DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted August 20, 2021

Dr. Luis Alvarez, Ph.D., Theradaptive, Inc.

Dr. Luis Alvarez, Ph.D., Theradaptive, Inc. Dr. Luis Alvarez

Summary: The translation of a medical product from discovery to development and eventual approval for use in humans usually starts with a question. For U.S. Army retired Lieutenant Colonel Luis Alvarez, Ph.D., that question was: How can we promote bone healing and regeneration after traumatic injuries? After serving in Iraq, Dr. Alvarez witnessed fellow Service Members lose their limbs after their bone injuries failed to heal, and he was determined to find a solution. He leveraged funding from CDMRP’s Peer Reviewed Orthopaedic Research Program (PRORP), Joint Warfighter Medical Research Program (JWMRP), Defense Medical Research and Development Program (DMRDP), and the Peer Reviewed Medical Research Program (PRMRP) to find answers. In the end, Dr. Alvarez was able to use the knowledge gained from his early research to attach stable biological elements, such as proteins, to a synthetic scaffold that could repair bone. Dr. Alvarez’s Osteo-Adapt technology takes advantage of the body’s natural healing process to repair bone fractures. Clinical trials in humans are expected to begin in 2022.

Details: Musculoskelatal injuries (MSKI), those affecting the bones, joints, and muscles, comprise ~50% of all combat wounds in recent conflicts (1). These injuries are often complex fractures of long bones that will not heal spontaneously within a patient’s lifetime, making them especially difficult to treat. MSKI are also the most common conditions resulting in Service Member separation from military duty. Additionally, among the general public, nearly 50% of Americans report a musculoskeletal condition, including low back pain, chronic joint pain, and arthritis (2). In the United States, musculoskeletal disorders cost over $200 billion annually in treatment and care expenses and lost wages (3).

Bone grafting, a surgical procedure of transplanting bone, is frequently used to treat some MSKIs, including fractures, bone void defects, and osteonecrosis (bone death), and is the second most frequent tissue transplantation worldwide (4). In brief, the body’s own cells that are involved in growth and repair are recruited to the site of the transplanted bone. This includes a specific kind of stem cell called mesenchymal stem cells. These stem cells will then respond to cellular signals in the body to turn into two key types of bone cells, chondroblasts and osteoblasts, which create cartilage and bone tissue, respectively (5). Bone grafts obtained from the same individual receiving the graft are called autografts and are the most frequent source for bone transplantation. However, a major limitation is the availability of enough bone autografts to treat large defects, such as those frequently seen in combat injuries and trauma. To address this, Dr. Alvarez set out to develop a synthetic bone scaffold that can mimic the ability of the real bone to promote bone regrowth and repair.

During his Ph.D. training at Massachusetts Institute of Technology, Dr. Alvarez discovered a novel way to attach a protein that is involved in cell and tissue growth, called epidermal growth factor (EGF), to a scaffold material commonly used as a bone void filler called beta-tri calcium phosphate (betaTCP) (6). Attaching the protein to the filler turned an otherwise inactive scaffold into one that can recruit and expand the stem cells that are required for bone regeneration. To further advance this discovery, Dr. Alvarez received his first award from the Congressionally Directed Medical Research Programs (CDMRP) through the PRORP in 2010. This award aimed to further develop this new method of linking growth proteins to the betaTCP scaffold material. Results from this research confirmed that a TCP-containing bone implant could be coated with virtually any growth protein, not just the one he originally worked with. To advance this development to the next level, Dr. Alvarez used the data generated from this PRORP award to support a research application to the JWMRP that was focused on conducting preclinical studies of a version of another growth protein, BMP-2, that could bind to the TCP scaffold. BMP-2, or bone morphogenetic protein-2, is important for bone healing and has been used in the clinic as a bone-inducing agent. BMP-2-containing medical devices have been marketed for three Food and Drug Administration (FDA)-approved indications: lumbar spinal fusion, tibial segmental defects, and alveolar ridge augmentation, and have shown exceptional efficacy. However, extremely high doses of BMP-2 are required to jump start bone formation at the site of the bone implant because the protein can freely migrate away from the intended site. Unfortunately, this spreading of high doses of BMP-2 can also lead to bone formation in other tissues, which can be extremely dangerous (7). Dr. Alvarez hypothesized that linking BMP-2 to the betaTCP scaffold would solve this problem and could decrease the amount of BMP-2 needed for effective bone regeneration.

