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Rebuilding What Cancer Has RavagedBy Sunita Patterson In the past, during tumor resections, surgeons had few options for repairing large torso wounds that were at high risk of infection. A cosmetically undesirable outcome—or even a permanent open wound requiring ongoing dressing changes—would sometimes be the best that could be offered. For cancer patients who need such extensive repair, reconstructive surgeons now have a solution—one that builds on the success of tissue engineering in patients with severe burns. Similar to the way skin substitutes can replace patients’ damaged skin and then prompt regeneration of new tissue, torso wounds can now be repaired with materials that not only resist infection but also encourage the patients’ own bodies to regenerate musculofascial tissue. The University of Texas M. D. Anderson Cancer Center has been a leader in developing and testing this technique for tissue engineering in the torso. Three basic elements are needed in tissue engineering, said Charles E. Butler, M.D., a reconstructive surgeon and professor in the Department of Plastic Surgery at M. D. Anderson. Those elements are (1) a matrix or scaffold that can serve as a support for the new tissue, (2) seed cells, and (3) substances such as growth factors, genetic material, or hormones that encourage the growth of the cells on the scaffold and their differentiation into specific tissue types. Dr. Butler’s work with regenerative tissues began in the 1990s, when he developed combinations of matrices and cells that organize to form a structure very close to that of normal skin, with a dermal and epidermal layer. For the past 10 years at M. D. Anderson, he has been developing ways to use similar dermal matrices internally, for structural reconstruction.
Those techniques, alone and in combination with complex flap reconstruction techniques, are now benefiting patients with ventral hernias; challenging chest wall, abdomen, and pelvic defects caused by tumor resections; and other cancer- related torso defects. Such wounds are difficult to close, are prone to infection, and were once considered impossible to repair without significant patient morbidity. A double-duty repair material To repair structural defects in the torso, surgeons use a range of materials with high tensile strength. Synthetic surgical and prosthetic meshes, such as those made of knitted polypropylene or polytetrafluoroethylene, are common but have several limitations, the most important being an increased risk of infection. Dr. Butler has had superior results with acellular dermal matrices, both human (HADM) and porcine (PADM). These commercially available materials are derived from human cadaver or porcine skin that has been decellularized and sterilized, leaving behind the extracellular matrix—a ubiquitous, nonspecific tissue matrix found in all mammals. Dr. Butler and others have found that in torso wound repair, such matrices can perform double duty as a repair material and as a scaffold. After HADM or PADM is placed in the body as part of a surgical repair, cells and blood vessels rapidly begin to grow onto it, and the matrix will recellularize and revascularize. Over time, it becomes integrated into the body’s musculofascial tissue. “This is true in vivo tissue engineering,” Dr. Butler said. “The patient’s body is the bioreactor. We place the matrix in, and the microenvironment that the matrix is in dictates what type of tissue it forms. The patient’s own cells go in, blood vessels go in, and soon it all starts to function and look more like your own tissue. That’s the fascinating thing about it. In fact, a year after surgical repair with HADM or PADM, it’s hard to tell, even under a microscope, where the introduced regenerated matrix leaves off and the patient’s own native tissues begin.” The benefits of a biologic scaffold Through clinical follow-up, comparative studies in animal models, and histologic analysis of tissue biopsies, Dr. Butler and his colleagues have learned much about what works well in torso repair, why it works, and how it might work better. In challenging cases, he has found several advantages to using biologic scaffolds—specifically, HADM and PADM—instead of synthetic mesh. When synthetic mesh is placed into a contaminated wound, or if a wound breaks down and the mesh becomes exposed, it often gets infected and eventually needs to be removed. In contrast, Dr. Butler has found, the biologic matrices have an inherent resistance to infection, and if infection does occur, it is much easier to treat, almost always without an operative procedure. Thus, biologic matrices can be used when there is some degree of bacterial contamination of the wound or a risk of contamination. In fact, the biologic matrices are so resistant to infection that under some circumstances they can even be left exposed to the air and treated as open wounds. Dr. Butler has treated patients in whom the skin could not be closed over the biologic matrix reconstruction, so the wound was covered with a dressing—and even though the matrix was exposed, the wound healed on its own. Another benefit of the biologic materials is that they have a propensity to resist adhesions to the bowel, a finding that Dr. Butler has verified in laboratory studies and published. Synthetic mesh, on the other hand, is seen by the body as a foreign object, so its components become encapsulated over time by abundant abnormal scar tissue. When synthetic mesh is used to repair wounds directly over the intestines, the scarring can cause adhesions that can twist the bowel, causing an obstruction or tearing a hole in the bowel wall and resulting in an abscess or fistula. The scarring and bowel adhesions can make reoperation even more difficult than the original surgery. A reduced likelihood of infection and adhesions is important for patients treated at M. D. Anderson, because many have had breaches of the bowel, have open wounds because of large tumor resections, or are at a high risk of wound-healing complications because of immunosuppression, previous surgeries, or postsurgical radiation treatment. With HADM and PADM, Dr. Butler has been able to perform torso reconstructions in many patients with such challenges—patients in whom surgery with synthetic mesh would be contraindicated. He recalled, for example, a patient treated for ovarian cancer who had an enterocutaneous fistula.
