BIOMIMETIC VASCULAR NETWORK AND DEVICES USING THE SAME

• US 20100234678A1
• Filed: 10/09/2009
• Published: 09/16/2010
• Est. Priority Date: 04/12/2007
• Status: Active Grant

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: Charles Stark Draper Laboratory Incorporated, The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Spool, Ira, Borenstein, Jeffrey T., Hoganson, David M., Vacanti, Joseph P., Pryor, Howard I.
• Granted Patent: US 8,951,302 B2
• Time in Patent Office: Days
• US Class Current: 600/36
• CPC Class Codes: A61F 2/022 Artificial gland structures using bioreactors hemodialysis A61M1/16; hemofiltration A61M1/34; other extracorporeal blood treatment A61M1/36
• CPC Class Codes: A61F 2/04 Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts A61F2/18, A61F2/20 take precedence; devices, other than stent-grafts, providing patency to, or preventing collapsing of, tubular structures of the body other than stent-grafts, e.g. stents A61F2/82; instruments specially adapted for placement or removal of stents or stent-grafts A61F2/95
• CPC Class Codes: A61F 2/06 Blood vessels
• CPC Class Codes: A61F 2/062 Apparatus for the production of blood vessels made from natural tissue or with layers of living cells prostheses made from natural tissue or living cells A61L27/507
• CPC Class Codes: A61F 2002/068 Modifying the blood flow model, e.g. by diffuser or deflector
• CPC Class Codes: G01N 33/5008 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics

Abstract

The invention provides method of fabricating a scaffold comprising a fluidic network, including the steps of: (a) generating an initial vascular layer for enclosing the chamber and providing fluid to the cells, the initial vascular layer having a network of channels for fluid; (b) translating the initial vascular layer into a model for fluid dynamics analysis; (c) analyzing the initial vascular layer based on desired parameters selected from the group consisting of a characteristic of a specific fluid, an input pressure, an output pressure, an overall flow rate and combinations thereof to determine sheer stress and velocity within the network of channels; (d) measuring the sheer stress and the velocity and comparing the obtained values to predetermined values; (e) determining if either of the shear stress or the velocity are greater than or less than the predetermined values, and (f) optionally modifying the initial vascular layer and repeating steps (b)-(e). The invention also provides compositions comprising a vascular layer for use in tissue lamina as well as a medical devices having a vascular layer and kits.

Claims

1-70. -70. (canceled)

71. An artificial vascular layer comprising:

a substrate defining a network of channels having at least one input channel and at least one output channel and at least two intermediate channels at least partially connecting the at least one input channel and the at least one output channel, each channel having a height, a length, and a width, and a diameter, wherein

the intermediate channels are formed in accordance with Murray'"'"'s law by varying said height and width of the intermediate channels with respect to adjacent channels, and

the length of at least one of the intermediate channels is formed based on the diameter of said channel, whereby said channel has a biomimetic length.

72. The artificial vasculature layer of claim 71, wherein the lengths of the intermediate channels conform to a polynomial equation relating mammalian vessel length to vessel diameter.

73. The artificial vasculature layer of claim 71, wherein at least one of the input channels trifurcates at least once.

74. The artificial vasculature layer of claim 71, wherein at least one of the intermediate channels has a bottom extending between opposing side walls to form bottom corners and further comprising fillets in the bottom corners.

75. The artificial vasculature layer of claim 71, further comprising a transition area at about an intersection between at least two of the channels having different dimensions, wherein the transition area is configured to reduce shear stress at the intersection.

76. The artificial vasculature layer of claim 75, wherein the transition area comprises a ramp providing a transition from a bottom of a first of the at least two channels to a bottom of a second of the at least two channels, wherein the first of the channels has a first height, and the second of the channels has a second height, different from the first height.

77. The artificial vasculature layer of claim 75, wherein the transition area comprises a fillet providing a transition from a bottom of a first of the at least two channels to a bottom of a second of the at least two channels, wherein the first of the channels has a first height, and the second of the channels has a second height, different from the first height.

78. The artificial vasculature layer of claim 71, wherein the channels include sidewalls, and wherein the sidewalls of at least one channel are tapered to control fluid flow through the at least one channel.

79. The artificial vasculature layer of claim 71, wherein the substrate comprises a collagen substrate.

80. The artificial vasculature layer of claim 79, wherein the collagen substrate comprises elastin.

81. The artificial vasculature layer of claim 79, wherein the collagen substrate comprises fibronectin.

82. The artificial vasculature layer of claim 71, comprising a collagen film deposited on the substrate.

83. The artificial vasculature layer of claim 71, wherein the substrate comprises silicone.

84. The artificial vasculature layer of claim 71, wherein an aspect ratio of the intermediate channels is 1:

1.

