Can growing blood vessels within a lab-engineered graft improve bladder reconstruction for children? For more than two decades, UC Davis pediatric urologic surgeon Eric Kurzrock has been developing and testing grafts to avoid the complications after standard enterocystoplasty, a surgery for bladder augmentation.

Now, a $4 million grant from the National Institutes of Health (NIH) will help his UC Davis research team test a bioengineered graft infused with ligands (molecules) to treat neuropathic bladders of children with spina bifida or spinal cord injuries.

A neuropathic, also called neurogenic, bladder is caused by dysfunctional nerve messaging between the nervous system and the bladder . The condition results in bladder control issues and kidney disease.

"The bladder is so unique because it is free floating with no supporting matrix of cells around it. It has been historically challenging for regeneration and augmentation," Kurzrock explained. Kurzrock is the chief of pediatric urologic surgery and professor of urology and pediatrics at UC Davis Children's Hospital. He is also vice chair of the Department of Urologic Surgery. "Patients with spina bifida or spinal cord injury may develop a neurogenic bladder, leading to problems with urination and kidney function. They may need bladder augmentation to enlarge their bladder."

The grant will bring together clinical and bioengineering expertise to develop and test an innovative technique to create vascularized grafts.

Bladder augmentation surgeries

In enterocystoplasty, the surgeon uses parts of the intestine or stomach as a graft to enlarge the bladder. The surgery requires an extensive abdominal operation and can have many short- and long-term complications.

Kurzrock found that the ideal substitute for the traditional bladder graft is bioengineered tissue. He developed an innovative method to solve a common problem in graft implants: the challenge of tissue contraction caused by inadequate blood supply. He devised a new procedure to create graft tissues with functioning blood vessels - a necessary condition for graft survival.

In 2022, Kurzrock published a study on vascularized grafts for bladder augmentation in mice and pigs. His study showed that bladder vessels will connect (inosculate) with graft vessels within a few days after transplantation. These connections facilitated blood flow to the entire graft.

A fortified scaffold to promote new blood vessels

Kurzrock is collaborating with UC Davis bioengineer Aijun Wang, an expert in designing and testing supportive structures called scaffolds. Wang has developed a scaffold made of engineered biomaterial modified with a ligand (special molecule known as LXW7) that specifically interacts with endothelial cells that help vascularization. The ligand, developed at UC Davis, helps the cells' attachment, migration and survival, which promotes formation of new blood vessels and reduces graft complications.

"When these molecules are added to scaffolds, they provide a gripping site for endothelial cells to bind. This allows for better interaction between the cells and their supportive structure, known as extracellular matrix," explained Wang, professor of surgery and biomedical engineering. He is also the vice chair for translational research, innovation and entrepreneurship in the Department of Surgery and the director of the Center for Bioengineering in Medicine at UC Davis.

How does the graft work?

The engineered graft is a pig tissue, processed to remove the cells and retain the protein structure of the matrix. This acellular scaffold prevents the host's natural rejection and immune response to new entrants.

The grafts are modified with the ligand then implanted on the rectus muscle bed. This implantation ensures optimum graft maturity and healthy functional vessels prior to bladder transplantation. The new connections provide channels for the blood to flow through the graft within days after transplant and prevent contraction.

"The rectus muscle bed serves as an incubator for the graft until it is vascularized and ready to be transplanted to the bladder," Kurzrock explained. "In fact, we may technically grow a graft in that space multiple times over the years."

"It's a brilliant idea to integrate the body's own healing potential," Wang said. "Adding newer bioengineering technologies, such as the ligand technology, will help in microvascular regeneration of the whole bladder matrix and nearby muscle cells."

The team will test the new graft in a pig model before extending this study to human clinical trials.