“She was living her life with a massive hernia and an ostomy bag, and no one was interested in operating on her because it was a contaminated wound with a large incisional hernia,” Dr. Butler said. Using HADM, he was able to repair the musculofascial defect and the skin deficiency during the same operation, without complications. Similarly, he has seen patients with large ventral hernias that surgeons had refused to electively repair because of patient cormorbidities or the extremely challenging nature of the defects. With the help of the biologic matrices and minimally invasive component separation (a technique that Dr. Butler pioneered), he has been able to repair those patients’ wounds. “So we’ve been able to make a huge, positive impact on their lives,” he said. Making a good thing better In 2005, Dr. Butler published a report on one of the first series of patients who were at high risk of mesh-related complications and underwent complex torso reconstructions using HADM. Recently, an updated study of the same group of 13 patients, now with a longer follow-up (a mean of 43.7 months for those who did not die of cancer), confirmed that HADM can be successfully used in challenging reconstructions in which previous radiation treatment, contact with viscera, or wound contamination is an issue. In addition to this and other clinical investigations, Dr. Butler also is conducting laboratory studies. He’s particularly interested in understanding how cells grow into the matrices to generate new tissue. “Where do the cells come from—the fascial edge, the subcutaneous fat, or the abdominal cavity?” he said. “How fast do they come in? How complete is the recellularization and revascularization? We want to know what’s really going on so we can harness and optimize this response.” Dr. Butler is also interested in whether the recellularization and revascularization process can be enhanced. In a novel syngeneic rat model, he is studying whether strategically introducing adipose-derived stem cells improves the outcome. “We want to see whether the wounds heal faster or stronger or better, or whether the tissue holds its shape better in the long term,” he said. “I think there’s potential for cellular therapy to help compromised patients with a difficult wound or infection.” A custom-designed scaffold from the lab In a parallel research effort, Dr. Butler has been collaborating with Anshu Bagga Mathur, Ph.D., director of research for the Tissue Regeneration and Molecular Cell Engineering Labs and an assistant professor in the Department of Plastic Surgery, to create an even better scaffold material—one that can be customized to the wound site or patient. “With the HADM or PADM, we can’t alter many of the inherent properties of tissue-derived matrix,” Dr. Butler explained. “It is what it is. We’d like to have greater control over the characteristics of the scaffold based on what type of reconstruction we need to do.”
In previous work, Dr. Mathur studied cell-substrate interactions—how a cell behaves and can be engineered when anchored to a surface or material—and the reformulation of silk fibers into matrices. At M. D. Anderson, she has combined those areas of research to develop a library of scaffolds that incorporate fibroin, the fibrous protein portion of the silk fiber, and chitosan, a glycosaminoglycan that mimics the biologic matrices. “Depending on how you combine the two components, you get different mechanical properties and a different microstructure,” Dr. Mathur said. The intent is to be able to pour the solution into a mold or manipulate its structure “from nanoscale to macroscale” by applying electrical forces so that the resulting scaffold has the nanostructure that the cells recognize and a macrostructure that is adapted to a patient’s specific geometric form. Not only are the scaffolds customizable, but they also eliminate the need for harvesting material from a human or animal source. Dr. Mathur coined the name “engineered biologics” for the scaffolds. “They are biologically derived, but we’re engineering the structure (nano to macro),” she explained. Dr. Mathur has been testing these scaffolds since 2004 in animal studies. In 2006, with Andrea S. Gobin, Ph.D., Drs. Mathur and Butler published results on engineered biologics for ventral hernia repair in a guinea pig model; an innovation grant from the U.S. National Institute on Aging is supporting further development of the application. Dr. Mathur has also collaborated with other plastic surgeons at M. D. Anderson to develop engineered biologics for bone regeneration in sheep, nanotherapeutic delivery via tissue flap in mice, and directional microvasculature growth in the mesentery of rats. “We found in those models that the silk fibroin–chitosan scaffold supports the growth of fascia and bone and directs endothelial cell migration for vascular growth, alluding to the overall regenerative capacity of the material,” Dr. Mathur said. “The microenvironment in which we implant the scaffold drives what kind of tissue will be formed.” She and Dr. Butler are currently testing the engineered biologic scaffolds in an abdominal-wall musculofascial model in guinea pigs. Dr. Mathur is also using the same material to make biodegradable nanoparticles containing therapeutic agents against cancer; results thus far indicate that the efficacy of drugs encapsulated in the material is increased using this delivery method in association with higher intracellular retention and increased bioavailability. A patent for the formulation is pending. “It’s a multifunctional material because of its biomimetic properties,” Dr. Mathur noted. The development of new scaffolds, as well as improved understanding of how best to use commercially available meshes and matrices, has benefited from the collaboration between Drs. Butler and Mathur. Dr. Mathur noted, “We’re very lucky to be at M. D. Anderson working with the reconstructive plastic surgeons. Surgeons have to have novel ways of overcoming issues that arise as they’re doing repairs. When we do any studies in the laboratory, we keep that in mind.” Outside the lab and back in the operating room, many patients have benefited already. “I used this technique today,” Dr. Butler said. “I used it yesterday, and I’ll be using it tomorrow. And with the breakthroughs we’re achieving in our clinical, basic science, and translational research, the rewards for our patients will increase even more in the future.”For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789. Other articles in OncoLog, April 2009 issue:
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