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Mesenchymal Stem Cells and an Advanced Synthetic Bio-textured Scaffold for the Restoration and Repair of Bone Defects

Funding Type: 
Strategic Partnership II
Grant Number: 
Funds requested: 
$10 121 275
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
This work is directly relevant to stem-cell derived therapy that will advance the treatment of a serious injury in humans. This research and product development will provide a novel method for bone graft to address the needs of spinal fusion patients. We will do translational studies to develop bone remodeling therapies. More than 400,000 Americans require surgery every year for debilitating spinal conditions at an annual cost of more than $3 billion. Spinal fusion surgery is often the only effective procedure for treating pathologic spinal conditions such as scoliosis, degenerative disc disease, spondylolisthesis, or spinal instability, which can cause severe pain by compressing spinal nerves. The traditional method is to remove the pathology compressing the spinal nerves, and then fuse the spine by removing the disc material and inserting a “cage” between the vertebrae. The current “gold standard” for spine bone replacement is the use of autologous bone harvested from the same patients’ hip. But the patient must undergo two surgeries, one for the hip and one for the spine. Bone chips are harvested from the patient’s hip and inserted into the cage. The bone eventually causes the vertebrae to fuse, which stabilizes the spine. Limitations of harvesting the bone graft from the patient include longer recovery time, increased blood loss, pain and co-morbidities associated with bone harvest from the hip. Patients may be relieved of their spinal conditions, but many end up with chronic hip pain. With the advancement of minimally invasive surgical techniques the opportunity to identify autograft bone replacements is imperative. The company’s new biomaterial is a synthetic bone graft alternative, which has been shown to stimulate differentiation of stem cells into bone forming osteoblasts. However, the major limitation is that it relies on the patient’s own cells to form new bone. Often, these patients are elderly or have co-morbidities such as diabetes or obesity that has a detrimental effect on their own regenerative potential. Higher yields of bone reformation could be achieved therapeutically by combining human bone marrow-derived stromal cells (hBMSCs) with the synthetic biomaterial. We have shown that stimulation of hBMSCs and differentiation to osteoblasts followed by attachment to the biomaterial enhances the efficacy of this approach. We will clinically evaluate a bone remodeling therapy utilizing a classic tissue-engineering approach that combines sources of cells, signaling factors, and a biomaterial scaffold. The novel cellular bone graft will be elaborated through this work without the need for autologous bone. In the long run this will improve the health of individuals with debilitating spinal conditions.
Statement of Benefit to California: 
An estimated 10 million adults suffer from chronic back pain annually, making back pain the number 1 cause of healthcare expenditures in the U.S. with a direct cost of more than $50 billion annually for diagnosis, treatment and rehabilitation. The majority of patients suffer spine problems related to degenerative conditions. These degenerative conditions can result in instability and intrusion into the spinal cord and surrounding nerves, causing back pain and/or radiating pain in the arms or legs. The State of California has approximately 12% of the US population which translates to 1.2 million chronic spine pain individuals with a direct cost of more than $6 billion annually for diagnosis, treatment and rehabilitation. Even for patients that had successful spinal surgery, other problems are associated with bone collection procedures and post-surgical scenarios. Accordingly, an urgent need for a less invasive, more efficient means of doing spinal fusion is needed. Tissue engineering of bone is important because it has a huge impact on the economy and patient welfare. With an aging population, the needs for improved grafting options that remove the collection of the patient’s own hip bone is necessary to address. Most currently available bone grafts require the patient’s own cells to enter the graft and form bone. Often, these patients are elderly or have co-morbidities such as diabetes or obesity that has a detrimental effect on their own cellular regenerative potential. Cell implants are a superior alternative for bone repair, particularly for spinal fusion where the endogenous source of progenitor cells is not present in sufficient quantities. This strategy has been brought to clinical trials using stimulated human bone-marrow derived stromal cells (hBMSCs) that have been expanded in cell culture to adopt an osteogenic lineage. By combining novel cell-stimulating technology and FDA-approved hBMSCs and matrix, a robust product will be created. An estimated 5% of the Californian population is expected to be personally impacted with a serious spinal condition at some point in their lives. Of these, 48,000 will be indicated for spinal fusion surgery each year. As such, spinal conditions are one of the most prevalent conditions faced by Californians, and this is only expected to increase as the population continues to age. An estimate of annual revenues for this product is in the $200-$800 million range within the first few years of full commercial launch. Thus, successful completion of this work will not only provide citizens of California much needed advances in bone healing technology of relevance to spinal conditions and improvement in health care but it will also provide high paying jobs and significant tax revenue. This product may also be significantly cheaper to produce than current state of the art technologies, which will result in lower costs to the health care system and increased profitability for the California-based companies.
