Oct
10
2015

Tissue Repair With Extra Cellular Matrix

You are about to learn about futuristic medicine that is already happening now. On September 5, 2015 I watched an interesting documentary on Discovery Channel while working out on the treadmill in the gym. This gave me the idea that this would be good material for a blog. After a little research on the Internet I found the full extra cellular matrix story, which you can read about below.

An amputated finger grows back

Lee Spievak, a man who loves flying model aircraft got his right middle finger chopped off at the end from a rotating model airplane propeller. His surgeon felt that there was nothing much that could be done. But his brother who works in regenerative medicine knew about a powder made from pig’s bladder tissue, which Dr Stephen Badylak from the University of Pittsburgh, had pioneered. His brother arranged for a sample of powder, extra cellular matrix (ECM) to be sent to Lee Spievak who sprinkled some on the open wound (the stump). Within two applications he started to see that new tissue was forming, within 4 weeks it sealed up the wound and he had grown a new finger, the same length as before. Within 4 months his nail, skin, his feeling and even his fingerprint were back to normal.

This story happened in Cincinnati in 2005. In this news story it is explained why the ECM powder worked so well: it prevented the wound from closing and it stimulated the body to heal.

A large thigh muscle defect grows back

Marine Sergeant Ron Strang was severely wounded by a roadside bomb in Afghanistan where a large part of his left quadriceps muscle (left thigh) was ripped off. After several surgeries the surgeons decided that Ron was a good candidate for part of a trial that is ongoing involving about 80 Veterans with similar injuries. Dr. Steven Badylak from the University of Pittsburgh suggested with the next surgery to put extra cellular matrix from pig bladder into the remaining quadriceps muscle to see whether it would regrow part of it. The surgery followed by physical exercise was so successful that Sergeant Strang is now able to run and do all the activities he wants. There is still a scar, but compared to the initial injury where a big chunk of muscle was missing, the remaining scar is insignificant.

Dr. Badylak explains in the video of the link that the sheet of extracellular matrix that was inserted immediately recruits the patient’s own stem cells, which makes new muscle cells, new nerve tissue, new skin, whatever is needed to heal what’s missing in the injured area.

Dog gut growing into a dog aorta

Dr. Badylak from the University of Pittsburgh had a veterinary medicine degree before he studied medicine and became a surgeon. From the beginning he was interested in regenerative medicine.

After he saw the success with Lee Spievak’s finger regeneration, he thought that there must be a way to regenerate other tissues. He started doing experiments on dogs where he removed part the arch of the aorta and replaced it with a piece of gut from the same dog to see whether the dog would survive and whether the gut would be strong enough to withstand the pressure from the outflowing blood in the aorta. He figured that the tubular structure of the gut would be a better template than the synthetic aorta pieces that are still used by thoracic surgeons. To his surprise the first dog (his own dog named Rocky) survived and did well. He accumulated data on a total of 15 dogs. All of them survived and did well. He could not understand what had happened, so he reexamined one of these dogs where he got histological samples and analyzed them under the microscope to see what was going on. He expected the typical findings of the gut transplant, but instead he found a new aorta with all of the histological findings of aortic tissue. The piece of gut had been transformed into aortic tissue!

Next Dr. Badylak repeated the surgical procedure, but this time he inserted a piece of gut from a cat, removed the lining of it (called mucosa) and the muscle layer, (called the muscularis), so there was only the extra cellular matrix left, a thin tubular structure of ECM. When he was done, he was wondering whether the catgut ECM would be rejected, because it came from another species and normally with whole organ transplants one can expect rejection of the foreign tissue. None of that happened. The experiment went flawlessly: the transplant survived like all the others and again the ECM had turned into dog aorta that was integrated without any scar formation! None of this fitted any conventional medicine model; it was the blueprint for the regenerative medicine model.

Dr. Badylak recognized that this was a huge step forward, and he would need easy access to ECM material. He got it from the pig slaughterhouses dotting the Indiana countryside surrounding Purdue. There would never be a shortage of tissue for preparing the scaffolding of the ECM for various applications.

