Sabine van Rijt

Osteosarcoma (OS) remains the most prevalent malignant bone tumor, with stagnant survival rates and high recurrence risk due to residual tumor cells, and limited post‐resection bone regeneration. Existing bifunctional bone graft substitutes integrating anticancer activity with osteogenesis are hindered by uncontrolled drug release and inefficient intracellular delivery. Here, we report a pH‐sensitive nano–microparticle linking strategy, in which imine bonds are used as interfacial linkers between therapeutic nanoparticles and bone scaffolds to enable tumor microenvironment–triggered, on‐demand nanotherapeutic release. In this study, we develop β‐tricalcium phosphate (β‐TCP) granules decorated with selenium (Se)‐doped mesoporous silica nanoparticles (SeMIA@TCP), in which nanoparticles are functionalized with imine bonds for acidic pH‐responsive detachment and alendronate for strong β‐TCP binding. This design ensures stable nanoparticle immobilization under physiological conditions while enabling selective release within the mildly acidic OS microenvironment. In vitro, the SeMIA@TCP showed significant pH‐dependent cytotoxicity toward OS cells, while maintaining low toxicity toward human mesenchymal stem cells (hMSCs) under physiological conditions, indicating a OS‐targeting profile. Furthermore, the released nanoparticles enhanced alkaline phosphatase (ALP) expression and mineralization in hMSCs, underscoring their osteogenic potential. Collectively, these results demonstrate the potential of tumor microenvironment–responsive Se‐doped MSN–assembled TCP granules as a design platform for bifunctional scaffolds in bone cancer treatment.

BACKGROUND: Neonatal hypoxic-ischemic (HI) brain injury is one of the leading causes of long-term neurological morbidity in newborns. Current treatment options for HI brain injury are limited, but mesenchymal stem cell (MSC) therapy is a promising strategy to boost neuroregeneration after injury. Optimization strategies to further enhance the potential of MSCs are under development. The current study aimed to test the potency of hypoxic preconditioning of MSCs to enhance the therapeutic efficacy in a mouse model of neonatal HI injury. METHODS: HI was induced on postnatal day 9 in C57Bl/6 mouse pups. MSCs were cultured under hypoxic (hypoxic-preconditioned MSCs [HP-MSCs], 1% O ₂ ) or normoxic-control (normoxic-preconditioned MSCs [NP-MSCs], 21% O ₂ ) conditions for 24 hours before use. At 10 days after HI, HP-MSCs, NP-MSCs, or vehicle were intranasally administered. Gold nanoparticle–labeled MSCs were used to assess MSC migration 24 hours after intranasal administration. At 28 days post-HI, lesion size, sensorimotor outcome, and neuroinflammation were assessed by hematoxylin and eosin staining, cylinder rearing task, and ionized calcium-binding adapter molecule 1 (IBA1) staining, respectively. In vitro, the effect of HP-MSCs was studied on transwell migration, neural stem cell differentiation and microglia activation, and the MSC intracellular proteomic content was profiled using quantitative Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). RESULTS: Intranasally administered HP-MSCs were superior to NP-MSCs in reducing lesion size and sensorimotor impairments post-HI. Moreover, hypoxic preconditioning enhanced MSC migration in an in vitro set-up, and in vivo to the lesioned hemisphere after intranasal application. In addition, HP-MSCs enhanced neural stem cell differentiation into more complex neurons in vitro but had similar anti-inflammatory effects compared with NP-MSCs. Lastly, hypoxic preconditioning led to elevated abundances of proteins in MSCs related to extracellular matrix remodeling. CONCLUSIONS: This study shows for the first time that hypoxic preconditioning enhanced the therapeutic efficacy of MSC therapy in a mouse model of neonatal HI brain injury by increasing the migratory and neuroregenerative capacity of MSCs.

