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1.  Intimal hyperplasia following implantation of helical-centreline and straight-centreline stents in common carotid arteries in healthy pigs: influence of intraluminal flow† 
Intimal hyperplasia (IH) is a leading cause of obstruction of vascular interventions, including arterial stents, bypass grafts and arteriovenous grafts and fistulae. Proposals to account for arterial stent-associated IH include wall damage, low wall shear stress (WSS), disturbed flow and, although not widely recognized, wall hypoxia. The common non-planarity of arterial geometry and flow, led us to develop a bare-metal, nitinol, self-expanding stent with three-dimensional helical-centreline geometry. This was deployed in one common carotid artery of healthy pigs, with a straight-centreline, but otherwise identical (conventional) stent deployed contralaterally. Both stent types deformed the arteries, but the helical-centreline device additionally deformed them helically and caused swirling of intraluminal flow. At sacrifice, one month post stent deployment, histology revealed significantly less IH in the helical-centreline than straight-centreline stented vessels. Medial cross-sectional area was not significantly different in helical-centreline than straight-centreline stented vessels. By contrast, luminal cross-sectional area was significantly larger in helical-centreline than straight-centreline stented vessels. Mechanisms considered to account for those results include enhanced intraluminal WSS and enhanced intraluminal blood–vessel wall mass transport, including of oxygen, in the helical-centreline stented vessels. Consistent with the latter proposal, adventitial microvessel density was lower in the helical-centreline stented than straight-centreline stented vessels.
PMCID: PMC3808545  PMID: 24132200
helical-centreline arterial stent; swirling intraluminal blood flow; intimal hyperplasia; vessel wall hypoxia; wall shear stress; blood–wall oxygen transport
3.  Manipulating the Microvasculature and Its Microenvironment 
The microvasculature is a dynamic cellular system necessary for tissue health and function. Therapeutic strategies that target the microvasculature are expanding and evolving, including those promoting angiogenesis and microvascular expansion. When considering how to manipulate angiogenesis, either as part of a tissue construction approach or a therapy to improve tissue blood flow, it is important to know the microenvironmental factors that regulate and direct neovessel sprouting and growth. Much is known concerning both diffusible and matrix-bound angiogenic factors, which stimulate and guide angiogenic activity. How the other aspects of the extravascular microenvironment, including tissue biomechanics and structure, influence new vessel formation is less well known. Recent research, however, is providing new insights into these mechanisms and demonstrating that the extent and character of angiogenesis (and the resulting new microcirculation) is significantly affected. These observations and the resulting implications with respect to tissue construction and microvascular therapy are addressed.
PMCID: PMC4096003  PMID: 24580565
angiogenesis; microvessels; microvascular orientation; microvascular remodeling; microvessel guidance; three-dimensional (3D) vascular constructs; matrix mechanics
4.  Direct-write Bioprinting Three-Dimensional Biohybrid Systems for Future Regenerative Therapies 
Regenerative medicine seeks to repair or replace dysfunctional tissues with engineered biological or biohybrid systems. Current clinical regenerative models utilize simple uniform tissue constructs formed with cells cultured onto biocompatible scaffolds. Future regenerative therapies will require the fabrication of complex three-dimensional constructs containing multiple cell types and extracellular matrices. We believe bioprinting technologies will provide a key role in the design and construction of future engineered tissues for cell-based and regenerative therapies. This review describes the current state-of-the-art bioprinting technologies, focusing on direct-write bioprinting. We describe a number of process and device considerations for successful bioprinting of composite biohybrid constructs. In addition, we have provided baseline direct-write printing parameters for a hydrogel system (Pluronic F127) often used in cardiovascular applications. Direct-write dispensed lines (gels with viscosities ranging from 30 mPa*s to greater than 600×106 mPa*s) were measured following mechanical and pneumatic printing via three commercially available needle sizes (20ga, 25ga, and 30ga). Example patterns containing microvascular cells and isolated microvessel fragments were also bioprinted into composite 3D structures. Cells and vessel fragments remained viable and maintained in vitro behavior after incorporation into biohybrid structures. Direct-write bioprinting of biologicals provides a unique method to design and fabricate complex, multi-component 3D structures for experimental use. We hope our design insights and baseline parameter descriptions of direct-write bioprinting will provide a useful foundation for colleagues to incorporate this 3D fabrication method into future regenerative therapies.
