Method and apparatus for measuring contraction characteristics of engineered heart tissue constructs

• US 10,172,712 B2
• Filed: 03/25/2014
• Issued: 01/08/2019
• Est. Priority Date: 03/25/2013
• Status: Active Grant

• Current Assignee: Technische Universitã¤T Hamburg-Harburg, Universitã¤Tsklinikum Hamburg-Eppendorf
• Original Assignee: Technische Universitã¤T Hamburg-Harburg, Universitã¤Tsklinikum Hamburg-Eppendorf
• Inventors: Eschenhagen, Thomas, Mannhardt, Ingra, Muller, Jorg, Warncke, Christoph, Weiser, Jordis
• Primary Examiner(s): Caputo, Lisa
• Assistant Examiner(s): Woodward, Nathaniel T
• Application Number:
  US14/780,199
• Publication Number:
  US 20160030177A1
• Time in Patent Office: 1,750 Days
• Field of Search: 738664
• CPC Class Codes: A61B 2562/0252 Load cells
• CPC Class Codes: A61B 2562/0261 Strain gauges
• CPC Class Codes: A61B 2562/028 Microscale sensors, e.g. electromechanical sensors [MEMS]
• CPC Class Codes: A61B 5/1108 of excised organs, e.g. muscle preparations
• CPC Class Codes: A61F 2/2472 Devices for testing
• CPC Class Codes: A61F 2240/008 Means for testing implantable prostheses
• CPC Class Codes: G09B 23/30 Anatomical models G09B23/281 - G09B23/288 take precedence

Abstract

The invention is directed to a novel method for measuring contraction characteristics of engineered heart tissue constructs (16) which is based on the mechanical coupling of the construct (16) to a support element (8) which comprises or is mechanically coupled to a piezoelectric element (10). An apparatus (1) for carrying out the method of the invention is also provided.

Claims

1. A method for measuring contraction characteristics of engineered heart tissue constructs, comprising the following steps:

providing at least one engineered heart tissue construct,

attaching each of said at least one engineered heart tissue construct to a separate first support element, which comprises or is mechanically coupled to a piezoelectric element which is the sensing element of a piezoelectric transducer, such that upon contraction of the respective engineered heart tissue construct a load is transferred to the respective piezoelectric element and the respective piezoelectric transducer generates and outputs a corresponding electrical sensor signal characteristic of the load and/or of a change of the load applied to the respective first support element by the respective engineered heart tissue construct due to the contraction thereof, and

analyzing, for each of said at least one engineered heart tissue construct, the sensor signal output by the respective piezoelectric transducer and deriving at least one contraction characteristic of said at least one engineered heart tissue construct on the basis of the analysis,

wherein the step of attaching each of said at least one engineered heart tissue construct to a separate first support element comprises, for each of said at least one engineered heart tissue construct, attaching the respective engineered heart tissue construct to at least one second support element, each being spaced with at least a portion thereof from the respective first support element and each engaging the respective engineered heart tissue construct at a location spaced from a location at which the respective first support element engages the respective engineered heart tissue construct, so that it is suspended between the respective first support element and the respective at least one second support element.

2. The method of claim 1, wherein each of the first support elements is attached to and extends from a base element, and wherein the method further comprises the step of arranging said base element such that each of the first support elements extends downwardly from the base element.

3. The method of claim 2, wherein the step of arranging said base element such that each of the first support elements extends downwardly from the base element comprises arranging the base element on the surface of a multi-well plate such that the base element is supported on the surface and each of said at least one engineered heart tissue construct is disposed in a separate one of the wells of the multi-well plate.

4. The method of claim 1, wherein each of the second support elements is attached to and extends from the base element such that, when said base element is arranged such that each of the first support elements extends downwardly from the base element, each of the second support elements likewise extends downwardly from the base element, so that each of said at least one engineered heart tissue construct is suspended on and between the respective first and second support elements.

5. The method claim 1, wherein each of the at least one first support elements is rigid, and wherein

for at least one of the at least one first support element each of the associated at least one second support element is rigid, so that the respective engineered heart tissue construct carries out an isometric contraction on the respective first and second support elements,

for at least one of the at least one first support element at least one of the associated at least one second support element is flexible, so that the respective engineered heart tissue construct carries out an auxotonic contraction on the respective first and second support elements, and/or

for at least one of the at least one first support element at least one of the associated at least one second support element can be selectively configured to assume a rigid state and a flexible state, and the method comprises selectively changing these second support elements between their rigid and flexible state and measuring both isometric and auxotonic contraction of the respective engineered heart tissue constructs.

