Dr. Luis Alvarez, CEO and Founder, Theradaptive02.17.23
Orthopedics has been around since the Middle Ages when battle-injured soldiers started treating injuries with rudimentary canvas splints. All those hundreds of years ago, at the dawn of orthopedics as a nascent practice, wartime injuries brought a high likelihood of death. Now, by contrast, the science has improved dramatically and most wounded servicemembers survive their injuries. Orthopedics has also improved the lives of millions of patients who suffer from a range of conditions from spinal degeneration to arthritic hips and knees.
However, the practice still has plenty of space to evolve and improve. Just as the history of wartime medicine illustrates how far we have come, saving lives and limbs that would never have previously been salvaged, the battlefield also highlights the limitations of current orthopedic best practices. Currently, when soldiers fall victim to trauma in 21st century war zones, for example from an improvised explosive device (IED), their limbs can be saved by surgical procedures at the time of injury, but they are later forced to undergo delayed amputation as the bones in the limb fail to heal.
This ability to carry out complex reconstructive surgery and repair catastrophic damage to the body demonstrates the miraculous power of modern medicine. However, veterans are not out of the woods yet. Too often, despite the initial treatment, they are forced to choose between remaining bedbound or undergoing delayed amputation and attempting to regain mobility with prosthetics. In one study of U.S. combat casualty amputations, 15.2% were performed more than 12 weeks after injury.1 Many more amputations occur in the weeks following traumatic injury, reflecting a wider problem within orthopedics.
Namely, fixing structural problems does not solve the issue. Damage to surrounding tissue often means the bone cannot heal and surgeons are forced to amputate in order to help patients regain mobility via prosthetics and avoid complications. In a survey conducted last year, it was found that 67% of military veterans with service-related injuries had musculoskeletal injuries,² underscoring the need for better treatments. Meanwhile, in the wider U.S. population, 900,000 Americans undergo spinal surgery each year,3 and come up against similar issues related to bone and tissue damage.
Consequently, in order to improve standards of care and boost patient outcomes, researchers are looking for ways to regenerate bone and surrounding tissue. However, orthopedics has been stalled on this issue for a few decades now. The tools are more advanced, as materials graduate from steel to titanium, making orthopedic devices more durable and hypoallergenic. Similarly, the surgical techniques used to implant orthopedic devices have become far less invasive, with smaller incisions translating to quicker recovery times and reduced risk of delayed amputation.
The methodology, however, is still fundamentally the same. We have not advanced beyond what is essentially bodily carpentry, repairing structural problems without helping the body to heal or integrate foreign materials into its ecosystem. The same companies are still selling the same technology, which fails to answer questions about regenerating bone and tissue for long-term improved outcomes.
Fortunately, change is finally afoot and there are new, groundbreaking treatments on the horizon. New discoveries in molecular biology mean regenerative medicine is creating a whole new toolkit for orthopedic surgeons; the regenerative medicine market was valued at $10.1 billion in 2022 and is expected to skyrocket to $83.2 billion by the end of this decade4 as it transforms the ways in which surgeons deliver implants and medical devices. Targeted protein delivery is also expected to disrupt adjacent fields, including dental, wound repair, vascular repair, targeted tissue therapeutics, and targeted cancer therapeutics.
In orthopedics, bioactive proteins like bone morphogenetic protein 2 (BMP2) are providing bone and tissue regeneration therapy where there had previously been no treatments available. However, while BMP2 promotes bone formation, its current commercial form lacks the precision to safely target a specific injury site. BMP2 often disperses, causing off-target effects in other areas of the body, such as forming bone in areas where it is not needed or causing inflammation that can be uncomfortable or even life-threatening. While these proteins offer a glimpse of what is to come, many surgeons refuse to use them because of their alarming side effects.
If the regenerative healing properties of a protein can be harnessed via better targeting, we will see a great leap forward in patient outcomes. It will become standard practice for orthopedic devices to be coated with an osteoinductive biologic that can heal the surrounding area and promote bone or tissue growth safely. Servicemembers who sustain trauma-related injuries will no longer have to undergo delayed amputations, and other orthopedic applications like spinal fusion will also enjoy a better success rate. With one in six people expected to reach the age of 60 by 20305—a 40% increase across this decade—more patients will suffer from age-related conditions like disc degeneration; 40% of adults over the age of 40 and 80% of patients over the age of 80 have at least one degenerated vertebral disc.6 If new treatments can be found, millions of people who would have otherwise suffered from debilitating back or joint pain in decades to come will be spared.
