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Dynamic Nanofibrous Hydrogels for Enhancing Stem Cells' Therapeutic Potency

Award Number: R00GM151459
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Dynamic Nanofibrous Hydrogels for Enhancing Stem Cells' Therapeutic Potency - Project Summary/Abstract Human mesenchymal stem cells (hMSCs) are considered a source for allogeneic therapies to treat diverse diseases. Due to the exponential increase in demand, there is a need for new strategies to produce potent hMSCs to serve diverse patient populations. Currently, conventional planar culture and bioreactors are used as scale-up manufacturing methods. However, these are not specifically tailored for hMSCs expansion. They may alter the cell phenotype and secretome, affecting clinical effectiveness. Further studies to understand the role of substrate mechanics on hMSC expansion are required to achieve reproducible production. Numerous scaffolding alternatives replicate several characteristics of the native extracellular matrix (ECM). However, its dynamic mechanics, which plays a fundamental role in regulating crucial cellular processes, has not been amply studied yet. Furthermore, most in-vitro substrates are static and supraphysiologically stiff. Static substrates have offered a substantial benefit for generating high cell numbers; however, hMSCs have been shown to retain mechanical information, limiting therapeutic capabilities. To address this problem, this proposed research seeks to investigate the role of dynamic cell-matrix interactions and nano-topographical cues on the immunomodulatory potential of hMSCs using a composite of electrospun-fibers encapsulated in a dynamic hydrogel, with the hypothesis that this composite biomaterial will promote high hMSCs production with relevant therapeutic value, while eliminating the limitations reported for the conventional cell culture systems. The K99 period will focus on engineering and characterizing the dynamic nanofibrous hydrogel composites to propel me toward establishing the mechanisms by which they modulate cell quality and potency attributes with relevant therapeutic value (during the R00 phase). In Aim 1, we will develop the dynamic nanofibrous system using a hyaluronic acid hydrogel network crosslinked via dynamic covalent hydrazone bonds that capture the viscoelasticity of ECM in tissues. Four variables, including the encapsulation of the electrospun collagen nanofibers at various densities, fiber diameter, fiber length, and the stress relaxation timescale of the hydrogel will be characterized in this aim to promote hMSC viability and proliferation. In Aim 2, hMSCs cell quality and potency will be assessed by measuring the effect of hydrogel parameters on cellular secretory activity. Immunomodulatory properties will be evaluated by quantifying lymphocyte suppression in co-culture, as well as expression of hMSC surface markers. The capacity of the hMSCs to differentiate will also be assessed. In aim 3, the mechanism linking the biophysical parameters of the nanofibrous hydrogel to hMSC secretory activity will be probed by examining cell adhesive proteins and the activation of transcription factors or sensors of mechanical cues. In sum, the proposed research will lead to new insights to produce hMSCs with high therapeutic value, which will enable new culture substrates that achieve control in reproducibility and cell quality to serve diverse patient populations.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $248,999 )
2025	2025	UNIVERSITY OF MIAMI	1320 SOUTH DIXIE HIGHWAY STE 650	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Biomedical Research and Research Training	000	3	6/24/2025	EXTENSION WITH OR WITHOUT FUNDS	$248,999
														Subtotal = $248,999

Grand Total All Awards = $248,999

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Dynamic Nanofibrous Hydrogels for Enhancing Stem Cells' Therapeutic Potency

Award Number: R00GM151459

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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