Funding opportunities

Translating stem cells into ligaments for regenerative medicine

Funding Type: 
Early Translational III
Grant Number: 
TR3-05477
Funds requested: 
$1 708 418
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
In California, over 12,000 people will rupture their anterior cruciate ligament (ACL) this year. Most of these people will sacrifice one of their healthy ligaments in order to reconstruct the ACL in an effort to stabilize the knee and prevent arthritis. Even though the surgeries are usually successful at stabilizing the knee, most people who undergo this operation experience pain and a loss of function at the donor site. Therefore, it is extremely important to develop new clinical choices to replace damaged ligaments. We have recently developed the first engineered ligaments containing both the ligament and bone. The ligament is made from stem cells isolated from a patient’s bone marrow, while the bone is made from the same calcium phosphate that makes up our skeleton. The ligaments are completely tailorable in their size and shape. Over the past 3 years, we have improved the ligament grafts to the point that they are ready for testing in appropriate animal models. This proposal will allow us to finalize the conditions in which to grow the grafts before implantation and assess their function once implanted. Upon successful completion of this work we will be close to reaching our goal of engineering ligament grafts to treat the thousands of Californians who must reconstruct their ACL each year.
Statement of Benefit to California: 
Approximately 1 in 3,000 people in California will rupture their ACL this year and need it reconstructed. For patients with active professions, such as policemen, firemen, construction, and crop workers, ACL reconstruction will mean a minimum of 6-12 weeks out of work costing Californians millions of dollars. Currently, the only clinical option is to reconstruct the ACL using part of the patient’s healthy patellar or hamstrings tendon (autografts) or a ligament taken from a cadaver (allografts). There are serious drawbacks to both autografts and allografts including donor tendon rupture and a 3-fold greater incidence of failure, respectively. Successful engineering of ligaments from bone marrow stromal cells would provide a novel clinical option and may accelerate return to activity resulting in easier rehabilitation, less time and money lost to disability, and an improved quality of life for tens of thousands of Californians annually.
Review Summary: 
This Development Candidate Feasibility proposal is intended to provide preclinical proof of concept for an engineered ligament to repair ruptured ligaments. The applicant argues that current treatments of ligament rupture have limitations: autografts are successful but result in donor site morbidity while allograft ligaments from cadavers are less successful than autografts. The engineered construct proposed in this application will contain both ligament and bone to accelerate repair and a goal is to be equivalent in strength and collagen content to natural adult ligament. The ligament component is made from stem cells isolated from a patient’s bone marrow, while the bone component of the construct is made from the same calcium phosphate that makes up our skeleton. The ligaments can be tailored in size and shape. The applicant proposes to optimize the cell source, finalize the chemical and mechanical conditions in which to grow the grafts before implantation, and assess graft function in a preclinical model. Objective and Milestones - Reviewers were unclear on the differences in what appeared to be redundancy between experiments already conducted to produce the preliminary data and proposed studies in the application. - Reviewers were unclear on how the proposed milestones would be used as gating parameters to determine how the project will proceed. Rationale and Significance - Reviewers were not convinced that there was sufficient rationale for developing a costly tissue engineered product to compete with currently available surgical solutions. - The concept of developing a mature, implantable ligament within the intended four-week timeframe was viewed as potentially significant, but the feasibility was questioned. Research Project Feasibility and Design - Intention to achieve ligament with tensile strength and composition equivalent to human tissue was not viewed as realistic based on the preliminary data. The target product profile and experimental design should also include minimum acceptable targets for these key parameters. - Reviewers criticized the experimental design for not including gait improvement as an outcome of the proposed large animal study. - The integration of the ligament with bone was considered novel and viewed favorably by the reviewers. Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team - The PI has a strong background in tissue engineering though s/he does not seem to have experience in translational research. - The team composition was viewed as appropriate. Collaborations, Assets, Resources and Environment - The budget was viewed as appropriate. - Excellent facilities and resources were available at the PI’s institution. Responsiveness to the RFA - There were some concerns expressed about responsiveness to the RFA as to whether a human stem cell is necessary, depending upon the results of the first aim which proposes to compare fibroblasts and stem cells.
Programmatic review: 
  • A motion was made to move this application from Tier 2 into Tier 3 (Not Recommended for Funding). Reviewers noted that the proposal has a number of flaws and were not convinced that the application addressed a major unmet medical need since surgical solutions are already available. The motion carried.
Conflicts: 

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