The most promising breakthroughs have come from advances in protein engineering. Naturally occurring proteins with useful characteristics like induction of bone regeneration can be identified and then re-engineered in the lab. Only in recent years has it become possible to modify bioactive proteins to bind to orthopedic devices, allowing them to stay in place long enough to take effect. For example, AMP2 is a variant of BMP2 that has been engineered to retain its bone-regenerating capabilities but with added precision using computational sequence optimization. The protein is designed to adhere to implantable substrates often used in orthopedics like void fillers, cages, and screws. The same binding technology has also been applied to other proteins relevant for dermal wound healing, cartilage repair, and even targeted oncology. This enables these approaches to take advantage of the localized and persistent presentation of proteins with a single dose acting over time spans exceeding months in many cases.
With proteins like AMP2, surgeons will also have more control over the therapeutic window, with the ability to tune the rate at which a biologic grows tissue. Proteins can also be engineered to survive terminal sterilization so they remain bioactive throughout the implant manufacturing process. Orthopedic procedures can then be complemented by powerful osteoinductive regenerative agents that allow bone and tissue around non-native materials to grow and heal. For example, in the case of spinal implants, bone can be induced to integrate with the implant, providing long-lasting stability and pain relief. Given the improved safety profile of these new proteins, due to their precise delivery and lower dose, physicians who were once wary about using biologics can be more confident in incorporating these novel therapeutics to treat their patients. These treatments will also be more cost effective because lower doses are required when proteins remain in the location of injury.
Orthopedics has come a long way from its bloody beginnings. If new technology enables surgeons to overcome the decades-old problem of integrating living tissues with implanted materials, then the industry can continue pushing the boundaries of what is possible. At the moment, patients who feel like they are failed by the current orthopedic procedures available should look to the revolution in biologic delivery as a real option for improving treatment outcomes.
References
A graduate of West Point, Dr. Luis Alvarez served in the U.S. Army for 20 years. Following a combat tour and seeing fellow servicemembers forced to undergo delayed amputations due to tissue damage, he was motivated to pursue a Ph.D. in biological engineering at MIT, where he was a Hertz Foundation Fellow. Dr. Alvarez founded Theradaptive following his time in the Army, using what he learned from his research to create a platform that can now deliver biologics in a highly targeted way. Previously, he was the founding deputy director of the U.S. Department of Defense’s Regenerative Medicine Program Office as well as lead for the DoD’s $720 million nerve agent pharmaceutical countermeasures program. As CEO and co-founder, Dr. Alvarez has seen the Theradaptive team grow from four to 25 people, with the FDA granting the company three breakthrough designations for various spine indications, accelerating the process of reaching approval.
However, the practice still has plenty of space to evolve and improve. Just as the history of wartime medicine illustrates how far we have come, saving lives and limbs that would never have previously been salvaged, the battlefield also highlights the limitations of current orthopedic best practices. Currently, when soldiers fall victim to trauma in 21st century war zones, for example from an improvised explosive device (IED), their limbs can be saved by surgical procedures at the time of injury, but they are later forced to undergo delayed amputation as the bones in the limb fail to heal.
This ability to carry out complex reconstructive surgery and repair catastrophic damage to the body demonstrates the miraculous power of modern medicine. However, veterans are not out of the woods yet. Too often, despite the initial treatment, they are forced to choose between remaining bedbound or undergoing delayed amputation and attempting to regain mobility with prosthetics. In one study of U.S. combat casualty amputations, 15.2% were performed more than 12 weeks after injury.1 Many more amputations occur in the weeks following traumatic injury, reflecting a wider problem within orthopedics.
Namely, fixing structural problems does not solve the issue. Damage to surrounding tissue often means the bone cannot heal and surgeons are forced to amputate in order to help patients regain mobility via prosthetics and avoid complications. In a survey conducted last year, it was found that 67% of military veterans with service-related injuries had musculoskeletal injuries,² underscoring the need for better treatments. Meanwhile, in the wider U.S. population, 900,000 Americans undergo spinal surgery each year,3 and come up against similar issues related to bone and tissue damage.
Consequently, in order to improve standards of care and boost patient outcomes, researchers are looking for ways to regenerate bone and surrounding tissue. However, orthopedics has been stalled on this issue for a few decades now. The tools are more advanced, as materials graduate from steel to titanium, making orthopedic devices more durable and hypoallergenic. Similarly, the surgical techniques used to implant orthopedic devices have become far less invasive, with smaller incisions translating to quicker recovery times and reduced risk of delayed amputation.
The methodology, however, is still fundamentally the same. We have not advanced beyond what is essentially bodily carpentry, repairing structural problems without helping the body to heal or integrate foreign materials into its ecosystem. The same companies are still selling the same technology, which fails to answer questions about regenerating bone and tissue for long-term improved outcomes.
