PP054 Simultaneous rapid preclinical therapeutic evaluation in a novel ex vivo bioreactor

ESMO Open

article

S. Bollenbecker¹  Z. Patel¹  Z. Punjani¹  A. Charania¹  H. Patel¹  M. Saleh¹  K. Budhwani¹ 

[1]Translational Research, CerFlux, Inc.

[2]Medicine, University of Alabama at Birmingham

关键词: Bioreactor;    Therapeutics;    Screening;   

DOI  :  10.1016/j.esmoop.2022.100729

学科分类：社会科学、人文和艺术（综合）

来源: BMJ Publishing Group

【 摘 要 】

Background: Although advances in high-throughput screening, combinatorial chemistry, databanks, and computational models have become more prevalent in recentyears, drug research and development remain capital and time-intensive. Expertsestimate that pharma spends $34.4 billion annually on preclinical research but 90% ofdrugs effective in pre-human studies fail in human trials. One explanation for thisdichotomy is that assays and methods for evaluating efficacy of novel treatmentsduring preclinical evaluation are simply inadequate. Static culture dishes fail torecapitulate the in vivo microenvironment, making cells far from physiologicallyrelevant. Animal models are limited indicators of success in subsequent human trials.Predicting which preclinical formulations will most likely succeed in clinical trials, bymatching them against patient biopsy specimens, could reduce cost and time-tomarket of new therapeutics.Methods: Soft lithography with SU-8 photoresist and polydimethylsiloxane (PDMS)was used to fabricate microporous thin membranes with uniform porosity. Electrospinning with collagen and Nylon was used to fabricate nanofibrous membranes withwell-interconnected, non-woven, nonuniform porosity. Multicellular biomimetichealthy and tumorous microtissue was cultured with pancreatic and colorectal celllines. Permeability assays were used to validate barrier and transport functions,scanning electron microscopy was used to validate morphology, and fluorescent andconfocal microscopy were used to observe migration, invasion, and metastasis.Results: Permeability assay confirmed transport and barrier functions wherein smallmolecules (10 kDa) diffused while larger molecules (500 kDa) were prevented fromflowing. Migration and invasion were observed when microfluidic circuits connectedto S2VP10-Luc ‘tumorous’ tissue upstream from ‘healthy’ vascular and muscle tissue.Moreover, subpopulations of invasive cells showed a more aggressive proliferationprofile compared to subpopulations of the same cell-line cancer cells that remained atthe original ‘tumorous’ site.Conclusions: Microfluidic ex vivo tissue models have the potential to transform disease treatment methods from bench to bedside by serving as a predictive personalized companion to guide treatment strategy and for narrowing down available leadand backup candidates along the drug discovery to market roadmap for novel therapeutic agents. Our model serves as a novel technique for rapid and comprehensivepharmacological testing that could dramatically alter patient outcomes during themost crucial time of their disease progression.

【 授权许可】

CC BY|CC BY-NC-ND