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Item does not contain fulltext, BACKGROUND: Testicular adrenal rest tumors (TART) are a common complication of unknown cellular origin in patients with congenital adrenal hyperplasia (CAH). These benign tumors have both adrenal and testicular characteristics and are hypothesized to either derive from cells of adrenal origin from the fetal adrenogonadal primordium or by atypical differentiation of adult Leydig-progenitor cells. OBJECTIVE: This study aims to unravel the identity and etiology of TART. METHODS: Co-expression of adrenal-specific CYP11B1 and Leydig cell-specific HSD17B3 in TART was studied using immunohistochemistry. We studied the possibility of TART being derived from atypical differentiation of adult Leydig-progenitor cells by the quantification of adrenal-specific enzyme expression upon adrenocorticotrophic hormone (ACTH)-like stimulation of ex vivo cultured platelet-derived growth factor receptor alpha-positive cells. By comparing the transcriptome of TART (n = 16) with the transcriptome of fetal adrenal (n = 13), fetal testis (n = 5), adult adrenal (n = 11), and adult testis (n = 10) tissues, we explored the identity of TART. RESULTS: We demonstrate co-expression of adrenal-specific CYP11B1 and testis-specific HSD17B3 in TART cells, indicating the existence of a distinct TART cell exhibiting both adrenal and testicular characteristics. Ex vivo cultured adult Leydig-progenitor cells did not express the ACTH-receptor MC2R but did express CYP11B1 upon stimulation. Unsupervised clustering of transcriptome data showed that TART was most similar to adult adrenal tissue, followed by adult testis tissue, and least similar to either fetal tissue. CONCLUSION: Our data suggest that TART is induced - most likely via activation of a cAMP/protein kinase A-dependent receptor - from a progenitor cell into a unique mature adrenal-like cell type, sometimes exhibiting both adrenal and testicular features.

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Contains fulltext : 205348.pdf (publisher's version ) (Closed access), Wounds often result in scarring, prolonged morbidity, and loss of function. New interactive and modifiable hydrogel wound dressings are being developed for these injuries. Polyisocyanopeptide (PIC) gel is a promising thermosensitive hydrogel having several characteristics that can facilitate wound repair, including ease of application/removal and strain-stiffening properties that mimic extracellular matrix components. However, it is unknown whether the PIC gel remains in the wound for a clinically relevant time period. Therefore, PIC polymers were functionalized with a DTPA group allowing labelling with Indium-111 (111In). Following application of this radiolabelled gel to splinted and non-splinted murine full-thickness skin wounds the signal was monitored using SPECT/CT imaging for 7 days. The SPECT signal from the PIC gel was highly stable and covered the complete wound area. Non-bound 111In-EDTA was rapidly cleared via the kidneys to the urine. The impact of PIC gels on wound repair was further studied visually and histologically. Radiolabelled PIC gel was observed to move both over and under the skin, while histological analysis demonstrated that part of the gel became encapsulated within the wound repair tissue, but did not delay wound closure or otherwise impair wound healing. This work illustrates for the first time the use of 111In-labelled PIC gels for diagnostic and monitoring purposes and describes the use of PIC in the (non-)splinted murine skin wound model. It was found that PIC gels remained in splinted and non-splinted full-thickness skin wounds during wound repair. This warrants the continuation of developing the PIC gel into a clinically advanced wound dressing.

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Radboud University, 21 september 2018, Promotor : Rowan, A.E. Co-promotor : Kouwer, P.H.J., Contains fulltext : 195018.pdf (publisher's version ) (Open Access)

Contains fulltext : 192456.pdf (publisher's version ) (Open Access)

Radboud University, 05 februari 2018, Promotores : Rowan, A.E., Zhan, Y., Xing, C. Co-promotor : Kouwer, P.H.J., Contains fulltext : 180514.pdf (publisher's version ) (Open Access)

Contains fulltext : 192101.pdf (publisher's version ) (Open Access)

