Journal article
Force-Bioreactor for Assessing Pharmacological Therapies for Mechanobiological Targets
Frontiers in bioengineering and biotechnology, Vol.10, 907611
07/01/2022
DOI: 10.3389/fbioe.2022.907611
PMCID: PMC9343955
PMID: 35928948
Abstract
Tissue fibrosis is a major health issue that impacts millions of people and is costly to treat. However, few effective anti-fibrotic treatments are available. Due to their central role in fibrotic tissue deposition, fibroblasts and myofibroblasts are the target of many therapeutic strategies centered primarily on either inducing apoptosis or blocking mechanical or biochemical stimulation that leads to excessive collagen production. Part of the development of these drugs for clinical use involves in vitro prescreening. 2D screens, however, are not ideal for discovering mechanobiologically significant compounds that impact functions like force generation and other cell activities related to tissue remodeling that are highly dependent on the conditions of the microenvironment. Thus, higher fidelity models are needed to better simulate in vivo conditions and relate drug activity to quantifiable functional outcomes. To provide guidance on effective drug dosing strategies for mechanoresponsive drugs, we describe a custom force-bioreactor that uses a fibroblast-seeded fibrin gels as a relatively simple mimic of the provisional matrix of a healing wound. As cells generate traction forces, the volume of the gel reduces, and a calibrated and embedded Nitinol wire deflects in proportion to the generated forces over the course of 6 days while overhead images of the gel are acquired hourly. This system is a useful in vitro tool for quantifying myofibroblast dose-dependent responses to candidate biomolecules, such as blebbistatin. Administration of 50 μM blebbistatin reliably reduced fibroblast force generation approximately 40% and lasted at least 40 h, which in turn resulted in qualitatively less collagen production as determined via fluorescent labeling of collagen.
Details
- Title: Subtitle
- Force-Bioreactor for Assessing Pharmacological Therapies for Mechanobiological Targets
- Creators
- Austin J. Scholp - Roy J. and Lucille A. Carver College of MedicineJordan Jensen - University of IowaSathivel Chinnathambi - University of IowaKeerthi Atluri - Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, United StatesAlyssa Mendenhall - University of IowaTimothy Fowler - University of IowaAliasger K. Salem - University of IowaJames A. Martin - University of IowaEdward A. Sander - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Frontiers in bioengineering and biotechnology, Vol.10, 907611
- DOI
- 10.3389/fbioe.2022.907611
- PMID
- 35928948
- PMCID
- PMC9343955
- NLM abbreviation
- Front Bioeng Biotechnol
- ISSN
- 2296-4185
- Publisher
- Frontiers Media S.A
- Grant note
- DOI: 10.13039/100000069, name: National Institute of Arthritis and Musculoskeletal and Skin Diseases, award: AR075137
- Language
- English
- Date published
- 07/01/2022
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Pharmaceutical Sciences and Experimental Therapeutics; Orthopedics and Rehabilitation; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering
- Record Identifier
- 9984277455102771
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