Hematopoietic Stem Cell Collection via Hypoxic Antioxidant Processing
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Solution Overview
Problem
Current hematopoietic stem cell transplantation (HCT) methods face challenges due to the limited availability of donor hematopoietic stem cells, which can compromise the success of the procedure, and existing collection methods often result in extraphysiologic oxygen shock/stress (EPHOSS) that leads to rapid differentiation of stem cells upon exposure to ambient air, reducing the number of hematopoietic stem cells (HSCs) collected.
Innovation Solution
The use of compositions and methods involving antioxidants such as N-acetyl-cysteine (NAC) and ascorbic acid 2-phosphate (AAP), and epigenetic inhibitors like Aurora kinase and DNA methyltransferase inhibitors, in combination with chilled conditions, to enhance the collection and processing of bone marrow, umbilical cord blood, and peripheral blood, thereby mimicking hypoxic conditions and reducing differentiation of HSCs to hematopoietic progenitor cells (HPCs).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If hematopoietic stem cells are collected using conventional methods, then the collection process is simple, but the number of HSCs collected is reduced due to rapid differentiation into progenitor cells upon exposure to ambient air
Solution Approach 1:
The patent applies the inert atmosphere principle by collecting and processing hematopoietic stem cells in a hypoxic environment (1-5% oxygen concentration) rather than ambient air. This hypoxic condition mimics the physiological environment of HSCs in vivo, preventing extraphysiologic oxygen shock/stress and the subsequent rapid differentiation into progenitor cells, thereby significantly increasing the number of HSCs recovered from bone marrow, cord blood, or peripheral blood sources.
Solution Approach 2:
The patent changes the oxygen concentration parameter from ambient levels (21%) to hypoxic levels (1-5%) during cell collection and processing. This parameter change fundamentally alters the cellular response, preventing oxidative stress and differentiation pathways that would otherwise be activated by high oxygen exposure, thus preserving HSC quantity and quality.
2Quantity of substance
If antioxidants are added to prevent oxidative stress, then HSC differentiation is reduced, but the composition complexity increases
Solution Approach 1:
The patent converts the harmful effect of oxygen exposure (which causes oxidative stress and differentiation) into a beneficial outcome by introducing antioxidants. Specifically, compounds like N-acetyl-cysteine (NAC) and ascorbic acid 2-phosphate (AAP) are added to scavenge reactive oxygen species generated during cell collection and processing, thereby preventing HSC differentiation while utilizing the unavoidable presence of oxygen in practical collection scenarios.
3Reliability
If HCT is performed to treat conditions associated with insufficient HSCs, then therapeutic effect is improved, but complications such as infections and graft-versus-host diseases increase
Solution Approach 1:
The patent applies preliminary action by performing hypoxic collection and antioxidant treatment before transplantation to pre-condition the HSCs in a way that enhances their survival and engraftment potential. By collecting cells under optimized hypoxic conditions and treating them with antioxidants prior to infusion, the method prepares the cells to better withstand the stresses of transplantation, thereby improving engraftment success and reducing complications without requiring more complex post-transplantation interventions.
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
This approach significantly increases the number of HSCs collected and retained, improving the efficacy of HCT by maintaining more stem cells and reducing the number of progenitor cells, facilitating better engraftment and therapeutic outcomes.
Implementation Method 1
compositions disclosed herein include a portion of bone marrow, umbilical cord blood, and/or peripheral blood of a subject; a first antioxidant; and a second antioxidant... the first antioxidant and the second antioxidant are independently selected from thiols, vitamin A, vitamin C, vitamin E, uric acids, melatonin, glutathione, n-acetyl-cysteine (NAC), and/or ascorbic acid 2-phosphate (AAP)
Implementation Method 2
the composition can be placed and/or maintained at a temperature from about 1° C. to about 5° C. or from about 18° C. to about 24° C.
Implementation Method 3
the compositions can be placed and/or maintained in ambient air (comprising from about 20% to about 21% O2) or in hypoxia (comprising from about 2.5% to about 3.5% O2)
Data Source
AI summary
Various aspects and embodiments disclosed herein relate generally to the modelling, treatment, reducing resistance to the treatment, prevention, and diagnosis of a condition/disease associated with insufficient quantity and/or quality of hematopoietic stem cells (HSCs) and differentiated blood cells thereof. Embodiments include compositions and methods for treating the condition/disease, comprising the step of providing to a subject at least one therapeutically effective dose of a composition disclosed herein. Other embodiments include methods for generating and/or collecting hematopoietic stem cells from a subject.