# US 2019/0376014 A1 · Apparatus and methods for in vitro preclinical human trials > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2019/0376014 A1 - Document ID: US20190376014A1 - Status: Published application - Kind: A1 - Application number: 16/479,297 - Filed: 2018-01-24 - Published: 2019-12-12 - Earliest claimed: 2017-01-25 - Assignees: The George Washington University a Congressionally Chartered Not-for-Profit Corporation - Inventors: Igor R. EFIMOV; Yun QIAO; Chaoyi KANG; Zhenyu LI; Quan DONG; Baichen LI - Web page: https://patentgrep.com/patent/US20190376014A1 ## CPC - C12M 23/16: {Microfluidic devices; Capillary tubes (integrated microfluidic structures B01L3/5027; microreactors B01J19/0093)} - A01N 1/122: Preservation or perfusion media - A01N 1/143: for organ perfusion - A01N 1/16: Physical preservation processes - A01N 1/162: Temperature processes, e.g. following predefined temperature changes over time - B01L 3/502715: {characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces} - C12M 27/02: {Stirrer or mobile mixing elements} - C12M 27/16: {Vibrating; Shaking; Tilting} - C12M 29/10: {Perfusion} - C12M 41/00: {Means for regulation, monitoring, measurement or control, e.g. flow regulation (controlling or regulating chemical, physical or physicochemical processes B01J19/0006; heating or cooling apparatus for laboratory use B01L7/00; electro optical investigation of individual particles, flow cytometers G01N15/14; automatic analysis G01N35/00; controlling or regulating in general G06N)} - C12M 41/06: {of illumination} - C12M 41/18: {Heat exchange systems, e.g. heat jackets or outer envelopes} - C12M 41/26: {of pH} - C12M 41/34: {of gas} - C12M 41/48: {Automatic or computerized control (automatic analysis G01N35/00)} - C12N 5/0657: {Cardiomyocytes; Heart cells} - C12N 5/0697: {Artificial constructs associating cells of different lineages, e.g. tissue equivalents (blood vessels C12N5/0691)} - C12N 9/226: {Class 2 CAS enzyme complex, e.g. single CAS protein} - C12N 15/11: DNA or RNA fragments; Modified forms thereof (DNA or RNA not used in recombinant technology, C07H21/00); {Non-coding nucleic acids having a biological activity} - G01N 1/36: Embedding or analogous mounting of samples - G01N 33/48707: {by electrical means (G01N33/49, G01N33/493 take precedence)} - G01N 33/5014: {for testing toxicity} - G01N 33/5088: {of vertebrates} - B01L 2200/025: Align devices or objects to ensure defined positions relative to each other - B01L 2200/10: Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept - B01L 2200/143: Quality control, feedback systems - B01L 2200/185: Long distance transport, e.g. mailing - B01L 2300/027: Digital display, e.g. LCD, LED - B01L 2300/0645: Electrodes - B01L 2300/0663: Whole sensors - B01L 2300/0819: Microarrays; Biochips - B01L 2300/10: Means to control humidity and/or other gases - B01L 2300/12: Specific details about materials - B01L 2300/18: Means for temperature control - B01L 2400/0415: electrical forces, e.g. electrokinetic - B01L 2400/0487: fluid pressure, pneumatics - C12N 2310/20: involving clustered regularly interspaced short palindromic repeats [CRISPR] - C12N 2521/00: Culture process characterised by the use of hydrostatic pressure, flow or shear forces - C12N 2800/80: Vectors containing sites for inducing double-stranded breaks, e.g. meganuclease restriction sites - G01N 2001/368: {Mounting multiple samples in one block, e.g. TMA [Tissue Microarrays]} - C12M: APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; {APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS} - A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS - B01L: CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) ## Abstract Systems comprising a microfluidic device are provided for maintaining and analyzing tissue slices. Methods for maintaining tissue slices in a microfluidic device are further provided. ## Claims ### Claim 1 A system for maintaining and analyzing tissue slices, comprising: a microfluidic device comprising at least one tissue culture chamber; one or more actuators disposed in an interior of the tissue culture chamber; one or more sensors disposed in the interior of the tissue culture chamber; and an electronics module comprising a microcontroller, wherein the electronics module is coupled to the one or more actuators and the one or more sensors by an array of electrodes. ### Claim 2 (depends on 1) The system of claim 1, wherein the one or more actuators comprises at least one of an electrical stimulator, a mechanical stimulator, a chemical stimulator, and an optical stimulator. ### Claim 3 (depends on 1) The system of claim 1, wherein the one or more sensors comprises at least one of a temperature sensor, an oxygen sensor, a pH sensor, a humidity sensor, one or an array of photodetectors, a force transducer, and an electrical sensor. ### Claim 4 (depends on 1) The system of claim 1, wherein the electronics module is configured to control the one or more actuators and receive data from the one or more sensors. ### Claim 5 (depends on 1) The system of claim 1, wherein the electronics module further comprises an integrated power