3D Nerve Spheroid System for High-Throughput Analgesic Screening
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Solution Overview
Problem
Current preclinical drug screening models for chronic pain management are inadequate, with conventional methods failing to identify safe and effective analgesics due to toxicity and inefficiencies, and there is a need for more physiologically relevant and high-throughput models that mimic in vivo pain processing.
Innovation Solution
A three-dimensional microphysiological system comprising spheroids of dorsal root ganglia and spinal cord cells with functional afferent nerve fibers, allowing for unidirectional synaptic communication and enabling the modulation of glutamatergic neurotransmission and calcium influx, which can be used to screen novel analgesics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional preclinical drug screening models are used, then existing methodology can be maintained, but the models fail to identify safe and effective analgesics due to toxicity and inefficiencies
Solution Approach 1:
The patent creates a simplified copy of the in vivo pain processing system using microphysiological spheroid cultures that replicate the essential neural circuitry (dorsal root ganglion neurons, spinal cord neurons, and afferent fibers) in a controlled in vitro environment. This copying allows for high-throughput drug screening while maintaining physiological relevance, resolving the contradiction between predictive accuracy and research efficiency.
Solution Approach 2:
The patent segments the complex in vivo pain processing system into discrete, isolatable spheroid cultures containing specific neural populations (DRG neurons, spinal cord neurons, and afferent fibers). This segmentation enables independent manipulation and high-throughput screening while preserving the essential functional relationships, thereby improving both predictive accuracy and productivity.
2Reliability
If in vivo experimentation is used to obtain functional data, then physiologically relevant data is obtained, but throughput is low and experimental control is limited
Solution Approach 1:
The patent creates a simplified copy of the in vivo pain processing system using microphysiological spheroid cultures that replicate the essential neural circuitry (dorsal root ganglion neurons, spinal cord neurons, and afferent fibers) in a controlled in vitro environment. This copying allows for high-throughput drug screening while maintaining physiological relevance, resolving the contradiction between predictive accuracy and research efficiency.
Solution Approach 2:
The patent transitions from three-dimensional in vivo tissue to controlled three-dimensional spheroid cultures in vitro, creating a new dimensional framework that combines the physiological complexity of in vivo systems with the controllability and throughput of in vitro systems. The spheroid geometry enables standardized high-throughput processing while maintaining neural circuit functionality.
3Reliability
If human pluripotent stem cell-derived cell types are used, then interspecies differences are eliminated, but model complexity increases
Solution Approach 1:
The patent segments the complex in vivo pain processing system into discrete, isolatable spheroid cultures containing specific neural populations (DRG neurons, spinal cord neurons, and afferent fibers). This segmentation enables independent manipulation and high-throughput screening while preserving the essential functional relationships, thereby improving both predictive accuracy and productivity.
Solution Approach 2:
The patent uses a partial approach by including only the essential neural populations required for pain processing (DRG neurons, spinal cord neurons, and afferent fibers) rather than attempting to replicate the entire nervous system. This partial model achieves sufficient translational relevance while minimizing complexity, allowing for effective drug screening.
Data Source
AI summary
The disclosure relates to a system and method of using the system to detect and monitor afferent synaptic nerve fiber function in vitro. The disclosure also relates to a method of screening for test agents or compounds that modulate nerve function, such as test agents that modulate pain sensation in a human subject, by exposing one or a plurality of test agents to systems comprising a first and second spheroid, wherein the first spheroid comprise cells from a mammalian dorsal root ganglia and the second spheroid comprises cells from a mammalian spinal cord.