Stefan Jockenhoevel’s research while affiliated with RWTH Aachen University and other places

Tissue‐mimetic scaffolds capable of actuating in response to environmental stimuli have great potential in soft robotics, especially if controllable at the molecular level. Elastin‐like recombinamers (ELRs) are biopolymers derived from natural tropoelastin intrinsically capable of responding to exogenous factors (e.g., pH, salt or temperature). A well‐designed and properly manufactured ELR scaffold should i) respond and adapt (actuate) according to external stimuli and ii) exhibit elastic properties to accommodate biomimetic actuation. However, current concepts typically use isotropic matrices, leading to isometric dimensional changes. In contrast, anisotropic actuation, a key feature in biological tissues at micro‐ and macroscopic level, allows directionally preferred responses but demands advanced design parallelled by an adequate fabrication scheme. Here, this challenge is addressed, by developing anisotropic elastin‐like scaffolds for directional, stimuli‐triggered actuation. Specifically, a fiber‐reinforced, elastin‐like tubular scaffold is developed with the capacity to actuate in an anisotropic and reversible manner in response to changes in solvent or temperature. Both the anisotropy and the degree of actuation can be efficiently controlled by changing the angle of the fiber‐reinforcement engineered within the elastin‐like matrix. The selection of the material and the straightforward fabrication make this scaffold versatile for applications that blends both soft robotics and tissue engineering.

Vascular grafts are crucial for treating cardiovascular diseases and providing vascular access for hemodialysis in end‐stage renal disease, conditions that affect millions of people globally. To address the persisting clinical need for better therapy for these conditions, new designs involving novel materials and innovative tissue‐engineered approaches are being developed. Successful clinical translation of such designs will require to ensure device safety, particularly sterility and mechanical integrity. The prevailing method for ensuring sterility is ethylene oxide sterilization, which requires a dry product. The challenge of drying biohybrid implants is substantial, as they contain multiple components (e.g., textile and hydrogel) with differing properties. To address this open question, the effects of different drying methods on the morphological and mechanical properties of biohybrid implants made from elastin‐like recombinamers (ELRs) are investigated. For that, mechanical characteristics defined in ISO 7198, as well as the cell attachment behavior on biohybrid vascular grafts, treated either with lyophilization (LYO) or CO2‐based critical point drying, are compared. The results show that the applied drying method can significantly influence the properties of the scaffolds and highlight the importance of developing implant‐specific drying schemes that ensure its safety and functionality.

Developing clinically viable tissue-engineered cardiovascular implants remains a formidable challenge. Achieving reliable and durable outcomes requires a deeper understanding of the fundamental mechanisms driving tissue evolution during in vitro maturation. Although considerable progress has been made in modeling soft tissue growth and remodeling, studies focused on the early stages of tissue engineering remain limited. Here, we present a general, thermodynamically consistent model to predict tissue evolution and mechanical response throughout maturation. The formulation utilizes a stress-driven homeostatic surface to capture volumetric growth, coupled with an energy-based approach to describe collagen densification via the strain energy of the fibers. We further employ a co-rotated intermediate configuration to ensure the model's consistency and generality. The framework is demonstrated with two numerical examples: a uniaxially constrained tissue strip validated against experimental data, and a biaxially constrained specimen subjected to a perturbation load. These results highlight the potential of the proposed model to advance the design and optimization of tissue-engineered implants with clinically relevant performance.

Pericytes are a key player in vascularization, protecting endothelial cells from external harm and promoting the formation of new vessels when necessary. However, pericytic identity and its relationship with other cell types, such as mesenchymal stromal/stem cells, is highly debated. This study compares the role of pericytes and unselected stromal cells in vascularization using multichannel microfluidic chips. In both angiogenesis and vasculogenesis, pericytes promote more vessel formation than stromal cells. Pericytes can wrap around endothelial vessels acting as mural cells, while stromal cells remain separated. Whole‐transcriptome sequencing confirms an upregulation of pro‐vascularization genes in endothelial cell‐pericyte co‐cultures, while metabolism increases and inflammation decreases in stromal cell co‐cultures. Treatment of stromal‐endothelial cell co‐cultures with either conditioned media or isolated extracellular vesicles from pericytes replicates the increase in vasculogenesis of the direct co‐cultures. Cytokine quantification reveals that interleukin 6 (IL‐6) is significantly increased in pericyte conditions. Blocking it with siltuximab results in a reduction of pericyte vasculogenic potential comparable to stromal cell levels, revealing that pericyte pro‐vascularization is mediated by IL‐6. This study provides new insights into the relationship between pericytes and endothelial cells and the elusive identity of mesenchymal stromal cells. These findings are relevant for both vascular biology and tissue engineering.

The development of cardiovascular implants is abundant, yet their clinical adoption remains a significant challenge in the treatment of valvular diseases. Tissue-engineered heart valves (TEHV) have emerged as a promising solution due to their remodeling capabilities, which have been extensively studied in recent years. However, ensuring reproducible production and clinical translation of TEHV requires robust longitudinal monitoring methods. Cardiovascular magnetic resonance imaging (MRI) is a non-invasive, radiation-free technique providing detailed valvular imaging and functional assessment. To facilitate this, we designed a state-of-the-art metal-free bioreactor enabling dynamic MRI and ultrasound imaging. Our compact bioreactor, tailored to fit a 72 mm bore 7 T MRI coil, features an integrated backflow design ensuring MRI compatibility. A pneumatic drive system operates the bioreactor, minimizing potential MRI interference. The bioreactor was digitally designed and constructed using polymethyl methacrylate, utilizing only polyether ether ketone screws for secure fastening. Our biohybrid TEHV incorporates a non-degradable polyethylene terephthalate textile scaffold with fibrin matrix hydrogel and human arterial smooth muscle cells. As a result, the bioreactor was successfully proven to be MRI compatible, with no blooming artifacts detected. The dynamic movement of the TEHVs was observed using gated MRI motion artifact compensation and ultrasound imaging techniques. In addition, the conditioning of TEHVs in the bioreactor enhanced ECM production. Immunohistology demonstrated abundant collagen, α-smooth muscle actin, and a monolayer of endothelial cells throughout the valve cusp. Our innovative methodology provides a physiologically relevant environment for TEHV conditioning and development, enabling accurate monitoring and assessment of functionality, thus accelerating clinical acceptance.

Biological and mechanical mismatches between engineered scaffolds and native tissues poses widespread challenges for tissue restoration. Native‐like anisotropy is a critical characteristic for functional tissue replacements, yet it is an often‐overlooked aspect when designing new scaffolds. In this study, fiber‐reinforced tubular scaffolds are developed, mimicking the anisotropic characteristics of natural tissues, using native‐like silk fibroin. To predict the mechanical behavior of these innovative scaffolds, a mathematical model is employed, utilizing the properties of the scaffolds’ constituent materials, and experimentally validated through tensile testing. This approach addresses significant challenges in the design of new scaffold implants by enabling to efficiently predict the performance of several configurations, narrowing down the experimental research space. The proposed platform constitutes an appealing tool for the development of clinically relevant tissue‐equivalents.