framework
Insights and innovations in sarcoidosis associated small fiber neuropathy
Full text linkThis thesis explores small fiber neuropathy (SFN) associated with sarcoidosis, focusing on its pathophysiology, diagnosis, symptomatology, and treatment options. Given the absence of a diagnostic gold standard and the complexity of proposed criteria, this research aims to improve diagnostic accuracy and therapeutic strategies for SFN and cardiac autonomic dysfunction in sarcoidosis patients. Key findings include: Symptomatology (Chapter 3): Patients with sarcoidosis-associated SFN exhibit a higher prevalence of fatigue, restless legs syndrome (RLS), pain, and cognitive impairment compared to those without SFN. These symptoms strongly correlate, suggesting a significant disease burden. Pain Phenotyping (Chapter 4): The newly developed SFN phenotyping questionnaire (SFNPQ) identified a high prevalence of cutaneous foot pain (67%) and muscular leg pain (77%) in sarcoidosis-associated SFN, offering a refined approach for clinical and research applications. Thermal Threshold Testing (Chapter 5): Thermal threshold testing (TTT) was evaluated for diagnostic accuracy, with findings supporting the use of multiple measuring sites and parameter selection. A novel parameter, TTT number of abnormalities (TTT NOAs), was introduced to improve diagnostic precision. Corneal Confocal Microscopy (Chapter 6): No significant reduction in corneal nerve fiber length (CNFL) or corneal nerve fiber area (CNFA) was detected in sarcoidosis-associated SFN, limiting the utility of corneal confocal microscopy (CCM) for diagnosis. However, automatic image analysis methods showed good agreement, facilitating future research. Phenotypic Variability (Chapter 7): SFN symptom patterns (length-dependent vs. non-length-dependent, intermittent vs. continuous) were analyzed, revealing that length-dependent continuous pain correlated with TTT NOAs at the feet. Other diagnostic modalities showed no significant associations, highlighting the need for improved diagnostic methods. Inflammatory Treatment Effects (Chapter 8): Infliximab significantly reduced sarcoidosis-related inflammation but did not alleviate SFN symptoms, suggesting a complex and possibly independent pathophysiological mechanism underlying SFN in sarcoidosis. Cardiac Autonomic Dysfunction (Chapter 9): [123I]-MIBG scintigraphy identified abnormalities in 44% of sarcoidosis patients, supporting its potential role in assessing unexplained cardiac symptoms and therapy-resistant cases. Overall, this research advances the understanding of sarcoidosis-associated SFN by refining diagnostic tools, characterizing symptomatology, and evaluating treatment efficacy. Future studies should focus on novel diagnostic methods and targeted therapies for SFN and autonomic dysfunction in sarcoidosis
Empowering Epidemiology with Life-Based Ethics: A Study of the Exposome and Exposomics
No full textThis dissertation examines the overarching beliefs and values driving exposomics, an innovative research venture in environmental science. Inspired by the success that the Human Genome Project had in creating technology to sequence the entire human genome, many environmental epidemiologists saw the need to improve their ability to measure environmental exposures. The idea of the exposome spurred a lot of research activity: exposomics researchers created new cohorts, improved measurement technologies and data analytics, and published many hundreds of studies. However, exposomics lacks an identification of overarching beliefs and values that allows researchers to drive the field toward scientific and technological progress. In particular, more research needed to be done to map the values that are relevant to exposomics. Using a systematic literature review and focus groups, this dissertation essentially identifies these values as: research goals, research standards, research tools, the trade between researchers and participants, health at a population and an individual level, occupational health, forensic science, and justice (in various domains). On the basis of this map and a conceptual-ethical analysis, this dissertation identifies and evaluates the fundamental beliefs and values of exposomics. It defines exposomics as a research program in environmental health aimed at enabling a comprehensive and discovery-driven approach to identifying environmental determinants of human health. Exposomics should fundamentally value the creation of such a comprehensive and discovery-driven approach. To uphold this value, exposomics requires a view of human beings as agents with the authority to master the environment for the pursuit of human health
Pertussis Immunization Before 24 Weeks of Pregnancy: Maternal Antibody Transfer, Reactogenicity and Acceptance
Full text linkIn this thesis, we describe several aspects of early maternal tetanus, diphtheria and acellular pertussis (Tdap) vaccination before 24 weeks of pregnancy in order to protect the infant against severe pertussis in the first months of life. Data from a longitudinal cohort study after maternal Tdap vaccination between 20-24 weeks of gestation were compared with a reference cohort after Tdap vaccination between 30-33 weeks of gestation. Pertussis-specific antibodies in term infants were compared with those of preterm infants, together with reactogenicity and acceptance of maternal Tdap vaccination before 24 weeks of gestation. The results indicate that vaccination before 24 weeks of gestation is suboptimal for transplacental antibody transfer and leads to two-fold lower antibody concentrations at the age of two months in term-born infants, compared with vaccination at 30-33 