Three dimensional construct for the design and fabrication of physiological fluidic networks

• US 8,147,562 B2
• Filed: 09/23/2003
• Issued: 04/03/2012
• Est. Priority Date: 09/23/2002
• Status: Active Grant

• Current Assignee: Charles Stark Draper Laboratory Incorporated, Massachusetts Institute of Technology, The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Vacanti, Joseph P., Borenstein, Jeffrey, Weinberg, Eli, Kaazempur-Mofrad, Mohammad R.
• Primary Examiner(s): Ford, Allison
• Assistant Examiner(s): Fernandez, Susan E
• Application Number:
  US10/528,737
• Publication Number:
  US 20060136182A1
• Time in Patent Office: 3,115 Days
• Field of Search: 435/325, 435/347, 435/395, 435/397, 435/401, 422/68.1, 422/99, 738/61, 738/617.1
• US Class Current: 623/23.72
• CPC Class Codes: B01L 3/5027 by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00
• CPC Class Codes: B33Y 80/00 Products made by additive manufacturing
• CPC Class Codes: C12M 25/14 Scaffolds; Matrices in general C12N5/0068
• CPC Class Codes: C12N 5/0062 General methods for three-dimensional culture
• CPC Class Codes: G16H 50/50 for simulation or modelling of medical disorders
• CPC Class Codes: Y10T 137/206 Flow affected by fluid contact, energy field or coanda effect [e.g., pure fluid device or system]
• CPC Class Codes: Y10T 137/212 System comprising plural fluidic devices or stages

Abstract

The present invention relates to methods for the design and fabrication of biological constructs, such as organ simulants or organ replacements, which contain complex microfluidic architecture. Designs of the present invention provide increased space in the lateral dimension, enabling a large number of small channels for small vessels.

Claims

1. A method of modeling and designing a physiologically based fluidic network in a three-dimensional construct for use as an organ simulant for a specific organ, comprising the steps of:

generating an initial design of an initial network in node-vessel format by stacking two-dimensional layers comprised of vessels connected by nodes and interconnecting the layers with vertical vessels such that the initial design is a three-dimensional design of a biological construct;

translating the initial design from node-vessel format into a set of matrix equations relating a pressure and a resistance for each vessel, thereby defining flow behavior in the network;

setting constraints on the set of matrix equations and determining a flow rate in each vessel, wherein the constraints include at least one physiological parameter associated with the specific organ;

solving the set of matrix equations for the pressure and resistance of each vessel based on the flow rate in each vessel and the constraints;

determining a geometry of each vessel on the basis of the corresponding resistance, thereby defining a final design of a final biological construct; and

producing the final biological construct for use as an organ simulant.

2. The method according to claim 1, wherein the generating step comprises the steps of:

creating layers wherein the vessels are generated using a hexagonal fractal algorithm;

stacking the layers to produce a three-dimensional design;

connecting nodes which are vertically aligned between stacked layers; and

adding inlet and outlet vessels to the initial design.

3. The method according to claim 1, wherein at least two different layer designs are used in generating the initial design.

4. The method according to claim 1, wherein the node-vessel format comprises a list of vessels and a list of nodes defining locations where vessels connect, wherein each vessel connects two nodes.

5. The method according to claim 1, further comprising a step of receiving a branching pattern indicating a number of vessels, interconnections between the vessels, and a tissue size to be supported by the fluidic network;

and wherein the initial design is generated on the basis of the received branching pattern.

6. The method according to claim 1, further comprising a step of applying a branching diameter rule to the initial design such that only similarly sized vessels are connected to each other.

7. The method according to claim 1, wherein the geometry of each vessel includes a width and a depth and is determined by calculating the width on the basis of the corresponding resistance and the depth corresponds to an etch depth.

8. The method according to claim 1, wherein the producing step is by soft-lithography techniques for use in tissue-engineered organs.

9. The method according to claim 1, wherein one of the constraints is a distance between the vessels to allow proper supply of nutrients and oxygen as well as processing of waste.

10. The method according to claim 1, wherein the initial network is designed to accommodate blood and setting the constraints includes matching physiological parameters at a boundary of the initial network with a boundary of the specific organ to allow implantation without disturbing blood flow.

11. The method according to claim 1, wherein the determining step includes creating a pattern with the vessels spaced evenly throughout that avoids sharp angles between intersecting vessels in the two-dimensional layers by defining a reference direction in a plane, defining a vessel length L, defining an origin, defining a maximum pattern diameter, creating three vessels with one node at the origin, each vessel having a length L wherein one of the vessels extends parallel to the reference direction, one of the vessels at 120 degrees from the reference direction, and one of the vessels at 240 degree from the reference direction, and iterating through each node by redefining the reference direction as a direction of a vessel connected to that node and redefining the origin as the current node.

12. The method according to claim 11, further comprising wherein the determining step further includes repeating iterating at each node until no nodes are outside the maximum network diameter.

13. The method according to claim 1, wherein the at least one physiological parameter is wall shear stress and the step of solving includes solving the set of matrix equations for flow in addition to pressure and resistance.

14. A method of designing and producing an organ simulant to replace or augment a target organ, comprising the steps of:

generating a three-dimensional design of the organ simulant having a construct that defines a physiologically based fluidic network, wherein the design is in node-vessel format by stacking a plurality of two-dimensional layers comprised of vessels connected by nodes and interconnecting the layers with vertical vessels;

translating the three-dimensional design from node-vessel format into a set of matrix equations relating performance parameters for each vessel;

setting constraints on the set of matrix equations to solve

the set of matrix equations to approximately match the performance parameters to physiological parameters of the target organ;

determining a geometry of each vessel on the basis of the solution of the set of matrix equations, thereby defining a physiologically based fluidic network of a revised three-dimensional design of the organ simulant; and

producing the revised three-dimensional design of the organ simulant.

15. The method according to claim 14, further comprising the step of determining a flow rate, pressure and resistance in each vessel.

16. The method according to claim 14, wherein the constraints include a distance between the vessels to allow proper supply of nutrients and oxygen as well as processing of waste.

17. The method according to claim 14, wherein the network is designed to accommodate blood and setting the constraints includes matching the physiological parameters at a boundary of the physiologically based fluidic network with a boundary of the target organ to allow implantation without disturbing blood flow.

18. The method according to claim 14, wherein the determining step includes creating a pattern with the vessels spaced evenly throughout that avoids sharp angles between intersecting vessels in the two-dimensional layers by defining a reference direction in a plane, defining a vessel length L, defining an origin, defining a maximum pattern diameter, creating three vessels with one node at the origin, each vessel having a length L wherein one of the vessels extends parallel to the reference direction, one of the vessels at 120 degrees from the reference direction, and one of the vessels at 240 degree from the reference direction, and iterating through each node by redefining the reference direction as a direction of a vessel connected to that node and redefining the origin as the current node.

19. The method according to claim 18, wherein the determining step further includes repeating iterating at each node until no nodes are outside the maximum network diameter.