A High-Throughput Platform To Investigate Angiogenesis In Perfused Human Capillaries

Tech ID: 21077 / UC Case 2009-437-0

Brief Description

A new platform to mimic the in-vivo formation of angiogenesis.

Full Description

The challenge to create an in-vitro perfused human capillary bed represents a completely new paradigm in the creation of 3-D tissues. By definition, a 3-D tissue requires enhanced transport of nutrients and waste relative to 2-D monolayer cultures. Current approaches to create such an environment have employed three primary approaches: 1) enhanced concentration gradients of nutrients and waste while relying on molecular diffusion (Brownian motion) as the mode of transport, 2) the creation of microchannels in the tissue to enhance advection (forced convection), or 3) forced interstitial fluid flow. In-vivo, diffusion of nutrients and waste is the mechanism of transport once solutes exit the capillary bed, and is generally limited to distances <250 J.1m. The rate of transport is proportional to the concentration difference between two points, and inversely related to the separation distance. Hence, numerous 3-D tissue models have been reported with dimensions on the order of 1-10 mm by simply enhancing the oxygen tension (room air is 160 mmHg compared to 20-30 mmHg in the interstitial tissue) and concentration of other nutrients (e.g., glucose).

More recently, microfabrication technology has led to the creation of precise microchannels on non-biological substrates (e.g., silicon or polydimethyl siloxane, PDMS) or within biological substrates such as collagen. While these approaches offer the distinct advantage of introducing advection as a mechanism of transport, even when "endothelialized", the channels are not human capillaries. Hence, while this approach may assist the creation of larger engineered tissues, they are of less benefit in understanding angiogenesis, cell migration, cell differentiation, and ischemia.

Interstitial fluid flow can markedly impact extracellular gradients of solutes, enhance transport of nutrients and waste, and significantly impact the development of both lymphatic and blood capillaries. These recent studies, as well as others including our group, highlight the ability to generate capillaries in 3-D, and also demonstrate that these capillaries can become functional upon implantation. However, perfusion of human (or other animal) capillaries in-vitro has not been demonstrated.

In short, there has been no description or success of creating actual human capillaries in vitro which are perfused with an appropriate fluid to deliver nutrients to a 3-D tissue. We have solved this problem by mimicking the in-vivo formation of angiogenesis using a precisely fabricated platform.

Suggested uses

The potential impact of mimicking the in-vivo formation of angiogenesis using a precisely fabricated platform can be encompassed in the broad areas of oncogenesis, ischemia, arterio-venous malformations, wound healing, drug delivery, and tissue growth, differentiation, and death. For example, the growth and development of tumors is a 3-D process that requires recruitment of host vessels for delivery of nutrients and metastasis of cells. All major modes of pharmacotherapy (e.g., oral, subcutaneous, intravenous, intramuscular) involve uptake and delivery of the drug by the circulatory system including the microcirculation. Capillary permeability and high-throughput screening are major areas of investigation which could be addressed by our proposed system. Finally, the "decision" by a tissue following insult to revitalize or undergo programmed death is poorly understood, yet is fundamental for our success in advancing human health, and must depend on a functional (Le., perfused) capillary bed.

Advantages

In short, there has been no description or success of creating actual human capillaries in vitro which are perfused with an appropriate fluid to deliver nutrients to a 3-D tissue. We have solved this problem by mimicking the in-vivo formation of angiogenesis using a precisely fabricated platform.

Patent Status

Country Type Number Dated Case
United States Of America Published Application 20120083425 04/05/2012 2009-437
 

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