A publication in Chemical Science

Groundbreaking flow production of biodegradable and biocompatible polymers for medical applications



Researchers from ULiège CiTOS have developed a low-footprint continuous flow process for the expedient production of challenging cyclic phosphate monomers (CPMs). The latter were successfully utilized for the preparation of unique biodegradable and biocompatible polyphosphoesters (PPEs), by a team from CERM. Their low toxicity was studied and confirmed at the University of Maastricht. The multidisciplinary research effort falls under the umbrella of an Interreg V-A Euregio Meuse-Rhine (EMR) program (IN FLOW). This work is now just accepted in Chemical Science.

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ynthetic polyphosphoesters (PPEs) are a class of organophosphorus polymers that have recently gained a renewed interest from the scientific community for potential biomedical applications (drug delivery systems and tissue engineering). PPEs are particularly appealing due to their tunable (bio)degradability and biocompatibility properties. However, commercial applications for PPEs have not emerged yet because of the cumbersome, inefficient, and hazardous production schemes toward their constitutive phosphate monomers. 

In order to propose concrete solutions for increasing the availability of CPMs, and therefore their corresponding PPEs polymers, to the scientific community, a multidisciplinary consortium bringing the areas of expertise of ULiège researchers from the CiTOS - Center for Integrated Technology and Organic Synthesis (MolSys Research Unit, Faculty of Science) and CERM - Center for Education and Research on Macromolecules (CESAM Research Unit, Faculty of Sciences) laboratories and from the University of Maastricht was established. Researchers at CiTOS, led by Jean-Christophe Monbaliu, with a longstanding reputation in the field of continuous flow manufacturing, have developed a miniaturized continuous flow production unit for accessing cyclic phosphate monomers. “The process allows to generate a variety of phosphate monomers in a record time and productivity, while alleviating the safety and quality concerns encountered in traditional batch procedures explains Jean-Christophe Monbaliu. Such accomplishment relies on the assets of continuous flow process technology with the concatenation of problematic steps and the accurate control of process conditions, hence providing extremely short reaction times and high productivities.” The process was designed to feed upon widely available and cheap resources, to maximize atom economy and sustainability.

The process devised at CiTOS produces high purity CPMs in less than 2 minutes. “Despite a very low footprint for the flow platform prototype the size of a regular chocolate box, impressive productivities of up to half a kilogram per day are accessible”, comments Romain Morodo, first author of the study and PhD researcher affiliated with CiTOS. “Besides, a large diversity of structures is also accessible, thus potentially feeding upstream the process of discovery for new molecular architectures”. The process was also further developed in a pilot continuous flow platform, achieving daily productivities of up to 2 kg.  

production continue polymeres

Integrated continuous flow production of cyclic phosphate monomers

The freshly produced monomers are then directly used in another module of the flow platform, enabling the preparation of novel PPEs with an enhanced precision and reproducibility” continues Jean-Christophe Monbaliu. Cytotoxicity assays confirm their viability for biomedical applications. Thermal properties are also evaluated for other PPEs, highlighting their potential use for novel flame-retardant materials. The development of such integrated and intensified continuous flow platform to produce both CPMs and their corresponding polymers opens new avenues toward the commercialization of novel PPE-based materials.

Research program IN FLOW was supported by the Interreg V-A Euregio Meuse-Rhine (EMR) program. IN FLOW, led by Prof. Christine Jérôme (CERM), was granted a € 2.1 M total budget from the European Regional Development Fund (ERDF). With the investment of EU funds in Interreg projects, the European Union directly invests in the economic development, innovation, territorial development, social inclusion and education in the Euregio Meuse-Rhine. 

Scientific reference

  1. Morodo, R. Riva, N. M. S. van den Akker, D. G. Molin, C. Jérôme and J.-C. M. Monbaliu, Accelerating the End-to-end Production of Cyclic Phosphate Monomers with Modular Flow Chemistry, Chem. Sci. 2022, 13, 10699-10706, https://doi.org/10.1039/D2SC02891C

Chemical Science is the Royal Society of Chemistry’s peer-reviewed flagship journal. The article has been highlighted as one the most impactful advancements in 2022 (2022 Chemical Science HOT Article Collection) and as a ChemSci Pick of the Week. Available online in open access.

Funding

Interreg V-A Euregio Meuse-Rhine (EMR) program (IN FLOW)

Contact

Romain Morodo

Raphaël Riva

Christine Jérôme

Jean-Christophe Monbaliu


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