6. An apparatus for carrying out the method of any of the preceding claims, comprising

a base element, and

at least one first support element attached to and extending from the base element, each of said at least one first support element comprising or being mechanically coupled to a piezoelectric element, which is the sensing element of a piezoelectric transducer,

wherein each of said at least one first support element comprises a support portion adapted for attaching an engineered heart tissue construct thereto, wherein after attaching an engineered heart tissue construct to the support portion the respective engineered heart tissue construct can be arranged such that upon contraction thereof a load is transferred to the respective piezoelectric element and the respective piezoelectric transducer generates and outputs a corresponding electrical sensor signal characteristic of the load and/or of the change of the load applied to the respective first support element by the respective engineered heart tissue construct due to the contraction thereof, and

at least one second support element for each of said at least one first support element, said at least one second support element attached to and extending from the base element, wherein

each of said at least one second support element comprises a support portion adapted for attaching an engineered heart tissue construct thereto, and

each support portion of each second support element is spaced from and arranged with respect to the support portion of the respective first support element, such that, after attaching an engineered heart tissue construct to the support portion of one of said at least one first support element and to the support portion of each associated second support element, the respective engineered heart tissue construct is engaged by the support portion of the respective first support element at a location spaced from the location at which the support portion of each of the respective at least one second support element engages the engineered heart tissue construct, so that it is suspended between the respective first support element and the respective at least one second support element.

7. The apparatus of claim 6, wherein each of said at least one first support element and each of said at least one second support element extend from a same side of the base element, and wherein the base element is adapted to be disposed on the surface of a suitably dimensioned multi-well plate, such that each of said at least one first support element and the associated at least one second support element extends into a separate one of the wells of the multi-well plate, and that each engineered heart tissue construct attached to the support portions of one of said at least one first support element and the associated at least one second support element is suspended on and between the respective first and second support elements and disposed inside the respective one of the wells of the multi-well plate.

8. The apparatus of claim 6, wherein each of the first support elements is rigid, and wherein

for at least one of the at least one first support element each of the associated at least one second support element is rigid, so that engineered heart tissue constructs attached to the support portions of one of these first support elements and the associated at least one second support element carry out an isometric contraction on the respective first and second support elements,

for at least one of the at least one first support element at least one of the associated at least one second support element is flexible, so that engineered heart tissue constructs attached to the support portions of one of these first support elements and the associated at least one second support element carry out an auxotonic contraction on the respective first and second support elements, and/or

for at least one of the at least one first support element at least one of the associated at least one second support element can be selectively configured to assume a rigid state and a flexible state, so that engineered heart tissue constructs attached to the support portions of these first support elements and the associated at least one second support element carry out isometric or auxotonic contraction, depending on the state of the respective at least one second support element.

9. The apparatus of claim 8, wherein, for at least one of the at least one first support element, at least one of the associated at least one second support element is selectively configurable to assume a rigid state and a flexible state, and comprises a flexible elongate tubular element and a rigid elongate element adapted to be selectively inserted into and removed from the tubular element for selectively configuring the respective second support element to be flexible and rigid.

10. The apparatus of claim 6, wherein

the support portions of the first and second support elements comprise or are made of silicone, and/or

each of the at least one first support element comprises an elongate section extending from the base element and the respective support portion is located at the longitudinal end of the elongate section remote from the base element, the support portion comprising a portion extending transversely with respect to the elongate section to opposite sides thereof, and/or

each of the at least one second support element comprises an elongate section extending from the base element and the respective support portion is located at the longitudinal end of the elongate section remote from the base element, the support portion comprising a portion extending transversely with respect to the elongate section to opposite sides thereof.

11. The apparatus of claim 6, wherein each of the piezoelectric transducers is electrically connected to electronic circuitry integrated into or disposed on the base element and adapted for conditioning, converting, processing and/or analyzing the respective sensor signals.

12. The apparatus of claim 6, wherein at least one of the at least one first support element comprises at least one strain gauge mechanically coupled to the respective first support element, such that after attaching an engineered heart tissue construct to the support portion of the respective first support element the engineered heart tissue construct can be arranged such that upon contraction thereof a load is transferred to the respective at least one strain gauge and the respective at least one strain gauge generates and outputs a corresponding electrical strain gauge signal characteristic of the static load applied by the respective engineered heart tissue construct to the respective first support element due to the contraction thereof.

13. The apparatus of claim 6, wherein the distance between said support portion of said at least one first support element and the support portion of the respective at least one second support element is between 5 and 50 mm.