Polymeric Cell Carriers with Sensitive Crosslinkers
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Solution Overview
Problem
The production of extracellular matrix by dense cells slows the digestion of porous gelatin microcarriers, leading to delayed cell disassociation, low cell recovery, and reduced cell viability, hindering their use in clinical applications.
Innovation Solution
Development of polymeric carriers crosslinked with redox sensitive, UV light sensitive, pH sensitive, or temperature sensitive moieties, such as disulfide bonds, photoreversibly dimerizable, or photocleavable groups, to facilitate controlled digestion and improve cell disassociation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If porous gelatin microcarriers are used as cell substrates, then cell attachment and proliferation are enhanced, but digestion time is delayed due to extracellular matrix production
Solution Approach 1:
The patent changes the chemical parameter of the crosslinker by incorporating sensitive moieties (redox, UV light, pH, or temperature sensitive) that allow the crosslinking bonds to be selectively broken under specific conditions. This enables controlled digestion of the microcarrier by adjusting environmental parameters without affecting cell proliferation during culture.
Solution Approach 2:
The patent makes the crosslinking structure dynamic and controllable. The crosslinkers remain stable during cell culture but can be dynamically deactivated by applying specific stimuli (reducing agents, UV light, pH change, or temperature change), allowing the microcarrier to transition from a stable support structure to a digestible form for cell recovery.
2Stability of the object's composition
If crosslinking is used to stabilize polymeric carriers, then structural integrity is improved, but digestion and cell disassociation are slowed
Solution Approach 1:
The patent uses crosslinkers with sensitive moieties that change their bonding properties in response to environmental parameters. During culture, the crosslinkers maintain structural integrity under normal conditions. For disassociation, specific parameters are changed (adding reducing agents, UV irradiation, pH adjustment, or temperature change) to break the crosslinks and enable rapid cell release.
Solution Approach 2:
The patent enables periodic functionality of the crosslinker - stable during the culture phase and labile during the recovery phase. The sensitive moieties allow the crosslinking to be reversibly controlled, permitting the carrier to alternately provide structural support and facilitate cell release at different time points in the process.
3Quantity of substance
If dense cell culture is performed on porous gelatin microcarriers, then cell density is increased, but complete digestion is delayed
Solution Approach 1:
The patent addresses the digestion delay caused by high cell density by using crosslinkers sensitive to external parameters. Instead of relying solely on proteolytic enzyme diffusion through the dense extracellular matrix, the crosslinking bonds can be broken by applying specific stimuli (reducing agents, UV light, pH change, or temperature change) that penetrate the matrix and directly cleave the crosslinks, enabling complete digestion even in dense cultures.
4Reliability
If prolonged digestion time occurs, then cell recovery is reduced, but complete carrier digestion is not achieved
Solution Approach 1:
The patent uses periodic action by applying controlled stimuli at specific time points. The sensitive crosslinkers remain intact during cell culture, then are selectively activated for digestion by applying the appropriate stimulus (reducing agent, UV light, pH change, or temperature change). This temporal control allows complete carrier digestion to be achieved rapidly without prolonged exposure that would harm cell viability.
Solution Approach 2:
The patent replaces the mechanical/enzymatic digestion process (which relies on proteolytic enzymes slowly degrading the gelatin matrix) with a chemical or physical activation mechanism. The sensitive moieties in the crosslinkers can be broken by reducing agents, UV light, pH change, or temperature change, providing a more efficient and controllable digestion mechanism that achieves complete carrier breakdown faster and with better cell recovery.
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 use of sensitive crosslinkers allows for faster and more controlled digestion of polymeric carriers, enhancing cell recovery and viability, and enabling more efficient cell collection and processing.
Implementation Method 1
the crosslinker includes the redox sensitive moiety, and the redox sensitive moiety includes a disulfide bond
Implementation Method 2
the crosslinker includes the UV light sensitive moiety, and the UV light sensitive moiety is a photoreversibly dimerizable moiety or a photocleavable moiety
Data Source
AI summary
Provided are methods of controlling disassociation of cells from a carrier, compositions, and methods of collecting cells. The methods of controlling disassociation of cells from a carrier may include contacting a polymeric carrier with one or more digesting agents to disassociate at least a portion of a plurality of cells from the polymeric carrier. The polymeric carrier may be crosslinked with a crosslinker including at least one of a redox sensitive moiety, a UV light sensitive moiety, a pH sensitive moiety, and a temperature sensitive moiety.