Cellular Compositions for Graft Tolerance via Deceased Donor Harvesting
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Solution Overview
Problem
Current methods for establishing mixed chimerism in organ transplant recipients rely heavily on living donors, who face significant risks and are often reluctant to donate due to the invasive procedures required, while deceased donors pose challenges in obtaining viable hematopoietic stem cells and T cells efficiently.
Innovation Solution
Development of new manufacturing processes and techniques for producing engineered hematopoietic cellular products from deceased donors, including new blood collection apparatuses, ex vivo extraction methods, and processing techniques to isolate CD34+ cells from bone marrow and CD3+ cells from non-bone marrow sources, optimizing yield and preserving cell functionality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If HSPCs are collected from living donors by surgical extraction, then sufficient quantity of HSPCs can be obtained, but the donor faces risks of infection, nerve and muscle damage, and requires general anesthesia
Solution Approach 1:
The patent extracts HSPCs from the bone marrow environment using mobilization agents that cause HSPCs to migrate from the bone marrow niche into the peripheral blood, where they can be collected by apheresis. This extraction approach avoids surgical bone marrow aspiration while still obtaining sufficient HSPC quantities.
Solution Approach 2:
The patent uses mobilization agents (such as G-CSF or other pharmacological agents) as intermediaries to facilitate the movement of HSPCs from bone marrow to peripheral blood. These agents mediate the transition of HSPCs to a collectible state without requiring surgical intervention or exposing the donor to surgical risks.
2Ease of operation
If apheresis is used to collect HSPCs from peripheral blood, then non-surgical collection is achieved, but the process takes up to six hours and may need to be repeated for several days
Solution Approach 1:
The patent applies preliminary action by administering mobilization agents to the donor before apheresis to pre-concentrate HSPCs in the peripheral blood. This preliminary mobilization step increases the HSPC density in blood, thereby reducing the apheresis duration and the number of collection sessions required.
3Ease of operation
If HSPCs are mobilized from bone marrow into blood using pharmacological agents, then non-surgical collection is enabled, but the donor receives no medical benefit and many are unwilling to donate
Solution Approach 1:
The patent makes the deceased donor's body serve multiple functions: the bone marrow and blood are harvested for HSPC and T cell collection, and any remaining tissues are donated for organ transplantation or other therapeutic uses. This multi-functional utilization of the deceased donor increases overall donation value and societal benefit.
4Quantity of substance
If deceased donors are used as source of HSPCs and T cells, then supply limitations of living donors are overcome, but challenges exist in obtaining viable cells efficiently
Solution Approach 1:
The patent segments the harvesting process into distinct components: HSPCs are extracted from bone marrow using one set of techniques (trephination, mobilization), while T cells are collected from blood using apheresis. This segmentation allows optimization of each cell type's collection method independently, improving overall efficiency and viability.
Solution Approach 2:
The patent applies preliminary action by pre-treating the deceased donor's body with mobilization agents before death or during the early post-mortem period to ensure HSPCs are mobilized into the blood and bone marrow is primed for efficient extraction. This preliminary preparation maximizes cell viability and yield when harvesting begins.
Data Source
AI summary
The invention provides cellular compositions that contain CD34+ cells derived from bone marrow of a decease donor and CD3+ cells derived from non-bone marrow of the deceased donor. The compositions are useful to promote mixed chimerism in recipients of solid organ transplants. The invention also provides methods of making and using such compositions. In certain embodiments, the invention further provides methods of analyzing and preparing blood and blood components from a deceased donor for use in compositions of the invention to promote mixed chimerism in solid organ transplant recipients.