A new era in efforts to treat patients with tissue loss or organ failure is under way, which has the potential to revolutionize the treatment of many diseases and conditions that otolaryngologists treat. As seen by Brian Nussenbaum, MD, of the Department of Otolaryngology in Washington University School of Medicine in St. Louis, advances in patient care have traditionally focused on surgical techniques, medical devices, and pharmaceuticals. However, he thinks that new and ongoing developments in the field of regenerative medicine may provide improved methods for replacement, repair, and restoration of tissue and organ function. Regenerative medicine is commonly called tissue engineering. Although both fields share a common goal, the field of tissue engineering, strictly speaking, incorporates principles of engineering in combination with applying biologic agents to generate new tissues. Currently, momentum building behind tissue engineering is moving beyond the innovators and pioneers of this field into the broader medical community and industry, and one day, is hoped to reach the people that will benefit from this shift the most-patients in need of care.
The Potential of Tissue Engineering
The introduction of tissue engineering approaches will represent a new era in our efforts as doctors to treat problems associated with tissue loss or organ failure, said Dr. Nussenbaum. Speaking to participants at the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) meeting in September who attended a miniseminar on tissue engineering, Dr. Nussenbaum emphasized that research and clinical activity in tissue engineering rapidly expanded starting in the 1990s and currently is progressing in virtually every field of medicine, with strong financial backing from industry.
According to Dr. Nussenbaum, any tissue engineering approach must take three critical components into consideration: signaling molecules, cells, and scaffold design. The investigator’s choice for each of these components depends on the characteristics of the type of tissue being repaired. (For a more detailed description of these components and how they work see www.nature.com/embor/journal/v5/n11/full/7400287.html .) Given these components, there are three major categories of potential regenerative therapies currently under investigation: recombinant protein therapy, cell therapy, and gene therapy.
Progress in each of these types of regenerative therapies is occurring, but all have limitations that will need to be overcome. According to Dr. Nussenbaum, recombinant protein therapy is limited by the large amounts of protein generally required, cell therapy is limited by safety issues, and gene therapy is similarly limited by safety issues along with immunological issues related to the use of delivery vectors.
As of September 2006, FDA-approved devices based on tissue engineering principles included autologous chondrocyte implantation for knee articular cartilage defects, cultured epidermal autografts for extensive burns or congenital nevi, and recombinant human bone morphogenetic protein for lumbar spinal fusion, said Dr. Nussenbaum, adding that most of the other work in regenerative therapies remain in the developmental phase. There are individual examples of using cell-based therapy for regenerating the distal portion of a patient’s thumb (Vacanti CA et al. NEJM 2001;344:1511-4), or producing vascular grafts (Naito Y et al. J Thoracic Cardiovasc Surg 2003;125:419-20), but these techniques are not currently in regular use.
For Bruce Baum, DMD, PhD, Chief of the Gene Transfer Section at the National Institute of Dental and Craniofacial Research of the NIH in Bethesda, MD, the most dramatic work in this field so far has come from researchers at Wake Forest who used tissue engineering to construct a functioning artificial bladder (Atala A et al. Lancet 2006;367:1241-6). Other notable work is from researchers in Germany who engineered a mandible (Warnke PH et al. Lancet 2004;364:766-70). That was also very dramatic as it corrected a severe disfigurement, said Dr. Baum.
Potential Applications in Otolaryngology
Therapies in various stages of development that will likely have a significant impact on the care of otolaryngology patients include regeneration of bone, cartilage, mucosa, nerve, skeletal muscle, salivary tissue, hearing and balance organs, endocrine organs, and trachea, said Dr. Nussenbaum.
Current preclinical research into a tissue-engineered trachea and tissue-engineered cartilage for ear and nasal reconstruction has shown promising results. Using cells from a sheep’s nasal septum and implanted in a nude mouse, researchers have been able to successfully create a tissue-engineered trachea. However, successful implantation of the created trachea into a tracheal defect has not yet been achieved (see Kojima K et al. FASEB J 2003;17:823-8]. Using autograft cartilage, promising results are also being shown in engineering cartilage for the ear and nose that may be indicated for such applications as microtia repair or cleft nasal repair (see Walton et al. Plast Reconstr Surg 2002;110:234-49 and Shieh SJ et al. Biomaterials 2004;25:1545-57).
Additional preclinical and bench work is under way for vocal fold scarring. Susan L. Thibeault, PhD, of the Division of Otolaryngology-Head and Neck Surgery at the University of Wisconsin-Madison, and colleagues run one of the active labs in the country that is trying to develop a biomaterial that can mimic the extracellular matrix to create tissue that can replace scarred vocal folds. Currently, there is no good surgical option to treat vocal fold scarring.
The major challenges are the fact that the vocal fold vibrates, so that anything we make has to mimic the biomechanical properties of the vocal fold, she said. It is difficult because most biomaterials that can mimic vocal fold properties also quickly degrade, and we want the materials to stay around for a while.
She is hoping that they will have a first product for FDA approval within three years.
Success of Tissue Engineering Products
According to Dr. Nussenbaum, experts from multiple disciplines will need to work together to make tissue engineering a success; these include clinical scientists, biologists, biomedical engineers, industry sponsors, and government agencies. To help expedite the developmental process and monitor both safety and efficacy, an international registry of clinical trials for tissue engineering products is now being developed by the Tissue Engineering and Regenerative Medicine International Society (TERMIS), a society formed in 2004.
Tissue engineering approaches have a great potential to benefit our patients to some degree in the future; these treatments will hopefully be performed by all otolaryngologists, and not just those in highly specialized practices, said Dr. Nussenbaum. It might be a treatment like injecting a molecule into the parotid gland of a patient with Sjögren’s syndrome to repair the organ and restore salivary production, or using regenerated cartilage derived from the patient’s own cells for a revision rhinoplasty or airway reconstruction, he said.
Although Dr. Nussenbaum feels that there is great potential for this newly developed field of medicine, there is still a great amount that we don’t know about the biologic processes that govern tissue regeneration. Dr. Nussenbaum stated that we need to avoid the hype that has been inherent to this field and concentrate efforts on well-designed clinical trials that prove safety and efficacy before proceeding with potentially very expensive and risky new procedures on patients.
Dr. Thibeault does not see tissue engineering as the answer to treatment of all disease types and conditions in the future. She does think that tissue engineering will add to the present armamentarium that will provide options for specific conditions that don’t have options right now, such as scarring of the vocal fold.
Dr. Baum, who is clinically trained as a dentist and is working on developing an artificial salivary gland, is also optimistic, albeit a bit more cautious. From my perspective, which is more focused, said Dr. Baum, I would say the field is making slow, steady progress.
Tissue engineering is rapidly moving medicine from its current concentration on external-focused treatments (surgical advancements, medical devices, drugs) to a more internal focus based on harnessing the body’s own ability to regenerate tissues. To date, most of the research in this area remains in the development phase, with some exciting possibilities for future treatments in otolaryngology. Active bench and animal studies include looking at developing tissue-engineered tracheas, cartilage for the ear and nose, carniomaxillofacial bones, and tissue-engineered products for vocal fold scarring. Success will depend on collaboration among clinical scientists, biologists, and biomedical engineers, as well as investment from industry and government agencies to bring these new therapies to patients.
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