Mesenchymal stem cells (MSCs) have demonstrated promising therapeutic potential across a wide range of diseases including (multi) organ injury in neonates. Despite the reported preclinical successes of MSC therapy, a major challenge in their clinical translation is a limited understanding of their biodistribution after administration. This knowledge gap needs to be addressed to allow clinical implementation. Accordingly, in this study, we propose that silica-coated gold nanoparticles (AuMS) are a promising tool for in vivo MSC tracing. This study explores the use of AuMS for both qualitative and quantitative MSC tracking in vivo after intravenous (I.V.) administration in a translational ovine model of preterm birth. Additionally, we assess the impact of AuMS labeling on the immunomodulatory functions of MSC, which play an important role in the therapeutic potency of these cells. Quantitative and qualitative assessment of AuMS-labeled MSC was performed in vivo using fluorescent microscopy and inductively coupled plasma mass spectrometry (ICP-MS), respectively. AuMS localization in the liver, spleen, and lung was demonstrated. In vitro studies showed that AuMS cellular uptake occurs within 6 h and remains internalized up to 72 h. Labeled MSC maintained their immune phenotype and did not alter their immunomodulatory capacity and proliferation abilities. Overall, we demonstrate that AuMS is a promising, biocompatible nanoprobe for MSC tracing up to 72 h post-I.V. administration.

Regenerative Medicine (RM) is a multidisciplinary field uniting science, technology, and entrepreneurship to develop curative health solutions. In response to labor market demand, Maastricht University (UM) has launched an undergraduate program, Reg...

The extracellular matrix (ECM) is a dynamic environment that is primarily built up from fibrous proteins (e.g., elastins, fibronectins, collagens, and laminins) and plays a vital role in tissue regeneration processes. Therefore, the development of supramolecular hydrogels that can mimic the ECM's dynamicity and fibrous structure is of great interest in regenerative medicine. However, such hydrogels generally have weak mechanical properties and poor structural stability, which significantly limits their potential applications. To overcome this drawback, we developed a new type of hybrid network composed of supramolecular assemblies with covalent nanoparticle-based crosslinkers. The ECM mimetic hydrogels were created through UV-initiated thiol–ene crosslinking between norbornene functionalized benzene-1,3,5-tri carboxamide (NBTA) macromonomers and thiol functionalized mesoporous silica nanoparticles (MSN). We hypothesized that the MSN would improve the mechanical properties by crosslinking the NBTA supramolecular fibrous hydrogels. Notably, the covalent incorporation of MSNs did not disrupt the fibrous morphology of the resulting NBTA–MSN nanocomposites. Furthermore, these supramolecular nanocomposites demonstrated higher structural stability and elasticity compared to pristine NBTA hydrogels. Rheology studies showed that the mechanical properties of NBTA–MSN hydrogels could be tuned by adjusting MSN wt%. Interestingly, NBTA–MSN nanocomposites exhibited self-healing and injectability despite the covalent crosslinking of MSNs. In vitro studies confirmed that NBTA–MSN nanocomposites showed good cytocompatibility and maintained the viability of encapsulated MG63 cells. As a proof of concept, we also demonstrated that MSNs could act as ion reservoirs for calcium and phosphate within the hydrogel networks in addition to being covalent crosslinkers. Taken together, our work offers a promising strategy to create hybrid, biomimetic supramolecular nanocomposite materials for various applications such as injectable materials for bone tissue engineering, and reinforced bioinks for 3D printing applications.

Doxorubicin (Dox) is a promising anticancer chemotherapeutic, which has been widely investigated in osteosarcoma (OS) treatment. However, there are several disadvantages regarding its clinical use. Specifically, Dox has low specificity toward cancer cells, which can lead to serious side effects. In addition, cancer cells can develop resistance toward Dox, reducing its therapeutic efficiency. Combination therapy (CT) facilitated by nanoparticle delivery systems is a promising strategy to overcome these drawbacks. In this study, we investigated the effectiveness of Dox and selenium (Se) CT using mesoporous silica nanoparticles (MSN) coated with hyaluronic acid (HA) as drug carriers. We hypothesized that combining Se as a second agent can increase Dox anti-OS effectiveness and that MSN can be used to facilitate dual drug delivery. In our system, HA was used as a gatekeeper to control the intracellular release of Se/Dox by means of its pH-responsive degradation. CT therapy using MSNs coated with HA led to a higher OS inhibitory efficiency in vitro compared to MSNs carrying either Se or Dox alone. This study demonstrates that using MSNs for the dual delivery of Se and Dox is a promising method for OS therapy.

This review describes in situ modification of MSNs and how this effects their material properties. It highlights their application in theranostics, oncology, and regenerative medicine field, concluding with future challenges for clinical use.