布里斯托大学Armstrong博士课题组招聘博士奖学金学生

申请流程：

项目信息

using advanced 3d bioprinting techniques to assemble complex models of the blood-brain barrier

supervisors

• dr james armstrong bristol medical school, university of bristol

• dr liliang ouyang mechanical engineering, tsinghua university

• prof. adam perriman cellular & molecular medicine, university of bristol

rationale

the blood-brain barrier (bbb) is a complex multicellular structure that ively regulates transport from the circulating

blood into the extracellular fluid of the central nervous system. for instance, this barrier permits the transport of essential

hormones and nutrients, while restricting passage of immune factors and pathogens.[1] the anatomical inaccessibility of the

bbb has restricted most studies to animal models, however this poses both ethical and technical challenges. this has led to

immense interest in tissue engineered models that can reproduce the structure and function of the bbb, however, it remains

a major challenge to re the physiological organization of the three discrete cell types. here, we will use two state-ofthe-art bioprinting methods to assemble tricultures of endothelial cells, pericytes, and astrocytes into a perfusable

microvascular network. this model will enable the interrogation into the structure-function relationships of barrier transport

in physiology and disease.[2] in addition, this will provide an accessible in vitro platform to test nanomaterial or ultrasoundbased therapeutic strategies that aim to bypass or disrupt the bbb in order to aid neurological drug uptake.[3-4]

aims & objectives

this is an interdisciplinary research project incorporating both engineering and translational biological research

- objective 1: to use two advanced bioprinting technologies to engineer the first perfusable, tri-culture model of the bbb

containing all three major cell components assembled within their native configuration.

- objective 2: to interrogate how fluid flow mechanics, disease-relevant genetic perturbations, and therapeutic interventions

(e.g., ultrasound or nanomaterial vectors) affect the multicellular interactions and ive barrier function of the bbb.

methods

this internationally collaborative phd project will be supervised between the university of bristol and tsinghua university,

institutions that are ranked 9th in uk and 1st in china, respectively (qs world university rankings 2021). the supervisory

team has extensive experience in developing bioprinting strategies that can be used to engineer complex tissues,[5-13] and in

this project, the student will take advantage of two state-of-the-art bioprinting methods recently pioneered by dr ouyang

and dr armstrong. void-free 3d bioprinting[5] will be used to fabricate gelatin methacryloyl (gelma) hydrogels with

perfusable vasculature of endothelial cells and pericytes. astrocytes will then be incorporated into the gelma matrix by

printing astrocyte-laden complementary network bioinks.[6] this tri-culture will be optimized and then systematically

perturbed by genetic modification, focused ultrasound stimulation, and drug exposure, with the effects upon cell

morphology characterized using immunofluorescence staining, live-cell confocal fluorescence microscopy, and electron

microscopy. this project will benefit from advanced bioprinting facilities available at both tsinghua university (via dr

ouyang) and the bristol centre for bioprinting (directed by prof. perriman), while dr armstrong provides leading expertise

in 3d cell culture, tissue engineering, and biological characterization. full training will be provided for all methods.

references

[1] r pandit, l chen & j götz “the blood-brain barrier: physiology and strategies for drug delivery” advanced drug

delivery reviews (2020).

[2] md sweeney, ap sagare & bv zlokovic “blood-brain barrier breakdown in alzheimer disease and other

neurodegenerative disorders” nature reviews neurology (2018).

[3] n lipsman, y meng, aj bethune, y huang, b lam, m masellis, n herrmann, c heyn, i aubert, a boutet, gs smith, k

hynynen & se black “blood-brain barrier opening in alzheimer’s disease using mr-guided focused ultrasound”

nature communications (2018).

[4] gc terstappen, ah meyer, rd bell & w zhang “strategies for delivering therapeutics across the blood-brain barrier”

nature reviews drug discovery (2021).

[5] l ouyang, jpk armstrong, q chen, y lin & mm stevens “void-free 3d bioprinting for in-situ endothelialization and

microfluidic perfusion” advanced functional materials (2020).

[6] l ouyang, jpk armstrong, y lin, jp wojciechowski, c lee-reeves, d hachim, k zhou, ja burdick & mm stevens

“expanding and optimizing 3d bioprinting capabilities using complementary network bioinks” science advances

(2020).[7] l ouyang, jpk armstrong, m salmeron-sanchez & mm stevens “assembling living building blocks to engineer

complex tissues” advanced functional materials (2020).

[8] c li, l ouyang, jpk armstrong & mm stevens “advances in the fabrication of biomaterials for gradient tissue

engineering” trends in biotechnology (2020).

[9] s correia carreira, r begum & aw perriman “3d bioprinting: the emergence of programmable biodesign”

advanced healthcare materials (2020).

[10] jpk armstrong & mm stevens “emerging technologies for tissue engineering: from gene editing to personalized

medicine” tissue engineering part a (2019).

[11] ad graham, sn olof, mj burke, jpk armstrong, ea mikhailova, jg nicholson, sj box, fg szele, aw perriman & h

bayley “high-resolution patterned cellular constructs by droplet-based 3d printing” scientific reports (2017).

[12] l ouyang, cb highley, w sun & ja burdick “a generalizable strategy for the 3d bioprinting of hydrogels from

nonviscous photo-crosslinkable inks” advanced materials (2017).

[13] jpk armstrong, m burke, bm carter, sa davis & aw perriman “3d bioprinting using a templated porous bioink”

advanced healthcare materials (2016).