With his 2014 JWMRP award, Dr. Alvarez and a team of collaborators at Mayo Clinic and the Cleveland Clinic Foundation established manufacturing processes to synthesize the modified BMP-2 protein and completed animal studies to evaluate safety and efficacy. Importantly, Dr. Alvarez also started the process for obtaining FDA regulatory approval for the BMP-2 scaffold product developed under this award, which they called Osteo-Adapt. In 2017, Dr. Alvarez received another award through the DMRDP to further scale up the Osteo-Adapt technology to allow for the design and 3D printing of different sizes of the scaffolds for use in the repair of human injuries, such as for tibial repair and spinal fusion, while maintaining compliance with FDA requirements. This work focused on a detailed characterization of the BMP-2 scaffold at a level that would satisfy FDA requirements. Further characterization studies and the final animal studies for Osteo-Adapt were funded by the PRMRP in 2019. The objective of this latest award is to complete the final preclinical studies required by the FDA and move forward with a clinical trial in humans, which is planned for 2022.

Successful translation of discoveries made at the laboratory bench into clinical application is critical for improving public health and requires the integration of scientists, clinicians, and funding agencies. The research efforts of Dr. Alvarez and his team have led to translation of a method for attaching proteins to a scaffold material into a new ‘bioactive’ scaffold material that mimics characteristics of real bone for the repair of human bone injuries. As exemplified in Dr. Alvarez’s funding history, the CDMRP is dedicated to the mission of advancing paradigm-shifting research. Through coordination across over 30 different programs and funding projects across the research spectrum, the CDMRP strives to ensure that questions like Dr. Alvarez’s can be answered, transforming healthcare for Service Members and the American public.

References:

1) Belmont PJ, Schoenfeld AJ, and Goodman G. Epidemiology of combat wounds in Operation Iraqi Freedom and Operation Enduring Freedom: orthopaedic burden of disease.  Journal of Surgical Orthopaedic Advances 19(1):2-7. PMID: 20370999.

2) Patzkowski JC, Rivera JC, Ficke JR, and Wenke JC. The changing face of disability in the US Army: the Operation Enduring Freedom and Operation Iraqi Freedom effect. Journal of the American Academy of Orthopaedic Surgeons 20(1)S23-30. doi: 10.5435/JAAOS-20-08-S23. PMID: 22865131.

3) American Academy of Orthopaedic Surgeons. One in two Americans have a musculoskeletal condition: New report outlines the prevalence, scope, cost and projected growth of musculoskeletal disorders in the U.S. Science Daily www.sciencedaily.com/releases/2016/03/160301114116.htm.

4)Busch A, Wegner A, Haversath M, Jäger M. Bone substitutes in Orthopaedic Surgery: Current status and future perspectives. Zeitschrift fur Orthopadie und Unfallchirurgie Jun;159(3):304-313. English. doi: 10.1055/a-1073-8473. Epub 2020 Feb 5. PMID: 32023626.

5) Ghiasi MS, Chen J, Vaziri A, Rodriguez EK, Nazarian A. Bone fracture healing in mechanobiological modeling: A review of principles and methods. Bone Reports Mar 16;6:87-100. doi: 10.1016/j.bonr.2017.03.002. PMID: 28377988; PMCID: PMC5365304.

6)Alvarez LM, Rivera JJ, Stockdale L, Saini S, Lee RT, Griffith LG. Tethering of epidermal growth factor (EGF) to Beta Tricalcium Phosphate (betaTCP) via fusion to a high-affinity, multimeric betaTCP-Binding Peptide: Effects on human multipotent stromal cells/connective tissue progenitors. PLoS One Jun 29;10(6):e0129600. doi: 10.1371/journal.pone.0129600. PMID: 26121597; PMCID: PMC4488278.

7)Tannoury CA, An HS. Complications with the use of bone morphogenetic protein 2 (BMP-2) in spine surgery. The Spine Journal Mar 1;14(3):552-9. doi: 10.1016/j.spinee.2013.08.060. Epub 2014 Jan 8. PMID: 24412416.

Links:

Public and Technical Abstracts: Assisted Bone Regrowth Engineering Advanced Materials for Tissue Regeneration

Public and Technical Abstracts: Targeted Therapeutics for Orthopedic Regeneration

Public and Technical Abstracts: Tethered Recombinant Human BMP2 Delivered with Beta-Tricalcium Phosphate Nanoparticles for the Treatment of Open Tibial Fracture

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Last updated Friday, August 20, 2021