# Designing cell-instructive hydrogels to understand and exploit mechanobiology

> **NIH NIH R35** · UNIVERSITY OF VIRGINIA · 2020 · $368,327

## Abstract

ABSTRACT
Anchorage-dependent cells sense the mechanics of their surroundings by pulling and pushing on the
extracellular matrix (ECM), and in response, generate intracellular signals in a process known as
mechanotransduction. Matrix mechanical properties regulate a range of cell behaviors such as traction force
generation, cytoskeletal organization, proliferation, migration, and differentiation, necessitating the
development of in vitro model systems to investigate and understand these cellular phenomena. My lab is at
the forefront of designing hydrogels as in vitro models that move away from static, monolithic constructs and
toward dynamic, interactive, and responsive materials that capture the complexity of native cellular milieus.
The proposed research program will address a critical bottleneck in the field of understanding and exploiting
mechanistic knowledge of cellular mechanotransduction toward addressing health challenges in disease and
tissue regeneration. Theme 1: How Do Time-Dependent Mechanics Affect Cellular
Mechanotransduction? While nearly all synthetic biomaterials present an elastic mechanical environment to
cells, most natural ECM materials are viscoelastic and exhibit complex time-dependent mechanical behavior.
There is still an unmet need for cell culture platforms that permit the design flexibility of synthetic materials
(e.g., spatiotemporal tuning of ligand presentation and stiffness) while also displaying viscoelastic mechanical
properties. This research theme will build on burgeoning efforts from my group to develop viscoelastic
hydrogels in order to test the hypothesis that in 3D cultures viscoelasticity, not stiffness-based signaling, is the
overriding factor required for active mechanotransduction in fibroblast activation and mesenchymal stromal cell
(MSC) differentiation. Theme 2: How Do Mechanics Regulate Growth Factor Signal Transduction? While
recent integral studies have explored the influence of stiffness, ligand presentation, and degradation on stem
cell proliferation and differentiation, little is known about how these properties contribute to transforming growth
factor-β (TGF-β) signal transduction. By investigating the combined influence of substrate biophysical and
biochemical properties, this theme will elucidate design rules for how cellular microenvironments influence the
mechanobiology of growth factor signal transduction, thus providing a framework for the design of biomaterials
that permit more efficient presentation of growth factors. Theme 3: Can We Engineer Thermoresponsive
Biomaterials for Stem Cell Maintenance and Expansion? The ability to efficiently generate large numbers
of specific, well-defined cell types is critical to the treatment of numerous diseases and disorders. This theme
will focus on the creation of thermoresponsive tunable biomaterials to optimize the expansion, maintenance,
and mechanical priming of MSCs, while also enabling facile cell harvesting and validation. Multiple levels o...

## Key facts

- **NIH application ID:** 10029307
- **Project number:** 1R35GM138187-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Steven Caliari
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,327
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029307

## Citation

> US National Institutes of Health, RePORTER application 10029307, Designing cell-instructive hydrogels to understand and exploit mechanobiology (1R35GM138187-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10029307. Licensed CC0.

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