supply. ### Claim 6 (depends on 5) The system of claim 5, wherein the power supply is a battery. ### Claim 7 (depends on 1) The system of claim 1, further comprising a central control unit coupled to the microcontroller, wherein the central control unit is configured to analyze data from the one or more sensors. ### Claim 8 (depends on 7) The system of claim 7, wherein the central control unit is wirelessly coupled to the microcontroller. ### Claim 9 (depends on 1) The system of claim 1, wherein a bottom portion of the at least one tissue culture chamber further comprises a substrate configured to receive a tissue slice. ### Claim 10 (depends on 9) The system of claim 9, wherein the substrate is polydimethylsiloxane (PDMS). ### Claim 11 (depends on 10) The system of claim 10, wherein the PDMS matches a stiffness of the tissue slice. ### Claim 12 (depends on 10) The system of claim 10, wherein the tissue slice is cardiac tissue. ### Claim 13 (depends on 9) The system of claim 9, further comprising a plurality of mechanical loading poles configured to secure the tissue slice within the tissue culture chamber. ### Claim 14 (depends on 13) The system of claim 13, wherein the mechanical loading poles provide mechanical stimulation to the tissue slice. ### Claim 15 (depends on 13) The system of claim 13, wherein the mechanical loading poles measure contractile force of the tissue slice. ### Claim 16 (depends on 1) The system of claim 1, wherein the microfluidic device comprises two or more tissue culture chambers, each tissue culture chamber having one or more actuators disposed in an interior of the tissue culture chamber and one or more sensors disposed in the interior of the tissue culture chamber, wherein the electronics module is coupled to the one or more actuators and the one or more sensors of each tissue culture chamber. ### Claim 17 (depends on 16) The system of claim 16, wherein the two or more tissue culture chambers are connected in series, in parallel, or any combination thereof. ### Claim 18 (depends on 1) The system of claim 1, further comprising a media reservoir, wherein the media enters the tissue culture chamber through an inlet and exits the tissue culture chamber through an outlet. ### Claim 19 (depends on 18) The system of claim 18, further comprising at least one pump configured to deliver the media to the tissue culture chamber. ### Claim 20 (depends on 19) The system of claim 19, wherein the pump is a piezoelectric pump, a peristaltic pump, or a syringe pump. ### Claim 21 (depends on 1) The system of claim 1, further comprising an oxygen tank, a gas exchanger, and a heater. ### Claim 22 (depends on 1) The system of claim 1, further comprising a housing, wherein the microfluidic device and the electronics module are disposed within the housing. ### Claim 23 (depends on 22) The system of claim 22, wherein the housing is a heat and oxygen insulating housing. ### Claim 24 (depends on 22) The system of claim 22, wherein a volume of the housing is from about 5,000 cubic centimeters to about 20,000 cubic centimeters. ### Claim 25 (depends on 24) The system of claim 24, wherein the volume of the housing is from about 10,000 cubic centimeters to about 15,000 cubic centimeters. ### Claim 26 (depends on 25) The system of claim 25, wherein the volume of the housing is about 30 cm by about 20 cm by about 20 cm. ### Claim 27 A method for maintaining one or more tissue slices in a microfluidic device, the method comprising culturing the one or more tissue slices in the microfluidic device, wherein the tissue slices are obtained from one or more organs, and wherein the microfluidic device comprises: a) one or more tissue culture chambers, wherein each tissue culture chamber provides a restricted environment supplied with oxygen and nutrients necessary to maintain a desired phenotype for each tissue slice; b) one or more actuators for maintenance of the one or more tissue slices or for phenotypic interrogation of the one or more tissue slices; c) one or more sensors for measuring one or more physiological parameters of the one or more tissue slices; and d) an electronics module comprising a microcontroller, wherein the electronics module is coupled to the one or more actuators and the one or more sensors by an array of electrodes. ### Claim 28 (depends on 27) The method of claim 27, further comprising the step of electrically, mechanically, optically, or chemically stimulating the one or more tissue slices. ### Claim 29 (depends on 27, 28) The method of claim 27 or 28, further comprising the step of measuring the one or more physiological parameters of the one or more tissue slices. ### Claim 30 (depends on 29) The method of claim 29, further comprising the step of analyzing the phenotype of the one or more tissue slices. ### Claim 31 (depends on 27) The method of claim 27, wherein the phenotype of the one or more tissue slices is interrogated by (1) electrically, mechanically, optically, or chemically stimulating the one or more tissue slices, (2) measuring the one or more physiological parameters of the one or more tissue slices, and (3) analyzing the phenotype of the one