Over the past 40 years nearly 45% of drugs withdrawn from the market have been due to cardiac safetyconcerns, contributing to the ever increasing cost and declining productivity of the biopharma R&D process.While the mechanisms of drug-induced cardiotoxicity vary widely by drug and target, the most common anddangerous manifestation is cardiac arrhythmia and sudden cardiac death. The biopharma industry has heavilyinvested in new tools that are sensitive to cardiotoxic effects, however, current preclinical models are acompromise in the structural, compositional, and functional complexity necessary to recapitulate and bepredictive of human cardiac electrophysiology. Further, understanding how patient-specific risk factors includinggenetic predisposition, age, sex, and underlying cardiovascular disease (e.g. fibrosis, ischemia, infarction)contribute to a drug-induced proarrhythmogenic state requires the development of entirely new in vitro modelsof impulse conduction disorders. In this proposal our objective is to develop a new bioengineered human ventricleas a predictive in vitro model for identifying drug-induced proarrhythmogenic risks in the human heart. Toovercome current limitations, FluidForm, Inc in collaboration with Carnegie Mellon University will develop a newfreeform reversible embedding of suspended hydrogels (FRESH) 3D bioprinted left ventricle model thatrecreates the laminar architecture of ventricular myocardium and has tailored structure and composition to mimicproarrhythmogenic disease states. Our preliminary data establishes that we can build a functional ventricle withcircumferential myofiber alignment, anisotropic action potential propagation, distinct arrhythmia featuresincluding rotors and multiple propagating waves, and complex biomechanical responses including wallthickening. Here we will improve ventricle performance for use in the biopharma R&D process via two researchaims. First, we will establish baseline sensitivity of the FRESH 3D bioprinted human ventricle model to knownproarrhythmogenic compounds and generate industry-standard does-response curves. Second, we willdemonstrate tunable sensitivity by controlling cardiomyocyte and collagen architecture to mimic fibrotic diseaseand incorporate iPS-derived human cardiomyocytes with known conduction mutations. This will allow us toachieve patient-specific disease models that show dose-response curves that are left-shifted forproarrhythmogenic compounds. Phase I proof-of-concept success will provide a strong foundation for a PhaseII SBIR project that will validate the complete FRESH 3D printed ventricle model in an in vitro high-contentimaging platform to assess electrophysiology and biological response, and provide a critically needed, industry-leading capability to accurately predict human arrhythmias in drug development.
Public Health Relevance Statement: Over the past 40 years nearly 45% of drugs withdrawn from the market have been due to negative effects on
the heart, contributing to the ever increasing cost and declining productivity of the biopharma R&D process.
While the mechanisms of drug-induced heart injury vary, the most common and dangerous manifestation is
cardiac arrhythmia with the most serious outcome being sudden cardiac death. Here we propose to develop a
bioengineered human ventricle as a predictive in vitro model for identifying drug-induced proarrhythmogenic
risks in the human heart. To overcome current limitations, FluidForm, Inc. and CMU will leverage our FRESH 3D
bioprinting technology to recreate the architecture of ventricular heart muscle and tailor structure and
composition to mimic patient-specific proarrhythmogenic disease states.
Project Terms: Action Potentials ; Adoption ; Adult ; 21+ years old ; Adult Human ; adulthood ; Age ; ages ; Architecture ; Engineering / Architecture ; Arrhythmia ; Cardiac Arrhythmia ; Heart Arrhythmias ; Back ; Dorsum ; Biomechanics ; biomechanical ; Biomedical Engineering ; bio-engineered ; bio-engineers ; bioengineering ; Calcium ; Cardiovascular Diseases ; cardiovascular disorder ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Cells ; Cell Body ; Collagen ; Contractile Proteins ; Dangerousness ; Disease ; Disorder ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Electrophysiology (science) ; Electrophysiology ; Neurophysiology / Electrophysiology ; electrophysiological ; Extracellular Matrix ; Cell-Extracellular Matrix ; ECM ; Fibrosis ; Foundations ; Heart ; Heart Injuries ; cardiac injury ; Heart Ventricle ; Cardiac Ventricles ; Human ; Modern Man ; In Vitro ; Industry ; Infarction ; infarct ; Ion Channel ; Ionic Channels ; Membrane Channels ; Ischemia ; Mutation ; Genetic Alteration ; Genetic Change ; Genetic defect ; genome mutation ; Myocardium ; cardiac muscle ; heart muscle ; Optics ; optical ; Organoids ; Patients ; Drug Prescriptions ; Drug Prescribing ; medication prescription ; prescribed medication ; Productivity ; Oryctolagus cuniculus ; Domestic Rabbit ; Rabbits ; Rabbits Mammals ; Research ; research and development ; Development and Research ; R & D ; R&D ; Risk ; Risk Factors ; Safety ; Science ; Family suidae ; Pigs ; Suidae ; Swine ; porcine ; suid ; Technology ; Testing ; Tissues ; Body Tissues ; Translating ; Universities ; Work ; sudden cardiac death ; base ; Organ ; improved ; Left ; Phase ; Biological ; Link ; Evaluation ; Cardiac Myocytes ; Cardiac Muscle Cells ; Cardiocyte ; Heart Muscle Cells ; Heart myocyte ; cardiomyocyte ; Left ventricular structure ; Left Ventricles ; heart rhythm ; cardiac rhythm ; drug sensitivity ; Collaborations ; Letters ; Intellectual Property ; Genetic Predisposition ; Genetic Susceptibility ; Inherited Predisposition ; Inherited Susceptibility ; genetic etiology ; genetic mechanism of disease ; genetic vulnerability ; genetically predisposed ; Genetic Predisposition to Disease ; tool ; Complex ; Treatment Period ; treatment days ; treatment duration ; Pattern ; System ; 3-D ; 3D ; three dimensional ; 3-Dimensional ; bioengineered tissue ; engineered tissue ; Tissue Engineering ; Performance ; success ; voltage ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Hydrogels ; Structure ; disorder model ; Disease model ; Modeling ; Property ; response ; drug development ; Cardiac Toxicity ; Cardiotoxic ; Cardiotoxicity ; Cardiac Electrophysiological Diagnostics ; cardiac electrophysiology ; Cardiac Electrophysiologic Techniques ; Dose ; Data ; Preclinical Models ; Pre-Clinical Model ; in vitro Model ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Process ; sex ; Ventricular ; Cardiac ; Development ; developmental ; cost ; three-dimensional modeling ; 3-D modeling ; 3D modeling ; next generation ; Outcome ; innovation ; innovate ; innovative ; drug testing ; drug detection ; induced pluripotent stem cell ; iPS ; iPSC ; iPSCs ; commercialization ; manufacturing scale-up ; Drug Targeting ; 3D Print ; 3-D print ; 3-D printer ; 3D printer ; 3D printing ; three dimensional printing ; Geometry ; differential expression ; differentially expressed ; transcriptional differences ; imaging platform ; Industry Standard ; bioprinting ; bio-printing ; phase 1 testing ; phase 1 evaluation ; phase I evaluation ; phase I testing ;