By now the surgeon had proven that the gut or ECM transplant was switching off an inflammatory reaction, which suppressed scar formation, and simultaneously promoted regeneration. But the missing puzzle still was how the aortic tissue was generated.

Dr. Badylak tested whether the procedure would work for large veins, smaller arteries, Achilles tendons, all in dogs and using pig’s ECM. The answer was it worked all beautifully with no scarring and perfect healing results. Control dogs who did not get the ECM, but were only operated on and then repaired conventionally in their Achilles tendon were developing a limp from scar tissue. This is what often happens in humans as well with conventional surgery. But none of the dogs that had 3 cm cuts and then were treated with pig’s ECT developed a limp or scarring. They healed perfectly.

In 1992 DePuy licensed Badylak’s ECM-derived “biologic scaffolds” for all orthopedic applications. DePuy is a big company that makes supplies for hip and knee replacements and much more. This was an ideal support for Dr. Badylak’s work.

In 1999 the FDA approved pig’s bladder ECM for human applications. This included the use of pig’s ECM for shoulder rotator cuff tears in patients, for abdominal hernias, for esophageal reflux damage, and even to induce the regrowth of the outer lining of the brain following brain surgery.

He could now continue his research and find out what the missing puzzle was: how did the body use the pig’s ECM and repair tissues?

Stem cell recruitment by ECM

Dr. Badylak was visiting a colleague of his in Los Angeles, Dr. John Itamur who had previously repaired a rotator cuff tear on a patient 8 weeks earlier using porcine ECM. The same patient had an unrelated shoulder injury for which he required surgery just adjacent to the previously repaired rotator cuff. The surgeon decided to take a small biopsy to see how the healing tissue looked. This was when Dr. Badylak came for a visit. The microscope showed a surprise: the scaffolding had disappeared as expected. But there were a lot of new cells there, which did not look like inflammatory cells, muscle cells or nerve cells; they were stem cells. Dr. Badylak read several papers that told him that ECM breaks down into so-called crypteins, which are peptides that have powerful stem cell recruiting properties.

In 2003 he started groundbreaking experiments in mice that proved this theory to be correct: he X-rayed a group of mice to kill all of their bone marrow stem cells. Then he injected stem cells tagged with a fluorescent marker to repopulate the bone marrow with these tagged stem cells from the same strain of mice. Now he removed a piece from the Achilles tendon and repaired the defect with pig ECM. Stem cells tagged with a fluorescent marker were flooding the Achilles tendon repair area. Even months after the Achilles tendon repair with ECM the new Achilles tendon was still filled with some of these tagged cells showing that some of them had matured into regenerated tissue.

Here is a 3 ½ minute video that shows the principal of wound healing using pig ECM when used in orthopedic surgery (repair of a rectus muscle tear).

You may wonder how Rocky, the initial dog did who had an aortic segment replaced by a piece of gut. Rocky lived for another 8 years and was healthy until the very end.

Tissue Repair With Extra Cellular Matrix

Tissue Repair With Extra Cellular Matrix

Conclusion

You saw how the observation of a healing finger turned into experiments on dogs where aortic defects and Achilles tendon defects could be healed without scarring. You learnt how pig’s or cat’s ECM were used as scaffolds that get absorbed, but they do recruit stem cells from the host’s body that subsequently do the healing. The exciting news about ECM is that it promotes healing and recruiting of stem cells, but at the same time it is suppressing inflammation and scar formation.

We already hear that ECM is used in hernia repairs, rotator cuff repairs for shoulder injuries, and also in hair transplants, where Acell material is mixed in to improve the transplant success.

It is being used in lower esophagus surgery in cancer cases and with reflux esophagitis.

What will ECM be used for next? We do not know everything, but it is a promising step into the future of regenerative medicine!

About Ray Schilling

Dr. Ray Schilling born in Tübingen, Germany and Graduated from Eberhard-Karls-University Medical School, Tuebingen in 1971. Once Post-doctoral cancer research position holder at the Ontario Cancer Institute in Toronto, is now a member of the American Academy of Anti-Aging Medicine (A4M).