weeks. In early premature infants, i.e. born before 32 weeks of gestation, this may be up to 3-fold lower antibody levels, while in late-preterm infants, i.e. born after 32 weeks of gestation, similar antibody concentrations were found in preterm infants. The side reactogenicity and acceptance were unaffected by earlier administration of Tdap-vaccination during pregnancy. More research is needed to investigate whether the impared transfer may lead to a weaker protection against pertussis. Beside the results of the cohort study, this thesis also describes antibody transfer after maternal Tdap vaccination in pregnant women with chronic inflammatory diseases who use immune-modulating medication. Also, the pertussis incidence in the Caribbean part of the Netherlands was estimated based on a serosurveillance study from 2017, which implicates that up to 8% of adolescents were recently infected by Bordettella pertussis
The role of business model-building and model-changing in driving healthcare value: A physiotherapy primary healthcare organisation perspective
No full textThe general purpose of this thesis is to gain insights into business model-building and model-changing related to healthcare value for physiotherapy primary healthcare organisation (PTPHO) within the context of Dutch PTPHOs. Physiotherapy provides services that develop, maintain and restore people’s maximum movement and functional ability at any stage of life when movement and function are threatened by ageing, injury, diseases, disorders or environmental factors. As in other Western countries, a significant proportion of physiotherapy services in the Netherlands is provided by PTPHOs. These micro (<10 employees) organisations are located in neighbourhoods close to where people live and work. Interaction with local neighbourhoods is important for PTPHOs, to attain and sustain healthcare value. The healthcare market in which Dutch PTPHOs operate is characterised by managed competition. With managed competition, business principles have been introduced. PTPHOs still struggle to make impact in this healthcare system approach. To enable PTPHOs to manage their organisation a ‘Healthcare value for PTPHOs framework and definition, was presented. Healthcare value for PTPHOs is “to continuously attain PTPHO-centred outcomes in coherence with patient- and stakeholder-centred outcomes, leveraged by an organisation’s capacity for change”. Concerning business model-building, it may be advisable for a PTPHO to apply a planned strategy, encourage organisational double-loop learning orientation and proactive market orientation and, business model novelty. It may also be desirable for a PTPHO to have interfaces in place for the use of internal organisation and external environment information. Regarding business modelchanging, it is suggested that a PTPHO may conduct business model change over-time that link the internal organisation and external environment by concurrent short-, medium- and long-term exploitation and exploration. Such a simultaneous approach may allow a PTPHO to adapt to a changing market in both an incremental and radical way. To stimulate transitions in healthcare, healthcare policy and health insurers could encourage PTPHO business model-building and model-changing. The combination of persistent use of health insurer-driven managed competition contracts and naturally efficient PTPHOs may have left too few means for these organisations to contribute to healthcare reforms and to attain and sustain healthcare value. Markedly, the insights gained in this dissertation suggest that PTPHOs may want to shift their attitudes toward new routines, business model novelty instead of efficiency, and business model change
Assessing and minimizing the risk of cerebrospinal fluid leakage after intradural surgery
Full text linkThis thesis evaluated the effectiveness of current sealants in preventing incisional CSF leakage. Subsequently, we developed a new dural sealant patch (Liqoseal) which should ultimately prevent incisional CSF leakage in patients. However, before clinical application, the effectiveness and the safety of this sealant in preclinical studies had to be evaluated. In this thesis the in vitro effectiveness and in vivo safety of Liqoseal have been studied
Heart Perfusion for Tailored Preservation and Regeneration: Innovative Techniques in the Surgical Treatment of Advanced Heart Failure
Full text linkEnd-stage heart failure occurs in 1-10% of cases of heart failure. There are two treatment options: mechanical support and heart transplantation. Both treatments have advantages and disadvantages. Heart transplantation is the gold standard but is limited by the availability of suitable donor hearts. This dissertation describes the potential added value of donor hearts after circulatory death in the Netherlands. In addition, restarting the central circulation in the donor (thoraco-abdominal normothermic regional perfusion) may have advantages over removing the heart directly and supplying it with blood and oxygen on a machine. The ethical dilemmas surrounding this technique are highlighted. Given the scarcity, making optimal use of available donor hearts is of great importance. To gain a better understanding of the development of primary graft failure after transplantation, the risk factors for primary graft failure have been investigated. Despite the expected increase in available donor hearts due to the use of donor hearts after circulatory death, it is expected that alternative treatment methods will be necessary to treat a larger group of patients with end-stage heart failure. The "Cardiovascular moonshot" aims to regenerate the heart outside the human body. As part of the "Cardiovascular moonshot", this thesis describes the establishment of a model to use machine perfusion of the heart for the application of alternative treatment methods
