Cardiosphere-Derived Cell Sheet for Myocardial Regeneration
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Solution Overview
Problem
The therapeutic benefits of adult stem cells in patients with infarcted myocardia have been modest due to transient paracrine effects associated with low retention of injected stem cells, with only 1-2% of cells retained in the heart at 1-month post-injection.
Innovation Solution
A method of producing thin, flexible, and durable cell sheets containing secondary spheroids derived from cardiosphere-derived cells, which are cultivated in a specific media to promote extracellular matrix formation and extended paracrine secretion, and then wrapped around a balloon stent catheter for intracoronary delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adult stem cells are injected into the heart, then paracrine factors are secreted to promote cardiac regeneration, but cell retention is low (only 1-2% retained at 1-month post-injection)
Solution Approach 1:
The stem cell population is segmented into cardiosphere-derived cells that self-assemble into spheroidal structures. These segmented cellular aggregates are then further organized into sheet formations, creating a hierarchical structure that improves retention while maintaining paracrine functionality.
Solution Approach 2:
The invention employs a nested structure where cardiosphere-derived cells form secondary spheroids that are nested within a three-dimensional sheet architecture. This nested organization allows the cells to maintain their paracrine secretory function while being protected within the structured formation, thereby improving retention.
2Duration of action of moving object
If stem cells are injected to promote cardiac regeneration, then paracrine secretion occurs, but the effects are transient due to low cell retention
Solution Approach 1:
The invention uses excessive action by providing a much larger initial cell dose through the sheet formation (containing billions of cells) compared to conventional injection methods. This excessive cellular input ensures that even with natural washout, sufficient cells remain to maintain prolonged paracrine secretion and therapeutic effect.
Solution Approach 2:
The three-dimensional sheet formation creates a continuous source of paracrine secretion by maintaining a large population of viable stem cells in situ. The structured formation ensures continuous cell presence and function, preventing the transient effects seen with conventional injection methods.
3Quantity of substance
If large numbers of stem cells are injected to improve retention, then cell quantity increases, but delivery efficiency and uniform distribution become problematic
Solution Approach 1:
The stem cells are preliminarily organized into pre-formed three-dimensional sheet structures containing billions of cells before delivery. This preliminary organization into a compact, structured format enables efficient delivery through standard catheter-based interventions while ensuring uniform distribution and high retention upon implantation.
Solution Approach 2:
The invention transitions from conventional two-dimensional monolayer or suspension cell delivery to a three-dimensional sheet formation. This dimensional change allows billions of cells to be delivered as a single integrated structure, improving delivery efficiency while maintaining uniform cell distribution throughout the therapeutic site.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The cell sheet delivery method enhances cell retention and prolongs paracrine secretion, leading to improved cardiac regeneration, reduced scar volume, and increased myocyte proliferation, with significant functional improvements and scar reductions observed at 1-month post-implantation.
Implementation Method 1
CDCs secrete paracrine factors which reduce scar volume and myocyte apoptosis, increase myocyte proliferation, and activate endogenous cardiac stem cells into producing new myocytes
Implementation Method 2
culturing the secondary spheroids for a second period of time in a second media comprising at least one of the ascorbic acid and an analog thereof, wherein the at least one of the ascorbic acid and an analog thereof is present in an amount effective to promote a formation of an extracellular matrix
Data Source
AI summary
A method of making a cell sheet comprising secondary spheroids, including (a) obtaining cardiosphere-derived cells; (b) cultivating the cardiosphere-derived cells for a first period of time in a first media comprising at least one of an ascorbic acid and an analog thereof, to form secondary spheroids; (c) transferring an amount of the spheroids formed in step (b) into a mold; (d) culturing the secondary spheroids for a second period of time in a second media comprising at least one of the ascorbic acid and an analog thereof, wherein the at least one of the ascorbic acid and an analog thereof is present in an amount effective to promote a formation of an extracellular matrix; and (e) culturing a product obtained in step (d) for a third period of time, in the absence of the at least one of the ascorbic acid and an analog thereof.