Disease Team Planning
Arthritis and other rheumatic diseases are among the most common of all health conditions and are the number one cause of disability in the United States. The annual economic impact of arthritis in the US alone is over $120 billion and is expected to grow significantly as the population increases and ages in the coming decades. Despite the broad impact of this disease, none of the available treatments can halt, reverse or change the course of progression. For severe joint disease, replacing the joint surfaces with artificial materials (total joint replacement) is the only available solution. However, the artificial joints seldom restore a full range of movement, and they have an increasing risk of failure over time. While the number of joint replacements approaches 1 million annually, approximately 160,000 joint replacement recipients must undergo a second "revision" surgery to correct complications. Revision surgery is technically demanding and is associated with substantially more surgical complications. Therefore, there is a major and rapidly growing clinical need for an alternative to the present-generation joint replacement devices. A biological replacement is universally regarded as the next major advance in joint replacement. Our objective is to develop a biological construct for joint repair that combines naturally occurring biomaterials with functioning tissue derived from stem cells. We propose to create large osteochondral (bone and cartilage) constructs replicating an entire joint. This biological "device" will be used to replace and repair a large area of a damaged or degenerative knee joint and be functional immediately after it is implanted. The complexity of the problem and the challenges of the approach require a multidisciplinary approach. We therefore propose to assemble a team of leading experts in the fields of orthopaedic surgery, rheumatology, bioengineering, chondrocyte and stem cell biology, and biomaterials and scaffold assembly. Our proposal's novel approach will combine technologies that are individually feasible. We will use recently developed biomaterials that are compatible with the human body and resemble native cartilage and bone. We possess the capability to assemble biomaterial scaffolds that mimic the shape of almost any articular joint. We can regulate the proliferation and differentiation of stem cells and can grow cartilage and bone tissue in bioreactors. We now have the opportunity to combine these independent technologies into one unified approach to repair or replace entire joints with a functional prosthesis.
Statement of Benefit to California:
Arthritis is the most common disabling disease. Over 10% of Californian residents suffer from some form of arthritis, the most common being osteoarthritis. This number will increase dramatically as the entire population in general and the “baby boomer” segment in particular, ages. The socioeconomic burden of medical treatment combined with lost productivity is close to $20 billion a year in California alone. Despite the vast amount of money spent in “treating” osteoarthritis, no treatment approach has been successful in preventing, reversing, or changing the course of osteoarthritis. This grant proposal falls under the mission statement of the CIRM of funding innovative clinically relevant research. The proposal will result in the clinical application of tissue- engineered products from stem cells. Specifically, a biological replacement for arthritic joints will address the existing weaknesses and complications of traditional joint replacement with artificial biomaterials. A biologic replacement would also allow younger patients to benefit from this surgery and would dramatically reduce the number of complications from artificial replacement. A biologic replacement could also be expanded to replace joints and bones affected by traumatic injuries, cancer, or other diseases. If successful, this will further validate the significance of the CIRM program and will help maintain California's leading position at the cutting edge of biomedical research. California has been at the forefront of biomedical research for more than 40 years and is internationally recognized as the biotechnology capital of the world. The recent debate over the moral and ethical issues of stem cell research has slowed the progress of scientific discoveries in this field especially in the US. The CIRM is a unique institute that fosters ethical stem cell research in California. The CIRM also serves as an exemplary model for similar programs in other states and countries.
Executive Summary The applicant proposes to establish a multidisciplinary team composed of orthopedic surgeons, stem cell biologists and bioengineers dedicated to the development of a biological device that would replicate an entire joint by growing stem cells on suitable biomaterials. The project encompasses both a stem cell biology and a bioengineering problem. Reviewers considered this a highly ambitious project with a laudable aim. However, the challenges in bringing this approach to the clinic appear considerable, and the concept is not yet ready for clincial study within 5 years. The justification for the concept was considered vague by one reviewer and the expertise of team members limited. The program director identified a number of barriers to successful stem cell based-tissue engineering approach to joint replacement, however, failed to lay out the team’s specific approaches. Additional evidence of the feasibility would have been helpful. The program director has experience in establishing goal-driven multidisciplinary teams for the development of innovative prostheses, however there is little evidence of leading and assembling a major effort of multi-independent investigators. There are two concurrent plans described for the research project that are detailed as would be necessary in the final proposal but no detail on how this will be fleshed out or studied during the planning stage. One reviewer expressed concern that three of the seven “Core Team” members will only serve as consultants. Overall, reviewers felt that this proposal did not warrant a planning award at this time. Reviewer Synopsis Arthritis and other rheumatic diseases result in very significant morbidity and are a very significant burden to the health care system. Joint replacement is a frequently performed surgical intervention the efficacy of which is limited by the lifespan of the implant and the frequent need to perform revision surgery. Seeking to