Jeroen CH Leijten

• PhD
• Professor at University of Twente

Light‐based volumetric bioprinting enables fabrication of cubic centimeter‐sized living materials with micrometer resolution in minutes. Xolography is a light sheet‐based volumetric printing technology that offers unprecedented volumetric generation rates and print resolutions for hard plastics. However, the limited solubility and reactivity of cur...

Extracellular matrix (ECM) guides cell behavior and tissue fate. Cell populations are notoriously heterogeneous leading to large variations in cell behavior at the single‐cell level. Although insights into population heterogeneity are valuable for fundamental biology, regenerative medicine, and drug testing, current ECM analysis techniques only pro...

The vascular tree is crucial for the survival and function of large living tissues. Despite breakthroughs in 3D bioprinting to endow engineered tissues with large blood vessels, there is currently no approach to engineer high‐density capillary networks into living tissues in a scalable manner. Here, photoannealing of living microtissue (PALM) is pr...

Osteoarthritis (OA) is a multifactorial degenerative joint disease of which the underlying mechanisms are yet to be fully understood. At the molecular level, multiple factors including altered signaling pathways, epigenetics, metabolic imbalance, extracellular matrix degradation, production of matrix metalloproteinases, and inflammatory cytokines,...

Organoids are engineered 3D miniature tissues that are defined by their organ-like structures, which drive a fundamental understanding of human development. However, current organoid generation methods are associated with low production throughputs and poor control over size and function including due to organoid merging, which limits their clinica...

Osteoarthritis (OA) is a musculoskeletal degenerative disease characterized by alterations in cartilage and subchondral bone leading to impaired joint function. OA disproportionally affects females more than males, yet the molecular mechanisms underlying these biological sex differences remain elusive. Current therapeutic strategies to halt the pro...

3D bioprinting approaches offer highly versatile solutions to replicate living tissue and organ structures. While current bioprinting approaches can generate desired shapes and spatially determined patterns, the material selection for embedded bioprinting has remained limited, as it has relied on the use of viscous, shear-thinning, or liquid-like s...

Particles are essential building blocks in nanomedicine and cell engineering. Their administration often involves blood contact, which demands a hemocompatible material profile. Coating particles with isolated cell membranes is a common strategy to improve hemocompatibility, but this solution is nonscalable and potentially immunogenic. Cell membran...

Background/Objectives: Hydrophobic microparticles are one of the most versatile structures in drug delivery and tissue engineering. These constructs offer a protective environment for hydrophobic or water-sensitive compounds (e.g., drugs, peroxides), providing an optimal solution for numerous biomedical purposes, such as drug delivery or oxygen the...

Mechanotransduction is widely used to guide cell fate in hydrogels. Traditionally, hydrogels contain adhesive ligands that dynamically bond with cells to stimulate biochemical signaling axes such as YAP‐TAZ. However, the molecular toolbox to achieve mechanotransduction remains virtually limited to non‐covalent bonds, which limits the ability to pro...

Microporous hydrogels have been widely used for delivering therapeutic cells. However, several critical issues, such as the lack of control over the harsh environment they are subjected to under pathological conditions and rapid egression of cells from the hydrogels, have produced limited therapeutic outcomes. To address these critical challenges,...

Mechanotransduction is widely used to guide cell fate in hydrogels. Traditionally, hydrogels contain adhesive ligands that dynamically bond with cells to stimulate biochemical signalling axis such as YAP-TAZ. However, the molecular toolbox to achieve mechanotransduction has remained virtually limited to non-covalent bonds, which limits our ability...

Osteoclasts, the bone resorbing cells of hematopoietic origin formed by macrophage fusion, are essential in bone health and disease. However, in vitro research on osteoclasts remains challenging due to heterogeneous cultures that only contain a few multinucleated osteoclasts. Indeed, a strategy to generate homogeneous populations of multinucleated...

Ensuring a sufficient oxygen supply is pivotal for the success of bioprinting applications since it fosters tissue integration and natural regeneration. Variation in oxygen concentration among diverse tissues necessitates the precise recreation of tissue-specific oxygen levels in imprinted constructs to support the survival of targeted cells. Altho...

