Archive for the ‘regenerative medicine’ Category

Penises grown in laboratories could soon be tested on men by scientists developing technology to help people with congenital abnormalities, or who have undergone surgery for aggressive cancer or suffered traumatic injury.

Researchers at the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina, are assessing engineered penises for safety, function and durability. They hope to receive approval from the US Food and Drug Administration and to move to human testing within five years.

Professor Anthony Atala, director of the institute, oversaw the team’s successful engineering of penises for rabbits in 2008. “The rabbit studies were very encouraging,” he said, “but to get approval for humans we need all the safety and quality assurance data, we need to show that the materials aren’t toxic, and we have to spell out the manufacturing process, step by step.”

The penises would be grown using a patient’s own cells to avoid the high risk of immunological rejection after organ transplantation from another individual. Cells taken from the remainder of the patient’s penis would be grown in culture for four to six weeks.

For the structure, they wash a donor penis in a mild detergent to remove all donor cells. After two weeks a collagen scaffold of the penis is left, on to which they seed the patient’s cultured cells – smooth muscle cells first, then endothelial cells, which line the blood vessels. Because the method uses a patient’s own penis-specific cells, the technology will not be suitable for female-to-male sex reassignment surgery.

“Our target is to get the organs into patients with injuries or congenital abnormalities,” said Atala, whose work is funded by the US Armed Forces Institute of Regenerative Medicine, which hopes to use the technology to help soldiers who sustain battlefield injuries.

As a paediatric urological surgeon, Atala began his work in 1992 to help children born with genital abnormalities. Because of a lack of available tissue for reconstructive surgery, baby boys with ambiguous genitalia are often given a sex-change at birth, leading to much psychological anguish in later life. “Imagine being genetically male but living as a woman,” he said. “It’s a firmly devastating problem that we hope to help with.”

Asif Muneer, a consultant urological surgeon and andrologist at University College hospital, London, said the technology, if successful, would offer a huge advance over current treatment strategies for men with penile cancer and traumatic injuries. At present, men can have a penis reconstructed using a flap from their forearm or thigh, with a penile prosthetic implanted to simulate an erection.

“My concern is that they might struggle to recreate a natural erection,” he said. “Erectile function is a coordinated neurophysiological process starting in the brain, so I wonder if they can reproduce that function or whether this is just an aesthetic improvement. That will be their challenge.”

Atala’s team are working on 30 different types of tissues and organs, including the kidney and heart. They bioengineered and transplanted the first human bladder in 1999, the first urethra in 2004 and the first vagina in 2005.

Professor James Yoo, a collaborator of Atala’s at Wake Forest Institute, is working on bioengineering and replacing parts of the penis to help treat erectile dysfunction. His focus is on the spongy erectile tissue that fills with blood during an erection, causing the penis to lengthen and stiffen. Disorders such as high blood pressure and diabetes can damage this tissue, and the resulting scar tissue is less elastic, meaning the penis cannot fill fully with blood.

“If we can engineer and replace this tissue, these men can have erections again,” said Yoo, acknowledging the many difficulties. “As a scientist and clinician, it’s this possibility of pushing forward current treatment practice that really keeps you awake at night.”

http://www.theguardian.com/science/2014/oct/05/laboratory-penises-test-on-men

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The mechanisms that drive axon regeneration after central nervous system (CNS) injury or disease are proposed to recapitulate, at least in part, the developmental axon growth pathways. This hypothesis is bolstered by a new study by O’Donovan et al. showing that activation of a B-RAF kinase signaling pathway is sufficient to promote robust axon growth not only during development but also after injury.

B-RAF was previously shown to be essential for developmental axon growth but it was not known if additional signaling pathways are required. In this study, the authors demonstrate that activation of B-RAF alone is sufficient to promote sensory axon growth during development. Using a conditional B-RAF gain-of-function mouse model, the authors elegantly prove that B-RAF has a cell-autonomous role in the developmental axon growth program. Notably, activated B-RAF promoted overgrowth of embryonic sensory axons projecting centrally in the spinal cord, suggesting that this pathway may normally be quiescent in central axons.

Could activated B-RAF also enhance axon regeneration in the adult central nervous system? The authors found that activated B-RAF not only enabled sensory axon growth into the spinal cord after spinal injury, but also promoted regrowth of axons projecting in the optic nerve. Regeneration in the injured CNS is prevented by both the poor intrinsic regrowth capacity of axons and by inhibitory factors in the tissue environment. Importantly, the B-RAF–activated signaling growth program was insensitive to this repulsive environment.