improve the nature of current joint replacement devices, the PI Dr D’Lima proposes to establish a multidisciplinary team comprising orthopedic surgeons, stem cell biologists and bioengineers dedicated to the development of a biological device in the form of a large osteochondral construct replicating an entire joint by growing stem cells on suitable biomaterials in a bioreactor. The PI has experience in establishing goal-driven multidiisciplinary teams having previously successfully directing a collaboration across a number of industrial partners including regulatory agencies that led to the development of the first transplantable small knee arthroplasty prosthe Reviewer One Comments Concept: The concept is that a biocompatible tissue for joint replacement should be possible with structural biomaterials and functional renewable stem cell derived cartilage. The plan is to use these components to form entire joints (knee) or large subsections of joint. There are biomaterials that are biocompatible and have mechanical properties similar to cartilage; embryonic and mesenchymal stem cells can be directed to form chondrocytes; combined these are said to have the potential to form whole complex 3-dimensional joints. It seems that this is a very complex problem that has a real need long term for joint replacement but the technologies may not be mature enough yet. The question of rejection of allograft cells is not even mentioned. Principal Investigator: Dr. D’Lima, is a trained orthopedic surgeon who has further training in Bioengineering (PhD 2007, UCSD). He is currently Assistant Professor at Scripps Research Institute and has been Director of the Orthopedic Research Laboratories, Scripps Clinic since 2001. He currently has several small ($25-32,000/yr) grants. While he has developed the first of several innovative protheses, there is little evidence of his orchestrating a major grant of multi-independent investigators. Planning Approach: There is a multidisciplinary core team assembled consisting of three cartilage/orthopedic specialists, a bimaterials, cartilage allograft surgeon, stem cell biologists, and cartilage and bone morphogenesis expert. There are two concurrent plans (construct development and validation/outcomes assessment) that are detailed as would be necessary in the final proposal but no detail on how this will be fleshed out or studied during the planning stage. Reviewer Two Comments Concept: • Concept: The overall objective is to develop a biologically compatible tissue for joint repair that combines structural biomaterials and functional, renewable, stem cell-derived cartilage. • Evidence / maturity: The PI identified a number of barriers to successful stem cell based-tissue engineering approach to joint replacement, however, failed to lay out the team’s specific approaches. The feasibility justification remains vague. Stem cell expertise needs to be strengthened. Principal Investigator: The PI is an assistant professor in arthritis research, and an expert in orthopedic research. Although the PI has experience as project leader for clinical, preclinical and translational studies, it remains to be tested whether the PI is capable of assembling and leading a large effort by core, specialty and clinical team. Planning Approach: • Specific activities for the planning phase are not described in details. It is unclear how the PI will coordinate the collaborations between different teams and direct and consolidate these different efforts. • Three of the seven “Core Team” members will only serve as consultants. If biomaterials and stem cells are the two key components, this arrangement is worrisome. • A range of vague and ambitious research activities are proposed for the “Disease Team Award” phase. It is unclear how these activities can be accomplished within a 4- to 5-year period. Reviewer Three Comments Concept: Arthritis and rheumatic diseases are a major economic burden which will increase as the population as a whole ages. Joint replacement is the only effective therapeutic option for end stage joint disease. However, of the 800,000 or so joint replacements performed per year in the US approximately 20% will eventually require a second revision surgery to correct complications. Given that 80% of artificial implants survive 15-20 years, there use in the elderly patient represents a satisfactory therapeutic outcome. The case for the plausibility of the target appears to be the lack of a satisfactory clinical option for joint replacement in younger patients based on the finite life span of artificial implants coupled with the lack of effectiveness of other therapeutic options (such as allografts of cadaveric bone). A more compelling case would be made by the applicant providing evidence of the proportion and absolute number of patients falling into the younger patient category. This is a highly ambitious project that is as much a stem cell biological as a bioengineering problem. The aim is certainly very laudable but the challenges in bringing this approach to the clinic appear considerable. Additional evidence of the feasibility of what is being proposed would have been helpful in assessing this proposal. Principal Investigator: Dr. D’Lima is an Assistant Professor at the Scripps Clinic and although relatively junior runs a large laboratory. He states he has been a PI in a number of multi-disciplinary projects encompassing translational research but he failed to provide the nature of these projects. In developing the first implantable Smart Knee Arthroplasty Prosthesis the PI was responsible for directing a collaboration across a number of industrial partners as well as negotiating the regulatory pathway and providing funding for the project. This is valuable experience that will be required for the project described in the current proposal. The PI has assembled a core team and has identified members of what are referred to as a speciality team (involving various basic research and clinic expertise) and a clinical and commercialisation committee to manage clinical trials, device development and interactions with the FDA. Members of the latter committee were not specified. Planning Approach: The PI proposes to develop two concurrent plans one for developing osteochondral constructs and a second for testing and validation of the constructs. In overall terms this seems a sensible strategy but as eluded to above, what would have been helpful in assessing this proposal was more data testing to the feasibility fabricating large osteochondral constructs ex vivo