Myocardial infarction (MI) is a significant cardiovascular disease that restricts blood flow, resulting in massive cell death and leading to stiff and noncontractile fibrotic scar tissue formation. Recently, sustained oxygen release in the MI area has shown regeneration ability; however, improving its therapeutic efficiency for regenerative medicin...

Blood scarcity is one of the main causes of healthcare disruptions worldwide, with blood shortages occurring at an alarming rate. Over the last decades, blood substitutes have aimed at reinforcing the supply of blood, with several products (e.g., hemoglobin (Hb)‐based oxygen (O2) carriers, perfluorocarbons (PFC)) achieving a limited degree of succe...

3D cellular spheroids offer more biomimetic microenvironments than conventional 2D cell culture technologies, which has proven value for many tissue engineering applications. Despite beneficiary effects of 3D cell culture, clinical translation of spheroid tissue engineering is challenged by limited scalability of current spheroid formation methods....

Osteoarthritis (OA) is a degenerative disease of the joints for which no curative treatment exists. Intra-articular injection of stem cells is explored as a regenerative approach, but rapid clearance of cells from the injection site limits the therapeutic outcome. Microencapsulation of mesenchymal stem cells (MSCs) can extend the retention time of...

Transplantation of microencapsulated pancreatic cells is emerging as a promising therapy to replenish β‐cell mass lost from auto‐immune nature of type I diabetes mellitus (T1DM). This strategy intends to use micrometer‐sized microgels to provide immunoprotection to transplanted cells to avoid chronic application of immunosuppression. Clinical appli...

Incorporating non-invasive biosensing features in organ-on-chip models is of paramount importance for a wider implementation of these advanced in vitro microfluidic platforms. Optical biosensors, based on Bioluminescence Imaging (BLI), enable continuous, non-invasive, and in-situ imaging of cells, tissues or miniaturized organs without the drawback...

Polyacrylamide (PAM) hydrogels are extensively used as extracellular matrix mimics to study specific cell-materials interactions. However, chemistries typically applied for biofunctionalization of PAM lack chemo-selectivity and control over ligand density, which undermine reproducibility of cellular behavior, which can lead to inconclusive experime...

We establish a versatile hydrogel platform based on modular building blocks that allows the design of hydrogels with tailored physical architecture and mechanical properties. We demonstrate its versatility by assembling (i) a fully monolithic gelatin methacryloyl (Gel-MA) hydrogel, (ii) a hybrid hydrogel composed of 1:1 Gel-MA and gelatin nanoparti...

Oxygenating biomaterials can alleviate anoxic stress, stimulate vascularization, and improve engraftment of cellularized implants. However, the effects of oxygen-generating materials on tissue formation have remained largely unknown. Here, we investigate the impact of calcium peroxide (CPO)-based oxygen-generating microparticles (OMPs) on the osteo...

Given the dynamic nature of engineered vascular networks within biofabricated tissue analogues, it is instrumental to have control over the constantly evolving biochemical cues within synthetic matrices throughout tissue remodeling. Incorporation of pro-angiogenic vascular endothelial growth factor (VEGF165) specific aptamers into cell-instructive...

The increased demand for personalized wearable and implantable medical devices has created the need for the generation of electronics that interface with living systems. Current bioelectronics has not fully resolved mismatches between biological systems and engineered circuits, resulting in tissue injury and pain. Thus, there is an unmet need to de...

Engineered living microtissues such as cellular spheroids and organoids have enormous potential for the study and regeneration of tissues and organs. Microtissues are typically engineered via self‐assembly of adherent cells into cellular spheroids, which are characterized by little to no cell–material interactions. Consequently, 3D microtissue mode...

Living microtissues are used in a multitude of applications as they more closely resemble native tissue physiology, as compared to 2D cultures. Microtissues are typically composed of a combination of cells and materials in varying combinations, which are dictated by the applications’ design requirements. Their applications range wide, from fundamen...