Review Summary: 
The applicant proposes to develop a combination product that can improve on the current methods for spinal column fusion, which often involve a pre-collection of bone tissue from the hip of the patient (an autograft). The proposed combination product consists of a synthetic bone graft alternative that will be combined with human bone marrow-derived stromal cells (hBMSC) that have been stimulated to differentiate into cells that can form new bone. The product would be implanted during lumbar spinal column stabilization surgery and would replace the need for an autograft. The applicant expects spinal column fusion surgery using this combination product to be suitable for a broad range of patients with degenerative disc disease and that it will eliminate some of the risks of the current treatment procedures. The proposed work under the grant would begin with preclinical studies, include submission of an IND, and proceed through initiation and completion of a Phase 1/2 clinical trial. Significance and Impact - Reviewers commented that the overall approach of this type of combination product (hBMSC plus a synthetic bone matrix) was not very novel, although they appreciated that pre-stimulating the hBMSC to differentiate to bone forming cells was a distinctive component. - While reviewers agreed that eliminating the need for an autograft by developing a standardized therapeutic product would likely broaden the patient pool eligible for a lumbar spinal fusion surgery, insufficient data were presented to assess the stated benefits of the proposed combination product. - Reviewers were enthusiastic about development of a combination product consisting of bone-forming cells and a synthetic scaffold and predicted that it could address unmet orthopedic medical needs. However, some felt the application overstated the potential impact and clinical competitiveness of the combination product for the intended patient population. Scientific Rationale and Risk/Benefit - The application contained inadequate information to assess the activity of the fully formulated combination product. - As the current methods of spinal column fusion are largely successful, reviewers were not convinced that the proposed combination product would provide sufficient additional benefit to outweigh potential product risks, which have not yet been described. - Reviewers expressed concern that plans were insufficient for monitoring ectopic osteogenesis in trial participants. - Convincing evidence was provided that effective methods had been developed to pre-stimulate the hBMSC to differentiate towards forming bone cells. However, the safety profile of these stimulated cells was not sufficiently described. Design and Feasibility - Preliminary data were lacking from studies using the fully formulated combination product in preclinical models. The team needs to describe the phenotype, immunogenicity and distribution of osteogenic-stimulated hBMSC in the synthetic bone matrix after delivery in a clinically relevant animal model. - The design of the proposed preclinical studies was considered insufficient to inform clinical dose and assure the safety of the therapeutic combination product in the proposed clinical indication. - Reviewers described the proposed methods for manufacturing the combination product as quite complex and insufficient data were presented to assess the feasibility of manufacturing and delivering a combination product that maintains the activity of the bone-forming cells. More extensive characterization of the osteogenic-stimulated hBMSC, both before and after formulation for delivery with the synthetic bone matrix, is needed. - Reviewers assessed the proposed design of the Phase 1/2 clinical trial as unlikely to provide a meaningful data set that would be sufficient for evaluation of product safety and therapeutic efficacy. Principal Investigator (PI), Development Team and Leadership Plan - The PI and members of the development team are experts in the advancement of medical devices for spinal applications; however, reviewers described the team as lacking in the specific knowledge required for manufacturing a combination product that includes human cells in a medical device. Collaborations, Assets, Resources and Environment - The team is skilled, has experience in developing orthopedic medical devices and is predicted to collaborate well.

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