Collagen is a natural polymer familiar to everyone. Leather is collagen. Gelatin, the powder in every jello box, is collagen. Collagen gives structure and shape to all the tissues in the body, just as it does for leather and jello. It’s use in biomedical products is at least 2,000 years old, perhaps beginning when sutures were made of catgut. For at least 100 years, collagen has been used as a simple patch to aid skin wound healing.
John A. M. Ramshaw has written a review of the current biomedical applications of collagen in the Journal of Biomedical Materials Research Part B. Collagen is a safe and clinically effective biomaterial, but it seems that there have not been many innovative new uses for this natural product. This may be the case because collagen has mainly been the focus of basic chemistry research and not materials research.
“It may be worth noting that for both biology and structure, the amount of knowledge is greatest at the smallest scale … but relatively little is known at higher structural orders, such as packing of collagen into fiber bundles and tissues … Yet it is these data that are of particular relevance to collagen-based biomaterial and tissue engineering scaffold performance.” — John A. M. Ramshaw1
Where does collagen come from?
Most biomedical collagen comes from animals. Both pig and cow collagen is widely used in commercial and research products. The stabilization treatments animal tissue receives reduces the immune system response, making them stable products to use in the body. Though disease transmission from these animals is practically non-existent, the non-zero chance of transmission has pushed researchers to pursue collagen sources from more primitive animals like fish, jellyfish, and chickens.
Researchers are also trying to find non-animal sources of collagen. Recombinant collagen, a product specified by genetic engineering, can be harvested from plants, yeast, and bacteria. So far, the yield of most non-animal sources of collagen is too low to be commercially relevant. This type of collage has, however, been demonstrated as safe for use. The main benefit to non-animal sources is the guarantee of no disease transmission or any other undetectable contaminants.
How is collagen used?
Collagen is used both in a solid, tissue-based form and as gelatin, a powder made by breaking up tissue with enzymes. The tissue-based form keeps its shape and strength. The best known use for tissue-based collagen is heart valve transplants. Heart valves from pigs and pericardium2 from cows are both used to replace faulty heart valves in humans. This treatment is proven and effective, but calcification of the transplanted tissue over time makes the transplanted valve inflexible and itself in need of replacement.
Gelatin, or reconstituted collagen
Collagen can be broken into smaller, water soluble, pieces using enzymes. The resulting powder, or transparent sheet, is called gelatin. Gelatin is also chemically treated to reduce the immune response, but because the enzymes destroy collagen’s large-scale structure, gelatin degrades quickly and does not have the strength of tissue-based collagen. Gelatin is also referred to as reconstituted collagen, because when dissolved in water and allowed to sit, the gelatin will reform a solid structure, or reconstitute, like jello in the refrigerator.
Research applications for gelatin are myriad. It is cheap, readily available, and has no immune system problems. Gelatin is often the biomedical collagen used first when showing proof-of-concept for a new research application. However, it has no other beneficial characteristics. It is used because it doesn’t get in the way, not because it does anything itself. Its most recent application has been in cell-delivery therapies to deliver chondrocytes for cartilage repair.
Extracellular matrix products
Technically, all extracellular matrix products (ECM) are collagen products. Collagen is the main structural component of all tissue-based materials. However, a distinction is usually made between biomedical collagen products and ECM, or decellularized tissue, because of the chemical treatments they receive. Collagen is stabilized chemically in a way that deactivates many proteins and reduces the immune response. ECM is treated with a more complex procedure that retains protein activity and removes everything that would cause an immune response.
What’s new with biomedical collagen products?
New sources of collagen
The main source of attention for moving collagen research forward seems to be finding non-animal sources of collagen. Fish, jellyfish, and chickens have all been used to find new sources of collagen that are not associated with human transmittable diseases. However, in conjunction with other research to find completely animal-free materials for growing primary human cells,3 non-animal sources like plants and bacteria are being studied.
It is now considered a relatively simple genetic engineering process to get plants and bacteria, usually E. coli, to produce recombinant4 proteins of many types. Plants, yeast, and E. coli have all been studied to find a non-animal source of collagen, but so far none are able to make collagen in large enough quantities to be commercially relevant. There have been detailed chemistry studies to show how similar they are to normal collagen, but at least in this review paper, there are still no studies of larger-scale material behavior.
Combining collagen with a synthetic component
Another trend seems to be combining tissue-based collagen with a synthetic polymer cage, or other reinforcement. Plastic mesh has been implanted under the skin of sheep, to produce a collagen covered plastic mesh. This mesh can be used in wound healing and blood vessel stabilization. Perhaps a new method to create a device, but not a new application for collagen.
Biomedical applications for collagen are still basic applications
Collagen products are safe, proven, and well tested. They will be used for years to come in essential biomedical applications like heart valve repair and wound healing. However, unless one considers decellularized tissues, there does not seem to be any consistent improvement of collagen as a biomedical product that would provide new functionality for this time-tested material. The decades old basic applications for collagen still seem to be the only applications, at least for tissue-based collagen.
- John A. M. Ramshaw. “Biomedical applications of collagens.” Journal of Biomedical Materials Research Part B 204B (2016), 665-675.
- Pericardium is the outer layer of tissue that covers the heart. It is manually shaped and stabilized for this application.
- In this context, a primary cell is one that is directly removed from a patient, such as taking bone marrow cells to grow in a lab for a tissue engineering therapy.
- Recombinant just means that the protein is made somewhere out of its normal context, ie. in a bacteria cell instead of a human cell.