Simultaneous self-organization of arterial and venous networks driven by the physics of global power optimization

Understanding of vascular organization is a long-standing problem in quantitative biology and biophysics and is essential for the growth of large cultured tissues. Approaches are needed that (1) make predictions of optimal arteriovenous networks in order to understand the natural vasculatures that originate from evolution (2) can design vasculature for 3D printing of cultured tissues, meats, organoids and organs. I present a method for determining the globally optimal structure of interlocking arterial and venous (arteriovenous) networks. The core physics is comprised of the minimization of total power associated with the whole vascular network, with penalties to stop arterial and venous segments from intersecting. Specifically, the power needed for Poiseuille flow through vessels and the metabolic power cost for blood maintenance are optimized. Simultaneous determination of both arterial and venous vasculatures is essential to avoid intersections between vessels that would bypass the capillary network. As proof-of-concept, I examine the optimal vascular structure for supplying square- and disk-like tissue shapes that would be suitable for bioprinting in multi-well plates. Features in the trees are driven by the bifurcation exponent and metabolic constant which affect whether arteries and veins follow the same or different routes through the tissue. They also affect the level of tortuosity in the vessels. The method could be used to understand the distribution of blood vessels within organs, to form the core of simulations, and combined with 3D printing to generate vasculatures for arbitrary volumes of cultured tissue and cultured meat

Determination of metal ion content of beverages and estimation of target hazard quotients : a comparative study

Background: Considerable research has been directed towards the roles of metal ions in nutrition with metal ion toxicity attracting particular attention. The aim of this study is to measure the levels of metal ions found in selected beverages (red wine, stout and apple juice) and to determine their potential detrimental effects via calculation of the Target Hazard Quotients (THQ) for 250 mL daily consumption. Results: The levels (mean ± SEM) and diversity of metals determined by ICP-MS were highest for red wine samples (30 metals totalling 5620.54 ± 123.86 ppb) followed by apple juice (15 metals totalling 1339.87 ± 10.84 ppb) and stout (14 metals totalling 464.85 ± 46.74 ppb). The combined THQ values were determined based upon levels of V, Cr, Mn, Ni, Cu, Zn and Pb which gave red wine samples the highest value (5100.96 ± 118.93 ppb) followed by apple juice (666.44 ± 7.67 ppb) and stout (328.41 ± 42.36 ppb). The THQ values were as follows: apple juice (male 3.11, female 3.87), stout (male 1.84, female 2.19), red wine (male 126.52, female 157.22) and ultra-filtered red wine (male 110.48, female 137.29). Conclusion: This study reports relatively high levels of metal ions in red wine, which give a very high THQ value suggesting potential hazardous exposure over a lifetime for those who consume at least 250 mL daily. In addition to the known hazardous metals (e.g. Pb), many metals (e.g. Rb) have not had their biological effects systematically investigated and hence the impact of sustained ingestion is not known

Development of a globally optimised model of the cerebral arteries

The cerebral arteries are difficult to reproduce from first principles, featuring interwoven territories, and intricate layers of grey and white matter with differing metabolic demand. The aim of this study was to identify the ideal configuration of arteries required to sustain an entire brain hemisphere based on minimisation of the energy required to supply the tissue. The 3D distribution of grey and white matter within a healthy human brain was first segmented from Magnetic Resonance Images. A novel simulated annealing algorithm was then applied to determine the optimal configuration of arteries required to supply brain tissue. The model is validated through comparison of this ideal, entirely optimised, brain vasculature with the known structure of real arteries. This establishes that the human cerebral vasculature is highly optimised; closely resembling the most energy efficient arrangement of vessels. In addition to local adherence to fluid dynamics optimisation principles, the optimised vasculature reproduces global brain perfusion territories with well defined boundaries between anterior, middle and posterior regions. This validated brain vascular model and algorithm can be used for patient-specific modelling of stroke and cerebral haemodynamics, identification of sub-optimal conditions associated with vascular disease, and optimising vascular structures for tissue engineering and artificial organ design

