In vitro microvascular engineering approaches and strategies for interstitial tissue integration.

The increasing gap between clinical demand for tissue or organ transplants and the availability of donated tissue highlights the emerging opportunities for lab-grown or synthetically engineered tissue. While the field of tissue engineering has existed for nearly half a century, its clinical translation remains unrealised, in part, due to a limited ability to engineer sufficient vascular supply into fabricated tissue, which is necessary to enable nutrient and waste exchange, prevent cellular necrosis, and support tissue proliferation. Techniques to develop anatomically relevant, functional vascular networks in vitro have made significant progress in the last decade, however, the challenge now remains as to how best incorporate these throughout dense parenchymal tissue-like structures to address diffusion-limited development and allow for the fabrication of large-scale vascularised tissue. This review explores advances made in the laboratory engineering of vasculature structures and summarises recent attempts to integrate vascular networks together with sophisticated in vitro avascular tissue and organ-like structures. STATEMENT OF SIGNIFICANCE: The ability to grow full scale, functional tissue and organs in vitro is primarily limited by an inability to adequately diffuse oxygen and nutrients throughout developing cellularised structures, which generally results from the absence of perfusable vessel networks. Techniques to engineering both perfusable vascular networks and avascular miniaturised organ-like structures have recently increased in complexity, sophistication, and physiological relevance. However, integrating these two essential elements into a single functioning vascularised tissue structure represents a significant spatial and temporal engineering challenge which is yet to be surmounted. Here, we explore a range of vessel morphogenic phenomena essential for tissue-vascular co-development, as well as evaluate a range of recent noteworthy approaches for generating vascularised tissue products in vitro.

Fluid-structure interactions of peripheral arteries using a coupled in silico and in vitro approach.

Vascular compliance is considered both a cause and a consequence of cardiovascular disease and a significant factor in the mid- and long-term patency of vascular grafts. However, the biomechanical effects of localised changes in compliance cannot be satisfactorily studied with the available medical imaging technologies or surgical simulation materials. To address this unmet need, we developed a coupled silico-vitro platform which allows for the validation of numerical fluid-structure interaction results as a numerical model and physical prototype. This numerical one-way and two-way fluid-structure interaction study is based on a three-dimensional computer model of an idealised femoral artery which is validated against patient measurements derived from the literature. The numerical results are then compared with experimental values collected from compliant arterial phantoms via direct pressurisation and ring tensile testing. Phantoms within a compliance range of 1.4-68.0%/100 mmHg were fabricated via additive manufacturing and silicone casting, then mechanically characterised via ring tensile testing and optical analysis under direct pressurisation with moderately statistically significant differences in measured compliance ranging between 10 and 20% for the two methods. One-way fluid-structure interaction coupling underestimated arterial wall compliance by up to 14.7% compared with two-way coupled models. Overall, Solaris™ (Smooth-On) matched the compliance range of the numerical and in vivo patient models most closely out of the tested silicone materials. Our approach is promising for vascular applications where mechanical compliance is especially important, such as the study of diseases which commonly affect arterial wall stiffness, such as atherosclerosis, and the model-based design, surgical training, and optimisation of vascular prostheses.

Quantitative and large-format histochemistry to characterize peripheral artery compositional gradients.

The femoropopliteal artery (FPA) is a long, flexible vessel that travels down the anteromedial compartment of the thigh as the femoral artery and then behind the kneecap as the popliteal artery. This artery undergoes various degrees of flexion, extension, and torsion during normal walking movements. The FPA is also the most susceptible peripheral artery to atherosclerosis and is where peripheral artery disease manifests in 80% of cases. The connection between peripheral artery location, its mechanical flexion, and its physiological or pathological biochemistry has been investigated for decades; however, histochemical methods remain poorly leveraged in their ability to spatially correlate normal or abnormal extracellular matrix and cells with regions of mechanical flexion. This study generates new histological image processing pipelines to quantitate tissue composition across high-resolution FPA regions-of-interest or low-resolution whole-section cross-sections in relation to their anatomical locations and flexions during normal movement. Comparing healthy ovine femoral, popliteal, and cranial-tibial artery sections as a pilot, substantial arterial contortion was observed in the distal popliteal and cranial tibial regions of the FPA which correlated with increased vascular smooth muscle cells and decreased elastin content. These methods aim to aid in the quantitative characterization of the spatial distribution of extracellular matrix and cells in large heterogeneous tissue sections such as the FPA. RESEARCH HIGHLIGHTS: Large-format histology preserves artery architecture. Elastin and smooth muscle content is correlated with distance from heart and contortion during flexion. Cell and protein analyses are sensitive to sectioning plane and image magnification.

Fluid-Structure Interaction Within Models of Patient-Specific Arteries: Computational Simulations and Experimental Validations.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide and its incidence is rising due to an aging population. The development and progression of CVD is directly linked to adverse vascular hemodynamics and biomechanics, whose in-vivo measurement remains challenging but can be simulated numerically and experimentally. The ability to evaluate these parameters in patient-specific CVD cases is crucial to better predict future disease progression, risk of adverse events, and treatment efficacy. While significant progress has been made toward patient-specific hemodynamic simulations, blood vessels are often assumed to be rigid, which does not consider the compliant mechanical properties of vessels whose malfunction is implicated in disease. In an effort to simulate the biomechanics of flexible vessels, fluid-structure interaction (FSI) simulations have emerged as promising tools for the characterization of hemodynamics within patient-specific cardiovascular anatomies. Since FSI simulations combine the blood's fluid domain with the arterial structural domain, they pose novel challenges for their experimental validation. This paper reviews the scientific work related to FSI simulations for patient-specific arterial geometries and the current standard of FSI model validation including the use of compliant arterial phantoms, which offer novel potential for the experimental validation of FSI results.