A Vision for the Future of Tissue Repair

Christ also is a recent recipient of a COULTER TRANSLATIONAL RESEARCH PARTNERSHIP-FUNDED PROJECT to define the ideal oxygen and pH requirements in a tissue manufacturing environment. He also ANNOUNCED THIS YEAR A NEW PARTNERSHIP with the Advanced Regenerative Manufacturing Institute’s BioFabUSA program for a new tissue foundry, a custom-designed tissue incubation system, or bioreactor, that will be used to automate the growth of muscle stem cells into implantable tissue patches.

An expert in tissue engineering, Christ understands the complexity of the biology needed to regenerate and replace damaged or destroyed tissue. He also realizes that exceptional expertise and persistence are required to translate discovery into practical therapy. He knows that achieving a project of this scope and ambition transcends the ability of any single person.

Eight years ago, Christ moved his research program to the University of Virginia because its biomedical engineering community gave him the platform he needed to engage such world-class colleagues as professors Silvia Blemker and Shayn Peirce-Cottler; recruit innovators from leading universities and bioscience companies; and enlist specialists from the world of regulation and manufacturing.

“With its emphasis on translation, UVA encourages thinking in terms of end-to-end solutions,” Christ said.

The Case for Urgency

The signature weapon of the wars in Iraq and Afghanistan was the improvised explosive device. These roadside bombs often produced extensive muscle damage that far exceeded the body’s regenerative capacity. The wounds, known as volumetric muscle loss injuries, were both disfiguring and debilitating.

On the civilian side, gunshot wounds, car accidents, equipment injuries, rotator cuff injuries and genetic anomalies such as cleft palate leave similar losses that require bridging with healthy, functional muscle tissue. Because there is no viable way to replace so much missing tissue, people often have no choice but to live with their wounds and disabilities.

For Christ, this is not an acceptable state of affairs. Motivated by society’s debt of gratitude to wounded veterans and the potential to bring these medical advances to the general population, he approaches the challenge with a sense of urgency.

It can take as long as 20 years to bring a new regenerative technology to market. We are trying to cut the process to seven to 10 years at most.

 - GEORGE CHRIST, PROFESSOR OF BIOMEDICAL ENGINEERING AND ORTHOPEDIC SURGERY

The strategies Christ has devised to accelerate this process are on display in his latest grant, the $2 million AFIRM III award. In addition to bringing his own expertise to the work, Christ has assembled a group of researchers with mutually reinforcing expertise in regenerative medicine to explore novel approaches to treatment.

The selection of the UVA team for the award and Christ’s ability to call on such eminent engineers and scientists to be a part of the project reflect the strength of the regenerative medicine program he has catalyzed here.

“To be selected to be part of AFIRM III is quite an honor,” Christ said. “It speaks to the decade or so that we have already committed to developing and evaluating novel and more effective tissue engineering and regenerative medicine platforms, more recently incorporating the computational modeling that colleagues Silvia Blemker and Shayn Peirce-Cottler are pioneering, as well as our expanding network of collaborators around the globe.”

My goal is to build completely native tissue, and to do so, I will need the best materials and the best people available at every step of the way. That kind of multidisciplinary collaboration is something that UVA has always done well.

 - GEORGE CHRIST, PROFESSOR OF BIOMEDICAL ENGINEERING AND ORTHOPEDIC SURGERY

At the core of the AFIRM III grant is a group that Christ has gathered to build a system for regenerating muscle. It includes LISA LARKIN, A PROFESSOR OF BIOMEDICAL ENGINEERING AT THE UNIVERSITY OF MICHIGAN; KEVIN HEALY, A PROFESSOR OF BIOENGINEERING AT THE UNIVERSITY OF CALIFORNIA AT BERKELEY; and LUKE BURNETT, CEO AND CHIEF SCIENCE OFFICER AT KERANETICS, an advanced biomaterials company in Winston-Salem, North Carolina.

Larkin is creating what she calls skeletal muscle units to replace lost tissue in large wounds. These are a composite engineered tissue product. They consist of skeletal muscle with bone tendon ends and functional interfaces between muscle and tendon (myotendinous junction) and tendon and bone (enthesis). However, successful repair using Larkin’s muscle units has been limited by scarring from fibrosis.

Healy and Burnett have each developed a therapeutic hydrogel that could mitigate fibrosis and promote healing. Working with Christ, Healy and WASHINGTON STATE UNIVERSITY COLLABORATOR GLENN PRESTWICH have developed Volumatrix, a hyaluronic acid-based hydrogel that embodies material features more favorable for robust muscle regeneration.

Burnett’s keratin-based hydrogel, KeraGenics Muscle, takes a different approach, providing a more favorable environment for cell infiltration and tissue repair.

Christ proposes to test each hydrogel with Larkin’s muscle units to assess their value in promoting integration with surrounding muscle and improving functional outcomes.

Silvia Blemker will use the massive data set collected as part of the AFIRM III award to build multi-scale models that connect volume, structure and material properties to force generation. Blemker is a professor of biomedical engineering and mechanical and aerospace engineering at UVA.

Christ is not simply interested in developing a system for regenerating muscle tissue. His goal is to create one that functions and behaves like the tissue the system replaces.

For this, he is relying on the expertise of BLEMKER, A PROFESSOR OF BIOMEDICAL ENGINEERING AND MECHANICAL AND AEROSPACE ENGINEERING AT UVA and a specialist in finite element modeling of muscle tissue. Blemker will use the massive data set collected to build multiscale models that connect volume, structure and material properties to force generation.

“The computer models make predictions that help design the most meaningful experiments to be performed in cell, tissue and animal model systems,” Blemker said. “The models also provide critical insight into the outcome of experiments, providing mechanistic information, which is exciting and beneficial.”

Blemker’s work will provide the team with an improved understanding of functional deficits associated with a muscle loss injury and the characteristics of regeneration needed to recover the function, Christ said.

“In other words, it gives us an objective standard for evaluating our results across multiple potential muscle injuries and many therapeutic solutions and possibilities,” he said.

Christ will also be turning to another UVA colleague, SHAWN RUSSELL, AN ASSISTANT PROFESSOR OF ORTHOPEDIC SURGERY AND MECHANICAL AND AEROSPACE ENGINEERING AT UVA. Russell will provide further insight on the impact of these treatments on gait and range of motion. Functional regeneration must not only improve the force of contraction but also restore more natural movement.

[Professor Silvia Blemker's work] gives us an objective standard for evaluating our results across multiple potential muscle injuries and many therapeutic solutions and possibilities.

 - GEORGE CHRIST, PROFESSOR OF BIOMEDICAL ENGINEERING AND ORTHOPEDIC SURGERY
 

In addition to its work on muscle, Christ’s team will examine the effectiveness of nerve repair technologies developed at INTEGRA LIFESCIENCES — a company that develops technology for surgical applications — by its chief scientist, Simon Archibald, and its senior director of research and development, Sunil Saini. The goal is to set the stage for the simultaneous nerve and muscle repair that is necessary for successfully treating volumetric muscle loss injuries.

The award also includes collaborators from the Department of Defense-funded ADVANCED REGENERATIVE MANUFACTURING INSTITUTE. Chief Regulatory Officer Richard McFarland will provide guidance on regulatory issues, and Chief Technology Officer Thomas Bollenbach will provide advanced biomanufacturing expertise. The idea is to conduct research from the start with product development and commercialization in mind.

“My goal is to build completely native tissue, and to do so, I will need the best materials and the best people available at every step of the way,” Christ said.