PMCID: PMC3772543  PMID: 21504055
Bioprinting; Regenerative Medicine; Tissue Engineering; Hydrogels; Biohybrid Devices
5.  Determinants of Microvascular Network Topologies in Implanted Neovasculatures 
During neovascularization, the end result is a new functional microcirculation comprised of a network of mature microvessels with specific topologies. While much is known concerning the mechanisms underlying the initiation of angiogenesis, it remains unclear how the final architecture of microcirculatory beds is regulated. To begin to address this, we determined the impact of angiogenic neovessel pre-patterning on the final microvascular network topology using an implant model of implant neovascularization.
Methods and Results
To test this, we used 3-D direct-write bioprinting or physical constraints in a manner permitting post-angiogenesis vascular remodeling and adaptation to pattern angiogenic microvascular precursors (neovessels formed from isolated microvessel segments) in 3-dimensional collagen gels prior to implantation and subsequent network formation. Neovasculatures pre-patterned into parallel arrays formed functional networks following 4 weeks post-implantation, but lost the pre-patterned architecture. However, maintenance of uniaxial physical constraints during post-angiogenesis remodeling of the implanted neovasculatures produced networks with aligned microvessels as well as an altered proportional distribution of arterioles, capillaries and venules.
Here we show that network topology resulting from implanted microvessel precursors is independent from pre-patterning of precursors but can be influenced by a patterning stimulus involving tissue deformation during post-angiogenesis remodeling and maturation.
PMCID: PMC3256738  PMID: 22053070
microcirculation; regeneration; bioprinting; vascular engineering; neovascularization
6.  Vessel Arterial-Venous Plasticity in Adult Neovascularization 
PLoS ONE  2011;6(11):e27332.
Proper arterial and venous specification is a hallmark of functional vascular networks. While arterial-venous identity is genetically pre-determined during embryo development, it is unknown whether an analogous pre-specification occurs in adult neovascularization. Our goal is to determine whether vessel arterial-venous specification in adult neovascularization is pre-determined by the identity of the originating vessels.
Methods and Results
We assessed identity specification during neovascularization by implanting isolated microvessels of arterial identity from both mice and rats and assessing the identity outcomes of the resulting, newly formed vasculature. These microvessels of arterial identity spontaneously formed a stereotypical, perfused microcirculation comprised of the full complement of microvessel types intrinsic to a mature microvasculature. Changes in microvessel identity occurred during sprouting angiogenesis, with neovessels displaying an ambiguous arterial-venous phenotype associated with reduced EphrinB2 phosphorylation.
Our findings indicate that microvessel arterial-venous identity in adult neovascularization is not necessarily pre-determined and that adult microvessels display a considerable level of phenotypic plasticity during neovascularization. In addition, we show that vessels of arterial identity also hold the potential to undergo sprouting angiogenesis.
PMCID: PMC3221655  PMID: 22132096
7.  Angiogenesis in a Microvascular Construct for Transplantation Depends on the Method of Chamber Circulation 
Tissue Engineering. Part A  2009;16(3):795-805.
Effective tissue prevascularization depends on new vessel growth and subsequent progression of neovessels into a stable microcirculation. Isolated microvessel fragments in a collagen-based microvascular construct (MVC) spontaneously undergo angiogenesis in static conditions in vitro but form a new microcirculation only when implanted in vivo. We have designed a bioreactor, the dynamic in vitro perfusion (DIP) chamber, to culture MVCs in vitro with perfusion. By altering bioreactor circulation, microvessel fragments in the DIP chamber either maintained stable, nonsprouting, patent vessel morphologies or sprouted endothelial neovessels that extended out into the surrounding collagen matrix (i.e., angiogenesis), yielding networks of neovessels within the MVC. Neovessels formed in regions of the construct predicted by simulation models to have the steepest gradients in oxygen levels and expressed hypoxia inducible factor-1α. By altering circulation conditions in the DIP chamber, we can control, possibly by modulating hypoxic stress, prevascularizing activity in vitro.
PMCID: PMC2862615  PMID: 19778185

Results 1-7 (7)