Embedded 3D bioprinting has great value for the freeform fabrication of living matter. However, embedded 3D bioprinting is currently limited to highly viscous liquid baths or liquid‐like solid baths. In contrast, prior to crosslinking, most hydrogels are formulated as low‐viscosity solutions and are therefore not directly compatible with bioprintin...

Advances in biomaterials, particularly in combination with encapsulation strategies, have provided excellent opportunities to increase reproducibility and standardization for cell culture applications. Herein, hybrid microcapsules are produced in a flow-focusing microfluidic droplet generator combined with enzymatic outside-in crosslinking of dextr...

Recapitulating inherent heterogeneity and complex microarchitectures within confined print volumes for developing implantable constructs that could maintain their structure in vivo has remained challenging. Here, we present a combinational multimaterial and embedded bioprinting approach to fabricate complex tissue constructs that can be implanted p...

Embedded 3D Printing In article number 2201392, Janko Kajtez, Jenny Emnéus, and co‐workers present a modular platform for bioengineering of neuronal networks via direct embedded 3D printing of human stem cells inside self‐healing annealable particle‐extracellular matrix (SHAPE) composites. The approach allows direct freeform patterning and function...

In additive manufacturing, bioink formulations govern strategies to engineer 3D living tissues that mimic the complex architectures and functions of native tissues for successful tissue regeneration. Conventional 3D-printed tissues are limited in their ability to alter the fate of laden cells. Specifically, the efficient delivery of gene expression...

3D Bioprinting In article number 2102697 by Jeroen Leijten, Su Ryon Shin, and co‐workers, mitigating the toxic effects from solid peroxides in self‐oxygenating living tissues is achieved by catalase‐mediated hydrolysis of hydrogen peroxide.

Human in vitro models of neural tissue with tunable microenvironment and defined spatial arrangement are needed to facilitate studies of brain development and disease. Towards this end, embedded printing inside granular gels holds great promise as it allows precise patterning of extremely soft tissue constructs. However, granular printing support f...

Oxygen releasing biomaterials can facilitate the survival of living implants by creating environments with a viable oxygen level. Hydrophobic oxygen generating microparticles (HOGMPs) encapsulated calcium peroxide (CPO) have recently been used in tissue engineering to release physiologically relevant amounts of oxygen for several weeks. However, ge...

Several bronchoscopic lung volume reduction (BLVR) treatments have been developed to reduce hyperinflation in emphysema patients. Lung bio-adhesives are among the most promising new BLVR treatment options, as they potentially provide a permanent solution for emphysematous patients after only a single application. To date, bio-adhesives have mainly...

Cell–Material Tethering Cells need to sense their environment in order to survive and function. In article number 2102660, Tom Kamperman, Jeroen Leijten, and co-workers present an enzymatic crosslinking strategy that can tether non-cell-adhesive materials to cells. By targeting the cellular adhesome, this cell–material tethering method enables cell...

Self-Oxygenating Tissues In article number 2100850, Jeroen Leijten and co-workers produce oxygen-generating micromaterials composed of polycaprolactone and calcium peroxide to engineer self-oxygenating living implants. Upon implantation, the self-oxygenation of tissues improve cell survival, enhance production of angiogenic factors, and orchestrate...

Nanoparticles have been used for engineering composite materials to improve the intrinsic properties and/or add functionalities to pristine polymers. The majority of the studies have focused on the incorporation of spherical nano-particles within the composite fibers. Herein, we incorporate anisotropic branched-shaped zinc oxide (ZnO) nanoparticles...

Cell–matrix interactions govern cell behavior and tissue function by facilitating transduction of biomechanical cues. Engineered tissues often incorporate these interactions by employing cell‐adhesive materials. However, using constitutively active cell‐adhesive materials impedes control over cell fate and elicits inflammatory responses upon implan...

Human in vitro models of neural tissue with controllable cellular composition, tunable microenvironment, and defined spatial patterning are needed to facilitate studies of brain development and disease. Towards this end, bioprinting has emerged as a promising strategy. However, precise and programmable printing of extremely soft and compliant mater...