85. A device comprising:

a first substrate defining a vasculature layer having at least one input channel, at least one output channel, and at least two intermediate channels at least partially connecting the at least one input channel and the at least one output channel, each channel having a height, a length, and a width, and a diameter;

a second substrate defining a cellular layer coupled to first substrate, the cellular layer defining a chamber for holding parenchymal cells and configured to receive oxygen and nutrients from a fluid in the vascular layer; and

a semi-permeable membrane separating the vasculature layer and the cellular layer;

wherein;

the intermediate channels are formed in accordance with Murray'"'"'s law by varying said height and width of the intermediate channels with respect to adjacent channels, and

the length of at least one of the intermediate channels is formed based on the diameter of said channel, whereby said channel has a biomimetic length.

86. The device of claim 85, wherein the semi-permeable membrane is configured to allow exchange of at least one small compound between a fluid or gas in the vascular layer and parenchymal cells in the chamber.

87. The device of claim 85, wherein the vasculature layer and cellular layer comprise a portion of a medical device for assisting or replacing an organ.

88. The device of claim 85, comprising a distribution network coupled to a nozzle for accepting an input fluid, the distribution network including a plurality of distribution channels for distributing the accepted fluid among the at least one input channels.

89. The device of claim 86, wherein the fluid is one of blood, plasma, and media.

90. The device of claim 86, wherein the at least one small compound is selected from the group consisting of oxygen, nutrients, carbon dioxide and waste.

91. The device of claim 85, wherein the parenchymal cells are derived from stem cells or from an organ selected from the group consisting of heart, liver, pancreas, intestine, brain, kidney, reproductive tissue, lung, muscle and bone marrow.

92. A method of manufacturing artificial vasculature, comprising:

providing a substrate;

forming, in the substrate, a network of channels, including at least one input channel, at least one output channel, and at least two intermediate channels at least partially connecting the at least one input channel and the at least one output channel, each channel having a height, a length, and a width, and a diameter, wherein

the intermediate channels are formed in accordance with Murray'"'"'s law by varying said height and width of the intermediate channels with respect to adjacent channels, and

the length of at least one of the intermediate channels is formed based on the diameter of said channel, whereby said channel has a biomimetic length.

93. The method of claim 92, comprising forming the at least one input channel, the at least one output channel, and the intermediate channels at least in part through a machining process.

94. The method of claim 92, comprising:

calculating a bifurcation angle for use in bifurcating an input channel into intermediate channels based on the diameter of the input channel; and

forming said channels using the calculated bifurcation angle.

95. The method of claim 92, wherein forming the network of channels comprises

generating an initial vasculature layer;

analyzing the initial vasculature based on desired parameters selected from the group consisting of a characteristic of a specific fluid, an input pressure, an output pressure, an overall flow rate, and combinations thereof to determine shear stress and velocity within the network of channels;

measuring the shear stress and the velocity and comparing the obtained values to predetermined values; and

determining if either of the shear stress or the velocity are greater than or less than the predetermined values.

96. The method of claim 92, comprising:

forming a cell layer defining a chamber for holding parenchymal cells;

coupling the cell layer and the substrate;

seeding cells into the chamber; and

nourishing the cells by passing blood through the network of channels in the substrate.

97. The method of claim 96, comprising providing a semi-permeable layer between the network of channels and the cell layer.

98. The method of claim 94, wherein forming channels using a machining process comprises machining a mold defining the inverse of the channels.

99. The method of claim 94, wherein forming channels using a machining process comprises directly machining the substrate.

100. The method of claim 94, wherein the machining process comprises electronic discharge machining.

101. The method of claim 97, wherein the semi-permeable layer has pores of between about 0.01 μ

m to about 20 μ

m.

102. The method of claim 95, comprising modifying the channels by adjusting an associated shear stress and velocity to reduce thrombus formation within the channels based on the comparison to the predetermined parameters.

103. A method of at least partially replacing the function of an organ in a patient, comprising:

providing an artificial organ device comprising a first substrate coupled to a second substrate and separated by a semi-permeable membrane;

wherein

the first substrate defines a vasculature layer having at least one input channel, at least one output channel, and at least two intermediate channels at least partially connecting the at least one input channel and the at least one output channel, each channel having a height, a length, and a width, and a diameter, the intermediate channels are formed in accordance with Murray'"'"'s law by varying said height and width of the intermediate channels with respect to adjacent channels, and the length of at least one of the intermediate channels is formed based on the diameter of said channel, whereby said channel has a biomimetic length, and

the a second substrate defines a cellular layer coupled to the first substrate, the cellular layer defining a chamber for holding parenchymal cells and configured to receive oxygen and nutrients from a fluid in the vascular layer; and

coupling the artificial organ device to at least one arterial vessel and one venous vessel of the patient.

104. The method of claim 103, comprising coupling the device to the blood supply of the patient.

105. The method of claim 104, wherein coupling the device to the blood supply comprises coupling the blood supply of the patient to a distribution network for distributing blood from the patient to a plurality of inlet channels.

106. The method of claim 105, wherein the artificial organ comprises a plurality of vasculature layers, and the distribution network couples the blood supply of the patient to at least one inlet of each of the vasculature layers.