Microfluidic models to study the nervous system and its connection to the periphery
Full text linkAmyotrophic lateral sclerosis (ALS) is an incompletely understood disease in which motor neurons and skeletal muscle cells are affected. One of the major hurdles that the field had to overcome, involved obtaining sufficient cells to study the disease in a controlled environment in the laboratory. The advent of induced pluripotent stem cell (iPSC) technology has allowed this. Importantly, iPSC-derived cells are increasingly being combined with culture methods that are more relevant than 2-dimensional approaches. In chapter 1, we highlight recent advances the ALS field has made, which in vitro models would be relevant to study the disease, and how microfluidic technology can be used to generate such models. Chapter 2 describes the differentiation of iPSCs from healthy and ALS donors into motor neurons and skeletal muscle cells. Importantly, motor neurons progenitors could be cryopreserved and subsequently demonstrated good viability upon thawing. Finally, we highlight how motor neurospheres and skeletal muscle cells can be co-cultured to form a neuromuscular junction (NMJ) model, and how the motor neurons can be integrated into the OrganoPlate. We subsequently developed a model that separates axons from a somatodendritic compartment in chapter 3. Diseases such as ALS are characterized by various axonal defects. Being able to separate the axons allows their specific interrogation. We demonstrate that the outgrowth is robust and can be targeted using a specific tubulin inhibitor, while axonal guidance cues deter outgrowing axons. We therefore argue that the neurite outgrowth model can be used in the fields of toxicology and regenerative medicine. We then utilized the developed protocols to compare iPSC-derived motor neurons from healthy and ALS donors in the OrganoPlate platform in chapter 4. For these comparisons, we focused on ALS risk gene ATXN2. Using different read-outs, donor-dependent differences could be elucidated. While these were not ALS-specific, it demonstrates the sensitivity of the assays. Additional read-outs and ALS genes should be considered, while model complexity can be increased to study additional ALS pathways. In chapter 5, we developed an approach to study calcium bursts in skeletal muscle and neuronal cells. Both iPSC-derived and primary skeletal muscle cells form multinucleated myotubes that contract upon an electrical stimulus. We demonstrate that contraction could be quantified through the assessment of calcium concentrations, and that this process can be inhibited. We finally demonstrate that calcium bursts in neuronal cells can be induced and inhibited as well. In chapter 6, the implications of this thesis are highlighted. We discuss how the developed models and read-outs can be used for specific applications. First, the models can be used to assess toxicological effects on neuronal or muscle cells, which holds potential in the field of drug development. In addition, increasing culture complexity may pave the way for the development of novel, relevant read-outs. The addition of glia and skeletal muscle cells are specifically highlighted. The high throughput of the OrganoPlate may ultimately be leveraged to screen a large number of therapeutics in the fields of toxicology and disease modeling
Long-Term Risk of Subsequent Neoplasms in 5-Year Survivors of Childhood Neuroblastoma: A Dutch Childhood Cancer Survivor Study-LATER 3 Study
No full textPURPOSE: Neuroblastoma survivors have an increased risk of developing subsequent malignant neoplasms (SMNs), but the risk of subsequent nonmalignant neoplasms (SNMNs) and risk factors are largely unknown. We analyzed the long-term risks and associated risk factors for developing SMNs and SNMNs in a well-characterized cohort of 5-year neuroblastoma survivors. METHODS: We included 563 5-year neuroblastoma survivors from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort, diagnosed during 1963-2014. Subsequent neoplasms were ascertained by linkages with the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank (Palga) and medical chart review. We calculated standardized incidence ratios (SIRs), absolute excess risk (AER), and cumulative incidences. Multivariable competing risk regression analysis was used to evaluate risk factors. RESULTS: In total, 23 survivors developed an SMN and 60 an SNMN. After a median follow-up of 23.7 (range, 5.0-56.3) years, the risk of SMN was elevated compared with the general population (SIR, 4.0; 95% CI, 2.5 to 5.9; AER per 10,000 person-years, 15.1). The 30-year cumulative incidence was 3.4% (95% CI, 1.9 to 6.0) for SMNs and 10.4% (95% CI, 7.3 to 14.8) for SNMNs. Six survivors developed an SMN after iodine-metaiodobenzylguanidine ( 131IMIBG) treatment. Survivors treated with 131IMIBG had a higher risk of developing SMNs (subdistribution hazard ratio [SHR], 5.7; 95% CI, 1.8 to 17.8) and SNMNs (SHR, 2.6; 95% CI, 1.2 to 5.6) compared with survivors treated without 131IMIBG; results for SMNs were attenuated in high-risk patients only (SMNs SHR, 3.6; 95% CI, 0.9 to 15.3; SNMNs SHR, 1.5; 95% CI, 0.7 to 3.6). CONCLUSION: Our results demonstrate that neuroblastoma survivors have an elevated risk of developing SMNs and a high risk of SNMNs. 131IMIBG may be a treatment-related risk factor for the development of SMN and SNMN, which needs further validation. Our results emphasize the need for awareness of subsequent neoplasms and the importance of follow-up care