Bioengineering of tissues and organs has the potential to generate functional replacement organs. However, achieving the full-thickness vascularization that is required for long-term survival of living implants has remained a grand challenge, especially for clinically sized implants. During the pre-vascular phase, implanted engineered tissues are f...

The increasing demand for wearable bioelectronic devices has driven tremendous research effort on the fabrication of bioelectronics in microscale. To ensure the functionality and reliability, wearable bioelectronics need to be integrated with independent and internal energy storage systems to avoid frequent charging process from external sources. T...

Oxygen is essential for the survival, function, and fate of mammalian cells. Oxygen tension controls cellular behaviour via metabolic programming, which in turn controls tissue regeneration, stem cell differentiation, drug metabolism, and numerous pathologies. Thus, oxygen-releasing biomaterials represent a novel and unique strategy to gain control...

Bioactive hydrogels based on naturally-derived polymers are of great interest for regenerative medicine applications. Among naturally-derived polymers, silk fibroin has been extensively explored as a biomaterial for tissue engineering due to its unique mechanical properties. Here, we demonstrate the rapid gelation of cell-laden silk fibroin hydroge...

Understanding the immune system is of great importance for the development of drugs and the design of medical implants. Traditionally, two-dimensional static cultures have been used to investigate the immune system in vitro, while animal models have been used to study the immune system’s function and behavior in vivo. However, these conventional mo...

To effectively apply microwell array cell delivery devices their biodegradation rate must be tailored towards their intended use and implantation location. Two microwell array devices with distinct degradation profiles, either suitable for the fabrication of retrievable systems in the case of slow degradation, or cell delivery systems capable of ex...

Cell-laden hydrogel microcapsules enable the high-throughput production of cell aggregates, which are relevant for 3D tissue engineering and drug screening applications. However, current microcapsule production strategies are limited by their throughput, multi-step protocols, and limited amount of compatible biomaterials. We here present a single-s...

Movement is essential to our quality of life, and regulates cell behavior via mechanical stimulation. Here, we report a monolithic microfluidic platform, in which engineered tissues composed of cells in a hydrogel are exposed to gradients of mechanical compression. Mechanical stimulation is applied through the deflection of a thin polydimethylsilox...

Microfluidic droplet generators excel in generating monodisperse micrometer-sized droplets and particles. However, the low throughput of conventional droplet generators hinders their clinical and industrial translation. Current approaches to parallelize microdevices are challenged by the two-dimensional nature of the standard fabrication methods. H...

In article number 1906330, Jeroen Leijten, Su Ryon Shin, and co‐workers develop 3D cartilage‐like tissue through local bioprinting of mesenchymal stem cell spheroids laden with soft and cell stimulating bioink within a mechanically robust hydrogel. This uncoupling of the micro and macro mechanical properties of the 3D printed construct allows it to...

Developing biomimetic cartilaginous tissues that support locomotion while maintaining chondrogenic behavior is a major challenge in the tissue engineering field. Specifically, while locomotive forces demand tissues with strong mechanical properties, chondrogenesis requires a soft microenvironment. To address this challenge, 3D cartilage‐like tissue...

Spatiotemporal control over engineered tissues is highly desirable for various biomedical applications as it emulates the dynamic behavior of natural tissues. Current spatiotemporal biomaterial functionalization approaches are based on cytotoxic, technically challenging, or non-scalable chemistries, which has hampered their widespread usage. Here w...

Adhesion to wet and dynamic surfaces is vital for many biomedical applications. However, the development of effective tissue adhesives has been challenged by the required combination of properties, which includes mechanical similarity to the native tissue, high adhesion to wet surfaces, hemostatic properties, biodegradability, high biocompatibility...

Micrometer-sized materials are key components for many life science applications including drug delivery, tissue engineering, and (bio)chemical purification methods. Microfluidic manufacturing platforms have advanced the production of micromaterials that are shape controlled, monodisperse, and chemically defined. Although different types of microma...

Treating joint diseases remains a significant clinical challenge. Conventional in vitro cultures and animal models have been helpful, but suffer from limited predictive power for the human response. Advanced models are therefore required to mimic the complex biological interactions within the human joint. However, the intricate structure of the joi...