Interestingly, the authors find that B-RAF synergizes with the PI3-kinase–mTOR pathway, which also functions downstream of growth factors. This opens the possibility that combinatorial approaches that integrate these two pathways may heighten regenerative capacity.

This in vivo study significantly advances the understanding of the role of MAP kinases in axon growth and suggests that reactivation of the B-RAF pathway may be exploited to promote axon regeneration in the injured central nervous system. An exciting future avenue will be to determine the downstream mechanisms controlled by B-RAF.

O’Donovan, K.J., et al. 2014. J. Exp. Med. doi:10.1084/jem.20131780.

http://jem.rupress.org/content/211/5/746.1.long

Scientists have now reported the first human recipients of laboratory-grown vaginal organs. A research team led by Anthony Atala, M.D., director of Wake Forest Baptist Medical Center’s Institute for Regenerative Medicine, describes in the Lancet long-term success in four teenage girls who received vaginal organs that were engineered with their own cells.

“This pilot study is the first to demonstrate that vaginal organs can be constructed in the lab and used successfully in humans,” said Atala. “This may represent a new option for patients who require vaginal reconstructive surgeries. In addition, this study is one more example of how regenerative medicine strategies can be applied to a variety of tissues and organs.”

The girls in the study were born with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, a rare genetic condition in which the vagina and uterus are underdeveloped or absent. The treatment could also potentially be applied to patients with vaginal cancer or injuries, according to the researchers.

The girls were between 13 and 18 years old at the time of the surgeries, which were performed between June 2005 and October 2008. Data from annual follow-up visits show that even up to eight years after the surgeries, the organs had normal function.

“Tissue biopsies, MRI scans and internal exams using magnification all showed that the engineered vaginas were similar in makeup and function to native tissue, said Atlantida-Raya Rivera, lead author and director of the HIMFG Tissue Engineering Laboratory at the Metropolitan Autonomous University in Mexico City, where the surgeries were performed.

In addition, the patients’ responses to a Female Sexual Function Index questionnaire showed they had normal sexual function after the treatment, including desire and pain-free intercourse.

The organ structures were engineered using muscle and epithelial cells (the cells that line the body’s cavities) from a small biopsy of each patient’s external genitals. In a Good Manufacturing Practices facility, the cells were extracted from the tissues, expanded and then placed on a biodegradable material that was hand-sewn into a vagina-like shape. These scaffolds were tailor-made to fit each patient.

About five to six weeks after the biopsy, surgeons created a canal in the patient’s pelvis and sutured the scaffold to reproductive structures. Previous laboratory and clinical research in Atala’s lab has shown that once cell-seeded scaffolds are implanted in the body, nerves and blood vessels form and the cells expand and form tissue. At the same time the scaffolding material is being absorbed by the body, the cells lay down materials to form a permanent support structure — gradually replacing the engineered scaffold with a new organ.

Followup testing on the lab-engineered vaginas showed the margin between native tissue and the engineered segments was indistinguishable and that the scaffold had developed into tri-layer vaginal tissue.

Current treatments for MRHK syndrome include dilation of existing tissue or reconstructive surgery to create new vaginal tissue. A variety of materials can be used to surgically construct a new vagina — from skin grafts to tissue that lines the abdominal cavity. However, these substitutes often lack a normal muscle layer and some patients can develop a narrowing or contracting of the vagina.

The researchers say that with conventional treatments, the overall complication rate is as high as 75 percent in pediatric patients, with the need for vaginal dilation due to narrowing being the most common complication.

Before beginning the pilot clinical study, Atala’s team evaluated lab-built vaginas in mice and rabbits beginning in the early 1990s. In these studies, scientists discovered the importance of using cells on the scaffolds. Atala’s team used a similar approach to engineer replacement bladders that were implanted in nine children beginning in 1998, becoming the first in the world to implant laboratory-grown organs in humans. The team has also successfully implanted lab-engineered urine tubes (urethras) into young boys.

The team said the current study is limited because of its size, and that it will be important to gain further clinical experience with the technique and to compare it with established surgical procedures.

Co-researchers were James J. Yoo, M.D., Ph.D., and Shay Soker, Ph.D., Wake Forest Baptist, and Diego R. Esquiliano M.D., Reyna Fierro-Pastrana P.hD., Esther Lopez-Bayghen Ph.D., Pedro Valencia M.D., and Ricardo Ordorica-Flores, M.D.,Children’s Hospital Mexico Federico Gomez Metropolitan Autonomous University, Mexico.

http://www.sciencedaily.com/releases/2014/04/140410194326.htm

Thanks to Dr. Lutter for bringing this to the attention of the It’s Interesting community.