GSAS Harvard Biotechnology Club

There is a significant shortage of organs available for transplant. In fact, over 10,000 people have died within the last 5 years waiting for an organ transplant. Patients who are lucky enough to get a transplant must worry about dangers like HIV and Hepatitis C. Further, because the organ is foreign, patients must fight its rejection, sometimes for the rest of their life, by taking expensive immuno-suppressants.

The field of tissue engineering is trying to alleviate some of these problems. In addition, the field is making advances in engineering body parts that are currently very hard to transplant, often reducing the invasiveness of current surgical techniques. In the future, we may be able to regenerate or replace aging tissues without needing human organs.

The basic technique for tissue engineering is described well by the following paragraph from Fibrogen:

"Start with some building material (e.g., extracellular matrix, biodegradable polymer), shape it as needed, seed it with living cells and bathe it with growth factors. When the cells multiply, they fill up the scaffold and grow into three-dimensional tissue, and once implanted in the body, the cells recreate their intended tissue functions. Blood vessels attach themselves to the new tissue, the scaffold dissolves, and the newly-grown tissue eventually blends in with its surroundings."

Fibrogen has developed a human collagen production technique. They hope to use this collagen as a matrix that will stimulate cell proliferation. They also have a few patents on uses for Connective Tissue Growth Factor (CTGF). This factor can stimulate growth of cartilage and bone, which is its normal function in fetal development.

Organogenesis has developed a product called Apligraf. This is a cellular, bi-layered skin substitute. It has an upper epidermal layer and a lower dermal layer. The dermis is made up of human fibroblasts, the epidermis is constructed of human keratinocytes. The keratinocytes are made to differentiate into all of the layers normally found in the epidermis. There are no blood vessels, sweat glands, immune cells or melanocytes, however, if the bi-layer is cut, it will heal itself. Apligraf has been FDA approved for marketing for diabetic foot ulcers.

Advanced Tissue Sciences is developing techniques for tissue generation using organ-specific cells seeded on a 3-D polymer scaffold. These cells can grow and divide, and importantly, they secrete extra-cellular matrix and growth factors.

Curis was formed by the merger of Reprogenesis, Creative Biomolecules, and Ontogeny. Curis has products for bone repair (OP-1 Implant) and for bladder replacement or repair (Neo-bladder). They are pursuing products in the field of guided tissue formation and pancreatic stem cells.

One can see that the scaffolding used in creating these tissues is a vital component of the system. It’s properties can determine the shapability of the tissue, the durability, the immune response to the implant, and its longevity. Degradable polymers are certainly flexible in design, and they degrade away such that the implant can really become a part of the patient. However, polymers do have limitations in that they are not natural body products and can risk raising an immune response. The goal with most of the products listed below is to implant the matrix at the site of injury and allow the patients own cells to proliferate and reconstitute the tissue guided by the scaffold. This should eliminate any immune response directed at incoming foreign cells contained in some of the artificial tissue products listed above. Further, these may also allow for the growth of blood vessels and other necessary factors within the graft, which the previous products have had trouble incorporating.

Unicare Biomedical has developed Unigraft – a bioactive glass granule system that forms a scaffold on to facilitate the repair and regeneration of osseous tissue.

SurModics develops matrices for growing tissues. Proteins, peptides, carbohydrates, and synthetic polymers are bonded to flat surfaces or cross-linked to make 3-D structures.

Surmodics has also worked on integrating special coatings into their matrices. One will promote migration of endothelial cells into the graft. Others will be anti-inflammatory of anti-fibrosis coatings for implants. An anti-microbial coating is shown to the right.

Anti-microbial coating

LifeCell has developed what must be the most closely matched matrix for skin grafts. They have a technique for removing all of the cells from a dermal layer, leaving the collagen and elastin backbone. Along with this extracellular matrix, there remain bioactive proteins and channels for blood vessels. This type of matrix avoids any cell-associated immune response or rejection, while providing the most wild-type scaffold for new cells to grow. This matrix also has the advantage that, due to its make-up and origin, it retains very similar elasticity and structure to actual dermis.

New tissues for implantation is not the only market that tissue engineering is useful for. Another major facet is the development of in vitro test tissues. Several companies are working on simulating tissue layers and types in petri dishes for testing of various pharmaceuticals and their effects. These systems are much more accurate for testing pharmacokinetics of drug absorption, adverse reactions of different cell types, etc than standard tissue culture mono-layers.

Organogenesis has a product similar to its Apligraf technology for use in in vitro testing.

TestSkin II. This can be used to research skin care products, drug metabolism, wound healing, and inflammation.

New information is always needed to improve tissue engineering systems, and that’s what Tissue Informatics provides. (www.tissueinformatics.com) The make a unique digital database of tissue structure and function at a microscopic level to assist tissue engineering companies with their designs.

Tissue engineering is a very young field, but is growing quickly due to the large market demand. Some new companies and their research areas are listed below:

Creative Scientific Technology is making synthetic matrices for replacement of human serum, saliva, and spinal fluid.

To learn about some of the current academic research in tissue engineering, take a look at the work of Dr. Robert Langer (MIT) or Dr. Joseph Vacanti (M.D. at Mass. General Hospital)