or more tissue slices. ### Claim 32 (depends on 31) The method of claim 31, wherein the desired phenotype of the tissue slice is maintained in the tissue culture chamber by electrically, mechanically, optically, or chemically stimulating the tissue slice to maintain the desired phenotype after the step of analyzing the phenotype of the one or more tissue slices. ### Claim 33 (depends on 27) The method of claim 27, wherein the desired phenotype of the tissue slice is maintained in the tissue culture chamber by (1) measuring the one or more physiological parameters of the tissue slice, (2) analyzing the phenotype of the tissue slice, and (3) electrically, mechanically, optically, or chemically stimulating the tissue slice to maintain the desired phenotype. ### Claim 34 (depends on 27, 28, 29, 30, 31, 32, 33) The method of any one of claims 27-33, wherein the physiological parameters are functional, metabolic, or transcriptional parameters. ### Claim 35 (depends on 34) The method of claim 34, wherein the functional parameters are electrical parameters or mechanical parameters. ### Claim 36 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35) The method of any one of claims 27-35, wherein the one or more actuators comprise at least one of an electrical stimulator, a mechanical stimulator, a chemical stimulator, and an optical stimulator. ### Claim 37 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) The method of any one of claims 27-36, wherein the one or more sensors comprise at least one of a temperature sensor, an oxygen sensor, a pH sensor, a humidity sensor, one or an array of photodetectors, a force transducer, and an electrical sensor. ### Claim 38 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37) The method of any one of claims 27-37, wherein the electronics module is configured to control the one or more actuators and receive date from the one or more sensors. ### Claim 39 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38) The method of any one of claims 27-38, wherein the microfluidic device further comprises a central control unit, wherein the central control unit is coupled to the microcontroller, and wherein the central control unit is configured to analyze date from the one or more sensors. ### Claim 40 (depends on 39) The method of claim 39, wherein the central control unit is wirelessly coupled to the microcontroller. ### Claim 41 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40) The method of any one of claims 27-40, wherein a bottom portion of the one or more tissue culture chambers comprises a substrate configured to receive the tissue slice. ### Claim 42 (depends on 41) The method of claim 41, wherein the substrate is polydimethylsiloxane (PDMS). ### Claim 43 (depends on 42) The method of claim 42, wherein the PDMS matches a stiffness of the cultured tissue. ### Claim 44 (depends on 41) The method of claim 41, wherein the substrate is a biocompatible porous substrate. ### Claim 45 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44) The method of any one of claims 27-44, wherein the one or more tissue culture chambers further comprise a plurality of mechanical loading poles, wherein the plurality of mechanical loading poles are configured to secure the tissue slice within the tissue culture chamber. ### Claim 46 (depends on 45) The method of claim 45, wherein the mechanical loading poles provide mechanical stimulation to the tissue slice. ### Claim 47 (depends on 45, 46) The system of claim 45 or 46, wherein the mechanical loading poles measure contractile force of the tissue slice. ### Claim 48 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47) The method of any one of claims 27-47, wherein the electronics module further comprises an integrated power supply. ### Claim 49 (depends on 48) The method of claim 48, wherein the power supply is a battery. ### Claim 50 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49) The method of any one of claims 27-49, wherein the microfluidic device further comprises a media reservoir, wherein media enters the tissue culture chamber through an inlet and exits the tissue culture chamber through an outlet. ### Claim 51 (depends on 50) The method of claim 50, wherein microfluidic device further comprises at least one pump configured to deliver the media to the tissue culture chamber. ### Claim 52 (depends on 51) The method of claim 51, wherein the pump is a piezoelectric pump, a peristaltic pump, or a syringe pump. ### Claim 53 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52) The method of any one of claims 27-52, wherein the microfluidic device further comprises an oxygen tank, a gas exchanger, and a heater. ### Claim 54 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47) The method of any one of claims 27-47, wherein the microfluidic device is a self-contained culture system designed for long-distance transportation, wherein the self-contained culture system comprises an integrated power supply, an oxygen tank, a gas exchanger, a heater, a pump, and a media reservoir, and wherein the self-contained culture system maintains viability of the one or more tissue slices during