Manchester BIOGEL
Physiologically Relevant 3d Tissue Models

Regardless of purpose or benefit, the usage of animals for clinical studies is cruel and unnecessary. This particular ethical issue raised by animal rights activists has led to, and rightly so, a search for alternative humane methods for clinical studies. Replacement (of animals), Reduction (of the number of animals), Refinement (of methods to alleviate pain and suffering of the animal used) - the Three R’s - in all areas has resulted in translational pharmaceutical research focusing on finding synthetic tissue models that can be used for drug discovery, tissue modeling and regenerative medicine. While it is true that animal models have played a vital role in developing a better understanding of diseases and therapy, limiting further usage of animals in research has found valid grounds among researchers. Differences in cell biology between animals and humans results in many late-stage drug failures because their toxicity is not discovered earlier, or they’re not effective in humans. Billions of pounds are at stake in testing new pharmaceutical or cosmetic compounds that rely on the cell culture of animal models. There is an approach that can eliminate this reliance.

One way to achieve this is by developing synthetic alternatives to animal-derived matrices. In 2005, a study published by Professor M.P. Lutolf of Stanford University and molecular engineer J.A. Hubbell under the topic “Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering” stated that a growing symbiosis between materials engineering and cell biology might ultimately result in synthetic materials that contain the necessary signals to recapitulate developmental processes in tissue- and organ-specific differentiation and morphogenesis.

Over the last decade, advancements in cell biology, tissue engineering, and microsystem technologies have paved the way in developing cell culture systems that better mimic the biological milieu of humans. Researchers in these fields have been able to bridge the gap between conventional cultures and complex native in vivo environments. Biomaterial systems like patterned glass substrates, elastomeric films, hydroxyapatite ceramics and fibrillar foams have been developed, but none have shown more promise than hydrogels. Based on over 40 years of combined research in hydrogels— water-swollen networks of polymers—in the University of Manchester, Professor Aline Miller and Professor Alberto Saiani established Manchester BIOGEL whose foundation in built on a platform technology that provides innovative peptide hydrogel materials that are redefining cell culture for life sciences. These hydrogels are made by combining Nature’s 20 amino acid building blocks into specific peptide sequences that spontaneously self-assemble to form fibrillar hydrogel networks that mimic both the structure and function of the cell’s natural extracellular matrix’s (ECM). “We provide reproducible and tunable scaffolds that replicate the three dimensional human physiological environments of all human tissues. This allows cells and organoids to grow in a more reproducible and reliable manner” says Aline.

3D Fibrillar Networks

Based on the core technology of self-assembling short-chain peptides into ß-sheet rich fibrillar hydrogels, Manchester BIOGEL has developed an innovative platform to manipulate the material properties and tailor them for specific applications. Interestingly, the ß-sheet rich fibre surface can be chemically functionalised with several biomimetic peptide sequences from essential ECM proteins like RGD (fibronectin), IKVAV (laminin), YIGSR (laminin) and GFOGER (collagen) allowing the hydrogels to contain (bio) chemical cues to control cell behaviour.

The journey to create these hydrogels started when Professors Miller and Saiani, tried to develop materials for applications using proteins. Since proteins are complex and unpredictable in how they behave, the duo decided to take short sections of the proteins, i.e. peptides, synthesise them, and control the molecule’s structure. They made use of Nature’s tool box and combined natural amino acids in specific ways to learn what combinations led to controlled self-assembly into ß-sheet fibres and also importantly, how those fibres came together to form three dimensional networks under physiological conditions.

Today, the highly modular hydrogels, PeptiGels®, can be tailored to match the properties of most in vivo tissues by modulating hydrogel mechanical strength (i.e. stiffness), (bio) chemical cues, functionality, and other components within the hydrogel system. The hydrogels are fully synthetic and are manufactured with no batch to batch variability, yet another reason to replace animal tissues as they lack consistency and reproducibility. Even when used on different assays, the consistency of Manchester BIOGEL’s hydrogels is that the results will be the same every time. This gives users the confidence to achieve reliable and consistent results, within the growing fields of 3D cell culture, tissue regeneration and drug discovery.

The hydrogels are also shear thinning which means they are injectible and sprayable. Consequently, they are finding application as bioinks for liquid handling systems and 3D bioprinting with any extrusion-based printer. Cells can be encapsulated and printed directly with structural definition and long-term viability and stability. Since these hydrogels are based solely on natural amino acids, they are biocompatible and cytocompatible hence have the potential to translate any lab research into the clinic to deliver life changing therapies.

A Boon for Life Sciences Professionals

Aline and Alberto realised they were able to control the structure and property-process relationship of the peptide materials while at the University of Manchester and that they could apply their materials to several life science and clinical applications. When they shared their progress in various conferences, cell biologists and clinicians requested to try the materials. The products were readily made available to them, and the duo helped them get started and adopt the technology.

The idea then grew from an academic endevour into a commercial venture, and they are now continuing to expand their work into new application areas through collaboration.

Currently, Manchester BIOGEL Ltd offers a family of peptide hydrogel products, PeptiGels® and PeptiInks®. Both have been used to support a range of application areas, such as organoids, stem cells, cancer, bioprinting, and regenerative medicine. One recent application that capitalizes on PeptiGel® tunability has just been published in the peer review journal Cancers. Here, the company utilised their hydrogel modularity and were able to match the differing stiffness and acidic conditions of healthy versus tumour tissue; in pancreatic ductal adenocarcinoma (PDAC), acidic fibrous tissue is present around the tumour which hampers drug delivery and impacts cancer cell survival and proliferation. The company was able to mimic independently the mechanical and chemical environment of both healthy and cancer tissue, and by working with Professor Armando del rio Hernandez at Imperial College London, they were able to see differences in the fundamental cell biological pathways in the different environments. Excitingly, this highlighted the need for stage-specific therapeutics and treatments in cancer patients. Being able to mimic the ECM for different types of healthy and/ or diseased tissues, opens up the opportunity for life science professionals to investigate and understand the differences in cellular pathways, enabling them to optimise their patientcentric care models.

The applicability of the technology is presented by Professor Miller and the team at key conferences around the world for the relevant application areas such as oncology, stem cells, regenerative medicine, or drug discovery. This, in turn, helps Manchester BIOGEL stay abreast with the latest technologies and the current challenges of the attendees in their respective life sciences fields. “We have our internal R&D capability, where we can test out the ideas and improve the application breadth of our technology, and we take that data to support the translation of our materials into the workflows of drug discovery CROs and larger Pharma industry,” says Professor Aline. “Importantly, we have the in house capability to troubleshoot any potential challenges or issues that our clients face.”

The focus has always been on supporting research in the field and working closely with customers, which has led to collaborative projects with several universities and companies. Manchester BIOGEL currently has 12 PhD CASE studentships across the U.K. and Ireland where the company tries out new materials applications. The U.K. government has awarded two Innovate Grants, enabling the company to continue working on cutting edge research and developing products to meet the demands of today’s customers. For her truly remarkable work in this field, Professor Miller is one of the finalists of the Great British Start-up Entrepreneur for the year 2021.

While the robust hydrogels are primarily used for research and development purposes, Manchester BIOGEL is striving hard to bag the ISO 9001 standardisation and inch closer towards the CE marking for European clinical trials. Besides, it is working on bolstering its PeptiKits, which extends to the already existing PeptiGels and Peptilinks. PeptiKits will offer a fully synthetic cell culture system including specific, synthetic growth factors and media to go along with the scaffolds for liver, kidney, cardiac cells, and others to allow for targeted organoid growth using fully animal free systems.