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** This article is open for review in the form of discussion / comments / suggestions. Feel free to participate in the comment section below **

We are in the midst of a renewed scientific interest for the large family of glycoprotein polymers that encompasses secreted mucins. Mucins are more attractive than ever as a study subject thanks to several recent exciting developments. The number of mucin-related publications has started to rise more sharply since the mid 2000s, with already over 1,800 articles published this year (see Figure 1).

Figure 1. Yearly number of publication related to mucins as reported by scicurve.com, using the keyword “mucins”.

This is because mucin research spans over many fields. Biologists have been intrigued by mucins since long. But more recently, microbiologists studying our microbiome have new reasons to find this class of biopolymers particularly exciting. For instance, they realized that intestinal mucus plays key roles in the behavior of both pathogenic and commensal bacteria. This will surely lead to many more microbiology studies with mucus/mucins as a key component (1,2). Similarly, recent findings in immunology describing interactions between dendritic cells and mucin-associated glycans will also attract attention to secreted mucins in that field (3).

Some physicists and biophysicists are also fascinated by mucins. Tribologists are trying to understand and recreate mucin’s efficient lubricity that is so precious for a healthy mouth and gastrointestinal tract (4,5). The field of oral drug delivery has been struggling with mucus and mucins for decade, now developing new methods to pass through- or to stick to- the mucus layer covering our gastrointestinal tract and deliver fragile and complex therapeutic proteins such as growth factors and antibodies (6). And finally, our group and others, are now looking at mucins as fascinating materials with potential high-value applications (7-10). Of course these are only a few examples, amongst tens of other scientific fields that rely on mucins to understand complex biological or physical systems.

 

Poor mucin quality halters mucin research.

Unfortunately, the poor quality of commercial mucins is a known fact. Harsh purification processes leave the mucins with altered physical and chemical properties. This has been well documented in several studies (5,11-13). In particular, the rheological properties of commercial mucin solutions were demonstrated to be very different from those obtained when purifying the mucins without the use of proteases or solvent precipitation. The presence of large quantities of impurities in these commercial preparations is also a known fact and clearly stated by the producers (product labeled as “partially purified”).

Figure 2. Rheological properties of native mucus and commercially-available mucin solution. The native mucus (5% mucin) is a gel, as suggested by the higher storage modulus than loss modulus. Commercially available mucins, even at high concentration do not show gel-like behaviors. This is probably do to a lack of mucin-mucin interactions. Data extracted from (11) using WebPlotDigitizer.

Unfortunately, regardless of the poor quality of commercially-available mucins, many research groups routinely use these mucins as a proxy to native mucins. This is understandable. Opting for commercial available pig gastric or bovine submaxillary mucins, two common model for human mucins, seems much more cost effective than setting up a purification pipeline in the lab. In-lab purification requires access to animal tissues, equipment, and specialized know-how. On the other hand, poor quality mucins will inevitably affect the quality of the research results and readers should thus take the conclusions of many studies with a grain of salt.

 

Creating a new source of high quality mucins.

particles-792301_640Over the past 4 years or so, I have been talking to commercial producers of mucins and in particular to Sigma-Aldrich (now a part of Merck) about the need to offer higher quality mucins to scientific communities. To this day, these discussions have not led to any concrete steps towards the commercialization of higher quality products. A phone conversation with the product manager of Sigma-Aldrich’s mucin products accompanied of a business advisor did not lead to a follow up. Other colleagues have had similar encounters, but with no concrete effect. The reasons for their reluctance are quite obvious to me.

  • There is no clear/ unified demand from the research community.
  • The extraction process of high quality mucins would be more costly and the yield would probably be low.
  • The size of the market for high quality mucins and its price point are also not obvious.

These questions amount to uncertainties that large companies have difficulties making positive business decisions on. So how do we solve this?

I believe that a small structure is going to have to take the risk; a startup. It needs to prove the existence of a market and clearly show the value that such a product could bring to research communities. I believe there is a significant market. The use of mucins from Sigma-Aldrich alone in scientific literature has only been constantly increasing over the past 15 years (see Figure 2). And virtually all of these publications would have benefited from better mucins. The demand for mucin preparations that are purer and of higher quality is also illustrated by a number of recent publications of updated and optimized purification protocols (5,14).

Figure 3.  Yearly count of  scientific publications and patents mentioning the use of Sigma-Aldrich mucins. We used Google Scholar (scholar.google.com) and the following keywords: “mucin (Sigma”; “PGM (Sigma”; “BSM (Sigma” -bifidus.

In summary, I see a few obvious scientific reasons why high quality mucins should be put on the market. It would:

  • Increase the quality of research results in the context of an increasing number of mucin-related fields.
  • Enable more subtle mucin-research, highlighting the importance of its non-glycosylated protein region and its complex glycans.
  • Lead to new discoveries and new technological applications for mucins.

But are there convincing business reasons too? The bit of data presented above are a small piece of the answer. A strong YES from the community would be even more convincing. You can help by answering the survey below if you are working with mucins. The results will be anonymized and posted openly on this blog for everyone to use. The data could serve as a starting point for a project aiming to make high quality mucin more broadly available.

 

 

References

  1. Co, J. Y.-T. The influence of mucins on bacterial communities. (Massachusetts Institute of Technology, 2015).
  2. Caldara, M. et al. Mucin biopolymers prevent bacterial aggregation by retaining cells in the free-swimming state. Curr. Biol. 22, 2325–2330 (2012).
  3. Shan, M. et al. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342, 447–453 (2013).
  4. Something about tribology
  5. Schömig, V. J. et al. An optimized purification process for porcine gastric mucin with preservation of its native functional properties. RSC Adv. 6, 44932–44943 (2016).
  6. Ensign, L. M., Cone, R. & Hanes, J. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. Adv. Drug Deliv. Rev. 64, 557–570 (2012).
  7. Duffy, C. V., David, L. & Crouzier, T. Covalently-crosslinked mucin biopolymer hydrogels for sustained drug delivery. Acta Biomater. 20, 51–59 (2015).
  8. Crouzier, T., Jang, H., Ahn, J., Stocker, R. & Ribbeck, K. Cell patterning with mucin biopolymers. Biomacromolecules 14, 3010–3016 (2013).
  9. Polak, R. et al. Sugar-mediated disassembly of mucin/lectin multilayers and their use as pH-Tolerant, on-demand sacrificial layers. Biomacromolecules 15, 3093–3098 (2014).
  10. Janairo, R. R. R., Zhu, Y., Chen, T. & Li, S. Mucin covalently bonded to microfibers improves the patency of vascular grafts. Tissue Eng. Part A 20, 285–293 (2014).
  11. Kocevar-Nared, J., Kristl, J. & Smid-Korbar, J. Comparative rheological investigation of crude gastric mucin and natural gastric mucus. Biomaterials 18, 677–681 (1997).
  12. Madsen, F., Eberth, K. & Smart, J. D. A Rheological Evaluation of Various Mucus Gels for Use in In‐vitro Mucoadhesion Testing. Pharm. Pharmacol. Commun. (1996).
  13. T. A. Waigh, et al. Entanglement Coupling in Porcine Stomach Mucin. Langmuir 18, 7188–7195 (2002).
  14. Madsen, J. B. et al. A simplified chromatographic approach to purify commercially available bovine submaxillary mucins (BSM). Prep. Biochem. Biotechnol. 45, 84–99 (2015).

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