1 oktober 2018, Contains fulltext : 196295.pdf (publisher's version ) (Closed access), Changing wound dressings inflicts pain and may disrupt wound repair. Novel synthetic thermosensitive hydrogels based on polyisocyanopeptide (PIC) offer a solution. These gels are liquid below 16 degrees C and form gels beyond room temperature. The architecture and mechanical properties of PIC gels closely resemble collagen and fibrin, and include the characteristic stiffening response at high strains. Considering the reversible thermo-responsive behavior, we postulate that PIC gels are easy to apply and remove, and facilitate healing without eliciting foreign body responses or excessive inflammation. Biocompatibility may be higher in RGD-peptide-functionalized PIC gels due to enhanced cell binding capabilities. Full-thickness dorsal skin wounds in mice were compared to wounds treated with PIC gel and PIC-RGD gel for 3 and 7 days. No foreign body reactions and similar wound closure rates were found in all groups. The level of macrophages, myofibroblasts, epithelial migration, collagen expression, and blood vessels did not significantly differ from controls. Surprisingly, granulocyte populations in the wound decreased significantly in the PIC gel-treated groups, likely because foreign bacteria could not penetrate the gel. RGD-peptides did not further improve any effect observed for PIC. The absence of adverse effects, ease of application, and the possibilities for bio-functionalization make the biomimetic PIC hydrogels suitable for development into wound dressings.

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Contains fulltext : 174408.pdf (publisher's version ) (Open Access), Artificial antigen-presenting cells (aAPCs) have recently gained a lot of attention. They efficiently activate T cells and serve as powerful replacements for dendritic cells in cancer immunotherapy. Focusing on a specific class of polymer-based aAPCs, so-called synthetic dendritic cells (sDCs), we have investigated the importance of multivalent binding on T-cell activation. Using antibody-functionalized sDCs, we have tested the influence of polymer length and antibody density. Increasing the multivalent character of the antibody-functionalized polymer lowered the effective concentration required for T-cell activation. This was evidenced for both early and late stages of activation. The most important effect observed was the significantly prolonged activation of the stimulated T cells, indicating that multivalent sDCs sustain T-cell signaling. Our results highlight the importance of multivalency for the design of aAPCs and will ultimately allow for better mimics of natural dendritic cells that can be used as vaccines in cancer treatment.

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Radboud University, 23 oktober 2017, Promotores : Vlieg, E., Rowan, A.E. Co-promotores : Enckevort, W.J.P. van, Elemans, J.A.A.W., Contains fulltext : 176715.pdf (publisher's version ) (Open Access)

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Contains fulltext : 177944.pdf (publisher's version ) (Closed access), Water-soluble polyisocyanopeptides (PICs) are a new class of synthetic polymers that mimic natural protein-based filaments. Their unique semiflexible properties combined with a length of several hundred nanometers have recently enabled a number of biomedical applications ranging from tissue engineering to cancer immunotherapy. One crucial step toward the further development of PICs for these applications is the efficient and controlled synthesis and purification of PIC-biomolecule conjugates. Considering the large size of PICs and the biomolecules to be conjugated, conjugation reactions do usually not proceed to completion due to steric effects. As a consequence, purification of the reaction mixture is necessary to separate the obtained bioconjugates from unreacted biomolecules. As a direct result of the semiflexible nature of PICs, standard polymer and protein purification methods based on molecular weight have not been successful. Here, we introduce a new affinity-based purification method utilizing biotin as an affinity tag. PICs decorated with a controlled and tunable density of biotin molecules (biotinPICs) were efficiently bound to and eluted from a monoavidin resin in buffered aqueous solution. Using these biotinPICs, two different protein conjugates were synthesized, one carrying the enzyme alkaline phosphatase (PhoA) and the other T-cell activating anti-CD3 antibodies. The resulting biotinPIC-protein conjugates were successfully obtained in high purity (>90%) and without any loss of protein activity. The high purity greatly simplifies the analysis of biotinPIC bioconjugates, such as the determination of the average number of biomolecules conjugated per biotinPIC chain. Most importantly, it allows for the direct and straightforward application of the obtained bioconjugates in the desired applications. The new method developed may further be adapted for the purification of other advanced bioconjugates that are difficult to obtain in high purity with the avail