long-distance transportation by providing optimal medium circulation, oxygenation, temperature control, and stimulation. ### Claim 55 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54) The method of any one of claims 27-54, wherein the one or more organs are human, murine, rabbit, swine, or canine organs. ### Claim 56 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55) The method of any one of claims 27-55, wherein at least one tissue slice is obtained from biopsy of the one or more organs. ### Claim 57 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56) The method of any one of claims 27-56, wherein the one or more organs are selected from the group consisting of: brain, heart, lung, liver, kidney, spleen, and skin. ### Claim 58 (depends on 57) The method of claim 57, wherein at least one tissue slice is obtained from a heart. ### Claim 59 (depends on 58) The method of claim 58, wherein the at least one tissue slice obtained from a heart is an atrial or ventricular tissue slice. ### Claim 60 (depends on 58, 59) The method of claim 58 or 59, wherein the one or more tissue culture chambers comprise field or point pacing electrodes. ### Claim 61 (depends on 60) The method of claim 60, wherein the one or more tissue culture chambers further comprise bipolar sensing electrodes for pseudo ECG recording or an array of unipolar electrodes for measuring electrical conduction. ### Claim 62 (depends on 61) The method of claim 61, wherein the pacing electrodes and sensing electrodes are platinum-iridium (Pt/Ir) electrodes. ### Claim 63 (depends on 61, 62) The method of claim 61 or 62, wherein the pacing electrodes and sensing electrodes are fabricated into the culture chamber for electrical stimulation and sensing. ### Claim 64 (depends on 61, 62, 63) The method of any one of claims 61-63, wherein pacing parameters are user or software adjustable to allow for optimization of a pacing protocol during culture. ### Claim 65 (depends on 58, 59, 60, 61, 62, 63, 64) The method of any one of claims 58-64, further comprising the step of inducing cardiac dysfunction by chronic pathological stimulation of the at least one tissue slice obtained from a heart. ### Claim 66 (depends on 65) The method of claim 65, wherein the chronic stimulation is alpha-adrenergic, beta-adrenergic, or adenosine stimulation. ### Claim 67 (depends on 65, 66) The method of claim 65 or 66, wherein the cardiac dysfunction is selected from the group consisting of: heart failure, bradycardia, tachycardia, and atrial fibrillation. ### Claim 68 (depends on 58, 59, 60, 61, 62, 63, 64, 65, 66, 67) The method of any one of claims 58-67, wherein the at least one tissue slice is obtained from a human donor heart rejected for transplantation or an explanted human heart. ### Claim 69 (depends on 68) The method of claim 68, wherein the heart is cardioplegically arrested following aortic cross-clamp. ### Claim 70 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69) The method of any one of claims 27-69, wherein the microfluidic device is interfaced with a second microfluidic device housing a plurality of microorganisms representing a human microbiome. ### Claim 71 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69) The method of any one of claims 27-69, wherein the microfluidic device comprises two or more tissue slices housed in two or more tissue culture chambers connected in series, in parallel, or any combination thereof. ### Claim 72 (depends on 71) The method of claim 71, wherein the two or more tissue slices are obtained from two or more organs. ### Claim 73 (depends on 72) The method of claim 72, wherein the two or more organs are different types of organs. ### Claim 74 (depends on 73) The method of claim 73, wherein the different types of organs are from the same donor. ### Claim 75 (depends on 73) The method of claim 73, wherein the different types of organs are from different donors. ### Claim 76 (depends on 72) The method of claim 72, wherein the two or more organs are the same type of organ obtained from different donors. ### Claim 77 (depends on 71, 72, 73, 74, 75, 76) The method of any one of claims 71-76, wherein the two or more tissue slices are cultured in two or more tissue culture chambers configured for interrogating organ interaction. ### Claim 78 (depends on 71, 72, 73, 74, 75, 76) The method of any one of claims 71-76, wherein the two or more tissue slices comprise a native tissue slice and an engineered tissue slice, and wherein the native tissue slice and the engineered tissue slice are cultured in tissue culture chambers configured for interrogating interaction between the native tissue slice and the engineered tissue slice. ### Claim 79 (depends on 71, 72, 73, 74, 75, 76) The method of any one of claims 71-76, wherein the two or more tissue slices are cultured in two or more tissue culture chambers connected in series to increase throughput of pre-clinical trials. ### Claim 80 (depends on 71, 72, 73, 74, 75, 76) The method of any one of claims 71-76, wherein the two or more tissue slices are cultured in two or more tissue culture chambers connected in parallel to test drugs at different