Rapid prediction of lab-grown tissue properties using deep learning

The interactions between cells and the extracellular matrix are vital for the self-organisation of tissues. In this paper we present proof-of-concept to use machine learning tools to predict the role of this mechanobiology in the self-organisation of cell-laden hydrogels grown in tethered moulds. We develop a process for the automated generation of mould designs with and without key symmetries. We create a large training set with $N=6500$ cases by running detailed biophysical simulations of cell-matrix interactions using the contractile network dipole orientation (CONDOR) model for the self-organisation of cellular hydrogels within these moulds. These are used to train an implementation of the \texttt{pix2pix} deep learning model, reserving $740$ cases that were unseen in the training of the neural network for training and validation. Comparison between the predictions of the machine learning technique and the reserved predictions from the biophysical algorithm show that the machine learning algorithm makes excellent predictions. The machine learning algorithm is significantly faster than the biophysical method, opening the possibility of very high throughput rational design of moulds for pharmaceutical testing, regenerative medicine and fundamental studies of biology. Future extensions for scaffolds and 3D bioprinting will open additional applications.Comment: 26 Pages, 11 Figure

High-throughput design of cultured tissue moulds using a biophysical model

The technique presented here identifies tethered mould designs, optimised for growing cultured tissue with very highly-aligned cells. It is based on a microscopic biophysical model for polarised cellular hydrogels. There is an unmet need for tools to assist mould and scaffold designs for the growth of cultured tissues with bespoke cell organisations, that can be used in applications such as regenerative medicine, drug screening and cultured meat. High-throughput biophysical calculations were made for a wide variety of computer-generated moulds, with cell-matrix interactions and tissue-scale forces simulated using a contractile-network dipole-orientation model. Elongated moulds with central broadening and one of the following tethering strategies are found to lead to highly-aligned cells: (1) tethers placed within the bilateral protrusions resulting from an indentation on the short edge, to guide alignment (2) tethers placed within a single vertex to shrink the available space for misalignment. As such, proof-of-concept has been shown for mould and tethered scaffold design based on a recently developed biophysical model. The approach is applicable to a broad range of cell types that align in tissues and is extensible for 3D scaffolds

Remote file access over low-speed lines

A link between microcomputer and mainframe can be useful in several ways, even when, as is usually the case, the link is only a normal terminal line. One interesting example is the ‘Integrated application’, which divides a task between microcomputer and mainframe and can offer several benefits; in particular, reducing load on the mainframe and permitting a more advanced user interface than possible on a conventional terminal. Because integrated applications consist of two co-operating programs, they are much more difficult to construct than a single program. It would be much easier to implement integrated applications concerned with the display and/or modification of data in mainframe files if the microcomputer could confine its dealings with the mainframe to a suitable file server. However, file servers do not appear practical for use over slow (compared to disc access speed) terminal lines. It was proposed to alleviate the problems caused by the slow link with extended file operations, which would allow time-consuming file operations such as searching or copying between files to be done in the file server. It was discovered after attempting such a system that extended file operations are not, by themselves, sufficient; but, allied to a record-based file model and asynchronous operations (i.e. file operations that do not suspend the user program until they complete), useful results could be obtained. This thesis describes FLAP, a file server for use over terminal lines which incorporates these ideas, and MMMS, an inter-application transport protocol used by FLAP for communication between the microcomputer file interface and the mainframe server. Two simple FLAP applications are presented, a customer records maintenance program and a screen editor. Details are given of their construction and response time in use at various line speeds

Simulated annealing approach to vascular structure with application to the coronary arteries

Do the complex processes of angiogenesis during organism development ultimately lead to a near optimal coronary vasculature in the organs of adult mammals? We examine this hypothesis using a powerful and universal method, built on physical and physiological principles, for the determination of globally energetically optimal arterial trees. The method is based on simulated annealing, and can be used to examine arteries in hollow organs with arbitrary tissue geometries. We demonstrate that the approach can generate in silico vasculatures which closely match porcine anatomical data for the coronary arteries on all length scales, and that the optimized arterial trees improve systematically as computational time increases. The method presented here is general, and could in principle be used to examine the arteries of other organs. Potential applications include improvement of medical imaging analysis and the design of vascular trees for artificial organs