Impact statement: This research deals with finding a proper bioengineering strategy to improve the outcome of islets transplantation for treatment of type 1 diabetes. It is focused on the mimicking of islet extracellular matrix niche in microwell islet delivery devices to improve their endocrine function.

Closure of ocular wounds after an accident or surgery is typically performed by suturing, which is associated with numerous potential complications, including suture breakage, inflammation, secondary neovascularization, erosion to the surface and secondary infection, and astigmatism; for example, more than half of post-corneal transplant infections...

Impact statement: This research deals with finding a proper bioengineering strategy for the creation of improved β-cell replacement therapy in type 1 diabetes. It specifically deals with the microenvironment of β-cells and its relationship to their endocrine function.

Compartmentalized Janus microparticles advance many applications ranging from chemical synthesis to consumer electronics. Although these particles can be accurately manufactured using microfluidic droplet generators, the per-nozzle throughputs are relatively low (~µl/min). Here, we use ‘in-air microfluidics’ to combine liquid microjets in mid-air,...

Single-cell-laden microgels effectively act as the engineered counterpart of the smallest living building block of life: a cell within its pericellular matrix. Recent breakthroughs have enabled the encapsulation of single cells in sub-100-μm microgels to provide physiologically relevant microniches with minimal mass transport limitations and favora...

Biophysical cues can potently direct a cell’s or tissue’s behavior. Cells interpret their biophysical surroundings, such as matrix stiffness or dynamic mechanical stimulation, through mechanotransduction. However, our understanding of the various aspects of mechanotransduction has been limited by the lack of proper analysis platforms capable of scr...

Objective: To explore the involvement of the WNT and BMP antagonists Dickkopf-related protein 1 (DKK1), Frizzled-related protein (FRZB) and Gremlin 1 (GREM1) in knee injury and osteoarthritis (OA). Design: The antagonists were immunoassayed in synovial fluid from a cross-sectional cohort of 9 knee healthy reference subjects, patients with recent...

Interleukin 1 beta (IL1β) and Wingless-Type MMTV Integration Site Family (WNT) signaling are major players in Osteoarthritis (OA) pathogenesis. Despite having a large functional overlap in OA onset and development, the mechanism of IL1β and WNT crosstalk has remained largely unknown. In this study, we have used a combination of computational modeli...

Recent years have seen tremendous advances in the field of hydrogel-based biomaterials. One of the most prominent revolutions in this field has been the integration of elements or techniques that enable spatial and temporal control over hydrogels’ properties and functions. Here, we critically review the emerging progress of spatiotemporal control o...

Nanoparticles have been used for engineering composite materials to improve the intrinsic properties and/or add functionalities to pristine polymers. The majority of the studies have focused on the incorporation of spherical nanoparticles within the composite fibers. Herein, we incorporate anisotropic branched-shaped zinc oxide (ZnO) nanoparticles...

In situ gelation of water-in-oil polymer emulsions is a key method to produce hydrogel particles. Although this approach is in principle ideal for encapsulating bioactive components such as cells, the oil phase can interfere with straightforward presentation of crosslinker molecules. Several approaches have been developed to induce in-emulsion gela...

Adverse immune reactions prevent clinical translation of numerous implantable devices and materials. Although inflammation is an essential part of tissue regeneration, chronic inflammation ultimately leads to implant failure. In particular, macrophage polarity steers the microenvironment towards inflammation or wound healing via the induction of M1...

The rapid development of new biomaterials and techniques to modify them challenge our capability to characterize them using conventional methods. In response, numerous high-throughput (HT) strategies are being developed to analyze biomaterials and their interactions with cells using combinatorial approaches. Moreover, these systematic analyses have...

In article number 1603711, Marcel Karperien, Jeroen Leijten, and co-workers present the first microfluidic approach that enables long-term 3D single cell culture by centering cells in microgels in a facile, modular, and widely applicable manner. A typical cell microencapsulation event using the delayed crosslinking approach enables a cell to be pos...