concentrations. ### Claim 81 (depends on 71, 72, 73, 74, 75, 76) The method of any one of claims 71-76, wherein the two or more tissue slices in two or more tissue culture chambers are exposed to different environments. ### Claim 82 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81) The method of any one of claims 27-81, wherein the microfluidic device comprises a real time digital or analog instrumentation that provides readouts from the one or more sensors. ### Claim 83 (depends on 82) The method of claim 82, wherein the microfluidic device comprises a real time digital instrumentation and an analog instrumentation that provide readouts from the one or more sensors. ### Claim 84 (depends on 82, 83) The method of claim 82 or 83, further comprising the step of monitoring the physiological condition of at least one tissue slice based on readouts provided by the instrumentation. ### Claim 85 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84) The method of any one of claims 27-84, further comprising the step of treating at least one tissue slice with a therapeutic virus comprising a therapeutic gene product. ### Claim 86 (depends on 85) The method of claim 85, further comprising the step of treating the at least one tissue slice with an enzyme prior to treatment with the virus to improve transduction efficiency. ### Claim 87 (depends on 86) The method of claim 86, wherein the enzyme is collagenase or a trypsin. ### Claim 88 (depends on 85, 86, 87) The method of any one of claims 85-87, wherein the virus is delivered via multiple microinjections using microcapillary needles to achieve uniform and sufficient viral transduction of the tissue slice. ### Claim 89 (depends on 85, 86, 87, 88) The method of any one of claims 85-88, wherein the virus is selected from the group consisting of: adenovirus, lentivirus, and adeno-associated virus. ### Claim 90 (depends on 85, 86, 87, 88, 89) The method of any one of claims 85-89, wherein the virus has a tropism-modification and carries a cell type specific promoter for high efficiency, targeted gene delivery to different cell types in the tissue slices. ### Claim 91 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84) The method of any one of claims 27-84, further comprising the step of seeding cells on at least one tissue slice for studying cell therapy. ### Claim 92 (depends on 91) The method of claim 91, wherein the cells are mammalian or bacterial cells. ### Claim 93 (depends on 92) The method of claim 92, wherein the mammalian or bacterial cells are engineered cells. ### Claim 94 (depends on 93) The method of claim 93, wherein the mammalian cells are genetically transformed cells. ### Claim 95 (depends on 92) The method of claim 92, wherein the mammalian cells are cells derived from adult stem cells or embryonic stem cells. ### Claim 96 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84) The method of any one of claims 27-84, further comprising the step of performing a gene-editing technique on at least one tissue slice for targeted genome editing. ### Claim 97 (depends on 96) The method of claim 96, wherein the gene-editing technique is based on CRISPR/Cas or TALENS technology. ### Claim 98 (depends on 97) The method of claim 97, wherein the gene-editing technique is based on CRISPR/Cas9 technology. ### Claim 99 (depends on 96, 97, 98) The method of any one of claims 96-98, wherein the gene-editing technique is used to create one or more mutations at a locus identified by a genome-wide associated study (GWAS). ### Claim 100 (depends on 96, 97, 98) The method of any one of claims 96-98, wherein the gene-editing technique is used to correct one or more mutations at a locus. ### Claim 101 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84) The method of any one of claims 27-84, further comprising the step of evaluating the performance of an implantable bioelectronics device built into the tissue culture chamber. ### Claim 102 (depends on 101) The method of claim 101, wherein the implantable bioelectronics device is a soft, conformal device. ### Claim 103 (depends on 101, 102) The method of claim 101 or 102, wherein the implantable bioelectronics device is biodegradable. ### Claim 104 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84) The method of any one of claims 27-84, further comprising the steps of culturing the one or more tissue slices with biomaterial and evaluating the safety or efficacy of the biomaterial. ### Claim 105 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84) The method of any one of claims 27-84, further comprising the step of exposing the one or more tissue slices to one or more physical fields. ### Claim 106 (depends on 105) The method of claim 105, wherein the one or more physical fields are selected from the group consisting of: electrical radiation, magnetic radiation, alpha-radiation, beta-radiation, and gamma-radiation. ### Claim 107 (depends on 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84) The method of any one of claims 27-84, wherein a plurality of treatment and modalities are used to study synergistic cardiotoxicity of multiple pre-clinical drugs combined.