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Radboud University, 28 april 2017, Promotor : Rowan, A.E. Co-promotor : Kouwer, P.H.J., Contains fulltext : 169131.pdf (publisher's version ) (Open Access), Cells in the human body show a large increase in stiffness when subjected to an external force, comparable to stretching a rubber band. This phenomena is known as strain stiffening and prevents natural cells and tissues from breaking when subjected to large external forces. In my thesis, I have shown that this strain stiffening response can be mimicked with synthetic hydrogels, which like natural cells contain a very large amount of water. The hydrogels used are based on polyisocyanides and they are the first example of a synthetic hydrogel that shows strain stiffening behaviour. These unique mechanical properties are the result of the unusual molecular structure of these gels. The polymers that make up the gel are aggregated into polymer bundles, which are much stronger than the single polymer chains. Such bundling of polymer chains is also common for polymers that control the mechanical stiffness of natural cells. The many similarities with biological materials make these gels a highly interesting synthetic mimic for a range of biomedical applications.

Contains fulltext : 177439.pdf (publisher's version ) (Closed access)

Contains fulltext : 178194.pdf (publisher's version ) (Open Access), One of the most intriguing and important aspects of biological supramolecular materials is its ability to adapt macroscopic properties in response to environmental cues for controlling cellular processes. Recently, bulk matrix stiffness, in particular, stress sensitivity, has been established as a key mechanical cue in cellular function and development. However, stress-stiffening capacity and the ability to control and exploit this key characteristic is relatively new to the field of biomimetic materials. In this work, DNA-responsive hydrogels, composed of semiflexible PIC polymers equipped with DNA cross-linkers, were engineered to create mimics of natural biopolymer networks that capture these essential elastic properties and can be controlled by external stimuli. We show that the elastic properties are governed by the molecular structure of the cross-linker, which can be readily varied providing access to a broad range of highly tunable soft hydrogels with diverse stress-stiffening regimes. By using cross-linkers based on DNA nanoswitches, responsive to pH or ligands, internal control elements of mechanical properties are implemented that allow for dynamic control of elastic properties with high specificity. The work broadens the current knowledge necessary for the development of user defined biomimetic materials with stress stiffening capacity.

Contains fulltext : 181946.pdf (postprint version ) (Open Access)

RU Radboud Universiteit, 3 oktober 2016, Promotor : Rowan, A.E. Co-promotores : Oosterwijk, E., Wilson, C., Contains fulltext : 159286.pdf (publisher's version ) (Open Access)

RU Radboud Universiteit, 25 april 2016, Promotor : Rowan, A.E. Co-promotor : Kouwer, P.H.J., Contains fulltext : 156339.pdf (publisher's version ) (Open Access)

Radboud Universiteit Nijmegen, 18 maart 2016, Promotor : Rowan, A.E. Co-promotor : Kouwer, P.H.J., Contains fulltext : 155400.pdf (publisher's version ) (Open Access)

Contains fulltext : 166670.pdf (Publisher’s version ) (Closed access), The discovery of the phenomenon known as aggregation-induced emission (AIE) has opened the door to a variety of brilliant organic solid-state light-emitting materials. While AIE is well established in linear optics, the development of AIE luminogens (AIEgens) with highly efficient nonlinear optical (NLO) effects remains relatively unexplored. Particularly, second-order NLO requires the AIEgens to be organized in a non-centrosymmetric fashion, and such examples are rarely reported. Here, an AIEgen, 2,7-di([1,1-biphenyl]-4-yl)-fluorenone (4-DBpFO), is designed and synthesized by introducing a carbonyl group onto the backbone of p-hexaphenylene. The restricted rotation of the compound upon aggregation results in a dramatic enhancement of the linear optical emission when forming self-assemblies. Furthermore, introducing the carbonyl group drives the formation of hydrogen bonded molecular chains, which are attached by the zigzag CH interactions in a non-centrosymmetric way. As a result, the dipole of each individual molecule contributes accumulatively to a macroscopic dipole of the formed 4-DBpFO microcrystals. This leads to a highly efficient second harmonic generation with very high laser damage treshold. This AIEgen, whose optical response is greatly enhanced in both linear and nonlinear optical regimes upon the formation of well-defined self-assemblies, has potential applications in next generation photonic circuits.

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