Axial Vascularization of Bioceramic Scaffolds for Segmental Bone Defects

AXIAL VASCULARIZATION OF BIOCERAMIC SCAFFOLDS FOR SEGMENTAL BONE DE-

FECTS.

1

1

1,2

H. Mangat , J. Barralet and N. Makhoul

1

Faculty of Dentistry, McGill University, Montreal, Canada

2

Division of Oral and Maxillofacial Surgery, McGill University, Montreal, Canada

The current gold standard for the reconstruction of critical-sized maxillofacial defects is the transfer of vascular-

ized bone flaps. These flaps have significant limitations including a size mismatch to the recipient site as well

as donor site morbidity, leading to compromised facial aesthetics and oral/masticatory function. Bone tissue en-

gineering presents a promising alternative to the current reconstruction techniques. However, tissue engineered

constructs have thus far failed to make a significant clinical translation, largely due to a lack of robust strategies

to generate patent vascularization (1).

In order to generate vessels large enough to perfuse clinically relevant scaffolds, two techniques exist: vessel

grafting (as in the AV Loop model) or collateralization (also known as arteriogenesis). Much of what is known

regarding collateralization is related to ischemic cardiac and brain injuries. In this literature, full or partial vessel

occlusion of blood vessels generates a hypoxic environment conducive to the expansion of vestigial collateral

vessels. The severity of occlusion is proportional to the intensity of arteriogenesis. Bone regeneration of seg-

mental bone defects has not yet implemented this knowledge. Only the arteriovenous (AV) loop model investi-

gated by independent German and US research groups, has displayed the necessary pro-angiogenic properties to

repair critical-sized defects (2). Therefore, the ideal strategy to vascularize large scaffolds must induce both ar-

teriogenesis and angiogenesis. The aim of this study is to optimize vascularization of a complex bioceramic

scaffold by improving the current AV loop model, and investigating the efficacy of inducing collateral vessels.

In this study, four models (Extrinsic Control, Intrinsic Control, Arteriogenesis and AV loop) were investigated

to identify the optimal strategy to vascularize bioceramic scaffolds. Following in vivo periods of 2 and 4 weeks,

tissue specimens were analyzed histologically (immunohistochemistry) to quantify the density of blood vessels,

and radiographically (micro-computed tomography) to determine the degree of graft resorption. The monetite

scaffolds were manufactured through rapid-prototyping and featured two designs (Figure 1). The first contains a

central lumen of constant diameter for the Control, Angiogenesis and AV loop group. The second design retains

a tapering central lumen to obstruct the artery distally - this was used in the arteriogenesis group. The femoral

vasculature was utilized, and a total of 30 Wistar rats were operated on (Figure 2).

At both 2- and 4-week time points, the arteriogenesis model displayed a greater density of blood vessels. Fur-

thermore, the arteriogenesis model had the highest rate of graft resorption, an indicator of total mass transfer

that can be correlated to the degree of scaffold vascularization. Based on the results of our study, the ideal strat-

egy to vascularize large scaffolds must induce both arteriogenesis and angiogenesis. Furthermore, we discov-

ered that the alteration of scaffold structure can manipulate vascular development and potentially enhance clini-

cally-relevant bone engineering.

References:

1.

Rouwkema J, Rivron NC, van Blitterswijk CA. Vascularization in tissue engineering. Trends Biotechnol. 2008

Aug;26(8):434 – 41.

2.

Arkudas A, Beier JP, Heidner K et al. Axial prevascularization of porous matrices using an arteriovenous loop pro-

motes survival and differentiation of transplanted autologous osteoblasts. Tissue Eng. 2007 Jul;13(7):1549 – 60 .

Figure 1: Monetite scaffolds including either a tapering (A) or non-tapering central channel (B).

Figure 2: Orientation of the

implanted scaffolds as ei-

ther encompassing the artery, or near the artery (extrinsic control group).