Fortunately, change is finally afoot and there are new, groundbreaking treatments on the horizon. New discoveries in molecular biology mean regenerative medicine is creating a whole new toolkit for orthopedic surgeons; the regenerative medicine market was valued at $10.1 billion in 2022 and is expected to skyrocket to $83.2 billion by the end of this decade4 as it transforms the ways in which surgeons deliver implants and medical devices. Targeted protein delivery is also expected to disrupt adjacent fields, including dental, wound repair, vascular repair, targeted tissue therapeutics, and targeted cancer therapeutics.
In orthopedics, bioactive proteins like bone morphogenetic protein 2 (BMP2) are providing bone and tissue regeneration therapy where there had previously been no treatments available. However, while BMP2 promotes bone formation, its current commercial form lacks the precision to safely target a specific injury site. BMP2 often disperses, causing off-target effects in other areas of the body, such as forming bone in areas where it is not needed or causing inflammation that can be uncomfortable or even life-threatening. While these proteins offer a glimpse of what is to come, many surgeons refuse to use them because of their alarming side effects.
If the regenerative healing properties of a protein can be harnessed via better targeting, we will see a great leap forward in patient outcomes. It will become standard practice for orthopedic devices to be coated with an osteoinductive biologic that can heal the surrounding area and promote bone or tissue growth safely. Servicemembers who sustain trauma-related injuries will no longer have to undergo delayed amputations, and other orthopedic applications like spinal fusion will also enjoy a better success rate. With one in six people expected to reach the age of 60 by 20305—a 40% increase across this decade—more patients will suffer from age-related conditions like disc degeneration; 40% of adults over the age of 40 and 80% of patients over the age of 80 have at least one degenerated vertebral disc.6 If new treatments can be found, millions of people who would have otherwise suffered from debilitating back or joint pain in decades to come will be spared.
The most promising breakthroughs have come from advances in protein engineering. Naturally occurring proteins with useful characteristics like induction of bone regeneration can be identified and then re-engineered in the lab. Only in recent years has it become possible to modify bioactive proteins to bind to orthopedic devices, allowing them to stay in place long enough to take effect. For example, AMP2 is a variant of BMP2 that has been engineered to retain its bone-regenerating capabilities but with added precision using computational sequence optimization. The protein is designed to adhere to implantable substrates often used in orthopedics like void fillers, cages, and screws. The same binding technology has also been applied to other proteins relevant for dermal wound healing, cartilage repair, and even targeted oncology. This enables these approaches to take advantage of the localized and persistent presentation of proteins with a single dose acting over time spans exceeding months in many cases.
With proteins like AMP2, surgeons will also have more control over the therapeutic window, with the ability to tune the rate at which a biologic grows tissue. Proteins can also be engineered to survive terminal sterilization so they remain bioactive throughout the implant manufacturing process. Orthopedic procedures can then be complemented by powerful osteoinductive regenerative agents that allow bone and tissue around non-native materials to grow and heal. For example, in the case of spinal implants, bone can be induced to integrate with the implant, providing long-lasting stability and pain relief. Given the improved safety profile of these new proteins, due to their precise delivery and lower dose, physicians who were once wary about using biologics can be more confident in incorporating these novel therapeutics to treat their patients. These treatments will also be more cost effective because lower doses are required when proteins remain in the location of injury.
Orthopedics has come a long way from its bloody beginnings. If new technology enables surgeons to overcome the decades-old problem of integrating living tissues with implanted materials, then the industry can continue pushing the boundaries of what is possible. At the moment, patients who feel like they are failed by the current orthopedic procedures available should look to the revolution in biologic delivery as a real option for improving treatment outcomes.
References
- bit.ly/odt230191
- bit.ly/odt230192
- bit.ly/odt230193
- bit.ly/odt230194
- bit.ly/odt230195
- bit.ly/odt230196
A graduate of West Point, Dr. Luis Alvarez served in the U.S. Army for 20 years. Following a combat tour and seeing fellow servicemembers forced to undergo delayed amputations due to tissue damage, he was motivated to pursue a Ph.D. in biological engineering at MIT, where he was a Hertz Foundation Fellow. Dr. Alvarez founded Theradaptive following his time in the Army, using what he learned from his research to create a platform that can now deliver biologics in a highly targeted way. Previously, he was the founding deputy director of the U.S. Department of Defense’s Regenerative Medicine Program Office as well as lead for the DoD’s $720 million nerve agent pharmaceutical countermeasures program. As CEO and co-founder, Dr. Alvarez has seen the Theradaptive team grow from four to 25 people, with the FDA granting the company three breakthrough designations for various spine indications, accelerating the process of reaching approval.
