Advances continue in Europe in tissue engineering

Various technologies in development may lead to faster, better healing of bone and cartilage

Issue: Issue 2 2005

New forms of cartilage repair and tissue engineering are close to clinical feasibility in the United States.

Physicians in Europe already are using a number of the technologies - or have them in trials - thanks in part to looser regulatory restrictions, and researchers are exploring many additional innovative treatments.

One of the most promising: autologous chondrocyte implantation (ACI). "When I first saw ACI, it was like the heavenly touch," said Tom Minas, MD, director of the Cartilage Repair Center at Brigham and Women's Hospital in Boston.

Researchers have known for some time that cartilage can be grown in a lab but there are still problems with the implantation and effective use of this artificial tissue. "It [requires] a slow rehabilitation because it has to grow inside somebody's knee, and of course there can be variability of the repair tissue in that there are inconsistent tissues, and failures do occur," Minas said at Orthopaedics Today NY 2004 - a comprehensive CME course in New York.

Universal donor needed

There are also difficulties related to periosteal harvesting, suturing and late complications, including stiffness and periosteal overgrowth, Minas said. Ideally there would be a universal donor or one source for cartilage repair cells but current research does not suggest that this is a possibility.

"We would like to have a minimally invasive delivery, something that is reproducible for every surgeon," Minas said. "We'd like an easy rehab for the patient … and something that will give us properties that mimic the normal viscoelastic properties and have integration to the adjoining bone and adjacent cartilage. And we would like to extend the indications for other joints … and it would be nice to have some noninvasive method of assessing the integration of the repair tissues."

The first generation of ACI included chondrocytes and periosteum but current research is attempting to replace the periosteum. There are several options for synthetic substitutes that Minas said are commercially available, including a polydioxone membrane that was tested in goats. Two weeks postoperatively with this product there was good maintenance of the membrane, and repair tissue was developing well.

European improvements

Several options available in Europe also attempt to improve on other areas in the first ACI models. One consists of cells seeded on a membrane, which can be used to make the procedure easier. "Instead of getting a cell suspension in a vial, you get a membrane that is laced with autologous chondrocytes, and it now becomes a cookie cutter approach," Minas said. "You template the defect, you cut out the membrane, you place the membrane, you do not suture."

Other types of implants are also being developed, including a matrix assisted ACI or MACI, which also involves a membrane seeded with cells. Europe already has made available hyaluronic esters, which involves creating a material that can be woven into different forms and laced with varying cell types. "For instance, they were actually making ACLs out of a fabric that was woven out of a resorbable synthetic hyaluronic acid, and lacing the bone ends with autologous osteoblasts and chondrofibroblasts," Minas said.

The advantages of some of these newer technologies include a lack of periosteal harvesting and generally less invasive, quicker procedures. These technologies are, however, still very expensive, and there the chance remains for tissue variation and failure.

New techniques

New ACI techniques focus on noninvasive delivery methods, including mini-arthrotomies and arthroscopic procedures. "Arthroscopic delivery of autologous cultured chondrocytes is already available now, and results are coming up to five years," Minas said.

Another implant uses an esterified hyaluronic acid, with autologous chondrocytes growing on the esters. "This is very much like the ACI technique in that a biopsy is taken, it is then grown, cultured, layered and recultured on a scaffolding of resorbable hyaluronic acid, [which] then dissolves within six weeks after implantation," Minas said. "Hyaluronic acid is a sugar, so it is sticky. Once you've done your debridement you can actually just lay this down without any sutures."

There has also been work done in animals with a hydrogel technology. Autologous chondrocytes are mixed in a gel, and the substance can then be polymerized with ultraviolet or other wavelengths so that it hardens with the addition of a photosensitive sealant. The hardening of the gel creates the cartilage repair.

"So are we there yet?" Minas asked. "We're on the right track. … Stem cells are, of course, ubiquitous, and they're most often found in fetal placental blood, but they're also found in other parts of the body, [such as] muscle. Gene therapy is a way in which we can alter the host response or a cellular response to make something that you want to make by introducing a vector, usually a virus or a plasmid into a cell, and turning on its DNA to do this." Minas said that gene therapy is probably furthest off in terms of practical usability, while other tissue engineering products may arrive for use in the very near future.

For more information:

Minas T. Tissue engineering and gene therapy: where are we clinically? Presented at Orthopaedics Today NY 2004 - A comprehensive CME course. Nov. 13-14, 2004. New York.