Mehdi Kazemzadeh-Narbat, Ph.D., PMP, CQA, Director, Regulatory Affairs, MCRA LLC05.21.24
There are mainly three kinds of orthopedic implant materials: metals, ceramics, and polymers. Since most orthopedic applications require load-bearing, metals are preferred over ceramics or polymers due to their high mechanical strength and fracture toughness. Thus, traditional metallic orthopedic implants are usually made of metals with satisfactory biocompatibility, high wear resistance, and adequate mechanical strength such as stainless steel, titanium (Ti) or its alloys (e.g., Ti-6Al-4V), and cobalt–chromium (Co-Cr) alloys.
However, metallic implants have the following limitations:
A growing body of clinical evidence supports Mg alloy use for orthopedic, dental, and sports medicine applications based on devices currently approved. In Europe, the MAGNEZIX Compression Screw received CE mark approval in 2013. Next up—expected later this year—is the RemeOs Screw from Bioretec. The Finnish firm received U.S. Food and Drug Administration (FDA) Breakthrough Device Designation for its screw in 2021 and De Novo marketing approval. The RemeOs Screw LAG Solid is the only approved Mg-based orthopedic screw designed for fracture and osteotomy repair as well as deformity or malalignment correction. FDA has also granted German manufacturer Medical Magnesium GmbH Breakthrough Device status for its orthopedic and trauma care plate system but this device has not yet been cleared/approved.
There seemingly are only two non-prosthetic Mg-based orthopedic implants. The first is OSTEOREVIVE developed by Bone Solutions Inc. and cleared by the FDA in 2023. OSTEOREVIVE is a bone void filler for bony voids or defects in the extremities, posterolateral spine, and pelvis. This product used OsteoCrete Mg-based bone void filler (FDA cleared in 2009) as a primary predicate.
Thankfully, FDA does not believe that Mg contributes to any osteogenic activity (drug action) for conventional bone growth. However, the agency still requires significant pre-clinical Special Controls (testing) for Mg-based orthopedic devices. Some of the regulatory challenges for Mg-based prosthetic orthopedic devices include:
References
Dr. Kazemzadeh-Narbat is a former FDA medical device reviewer who joined MCRA in 2020. He has worked on a wide range of products through hundreds of FDA reviews and numerous engagements at MCRA. Dr. Kazemzadeh-Narbat is a biomedical engineer with five years of FDA experience in medical device regulation. At MCRA, Dr. Kazemzadeh-Narbat provides guidance on regulatory strategies and submissions development across various therapies including orthopedic, general hospital, cardiovascular, neurologic, and as well as antimicrobial devices, drugs, and combination products.
However, metallic implants have the following limitations:
- Stress shielding: By Wolff's law, bone remodels in response to the loads it is placed under. As a result of high Young’s modulus of such metals, stress shielding may cause implant loosening due to bone density reduction (osteopenia); the removal of typical stress from the bone often triggers revision surgery.
- Non-degradability: Remaining as permanent fixtures may cause possible unexpected clinical complications, such as pain or impaired function of the metallic implants due to their non-degradability. This phenomenon requires the implant be removed.
- Possible toxicity: None of the traditional metals—not even titanium—is completely benign in vivo. Consequently, the possible release of toxic metallic ions and/or particles from these implants through corrosion or wear processes over time may collect in the bone and surrounding tissue. Development of local and systemic toxicity caused by metallosis has been reported as a major cause of implant rejection and revision.
- Radiography artifacts: Both titanium and stainless steel can create artifacts in radiography that confound visualization of bone healing progression.
- Mg degrades and forms non-toxic MgO reaction products that are almost completely excreted in urine.
- Mg and Mg alloys’ low elasticity modulus is close to natural bone. This metal creates a uniform stress distribution when subjected to external forces and reduces the risk of stress shielding.
- Mg alloys maintain mechanical integrity over a 12–18 week period while the bone tissue gradually heals, eventually being replaced by natural tissue. This process creates no added pain and helps surgeons avoid fractures during implant removal.
- Mg and its alloys’ density (~1.74 g/cm3) is similar to the density of human bone (1.7-2.0 g/cm3). Magnesium is 75% lighter than steel, and 50% lighter than titanium.
- Mg’s fracture toughness is greater than ceramic biomaterials such as hydroxyapatite. However, its elastic modulus and compressive yield strength are closer to natural bone than other commonly used metallic implants. Mg also provides greater strength than resorbable polymers.
- Mg is essential to human metabolism and is naturally found in bone tissue. An average adult houses approximately 1 mole of Mg (21 g-28 g): about 60% in bone, nearly 40% in soft tissue, and less than 1% in serum. Mg alloy absorption releases Mg, Ca, Zn, and Mn, which are essential elements in bone and soft tissue and utilized beneficially in the body.
- Since Mg reportedly increases the pH of its local physiological environment, it has been associated with Ca2+ binding and bone healing promotion. The high alkalinity also reportedly has some anti-microbial and anti-biofilm effects.
- Mg implants exhibit substantially less image artefact in radiography, CT, and MRI, and improves post-operative imaging, thanks to their similar density to native bone, which provides an improved field of view of healing bone.
- Rapid absorption: Magnesium has low corrosion resistance. In the body’s high chloride environment, Mg is turned into a soluble, non-toxic oxide that is excreted in urine. Pure magnesium corrodes too quickly in the physiological pH (7.4–7.6) realm, which results in premature mechanical integrity before the tissue has sufficiently healed. To tailor its corrosion rate, magnesium can be alloyed by elements such as zinc, aluminum, and manganese, or used with protective coatings.
- High hydrogen emission: Local hydrogen build-up during Mg’s corrosion process accumulates at a rate (~0.01 mL/cm2/day) that is too fast to be dealt with by surrounding tissue. Hydrogen bubbles may cause host tissue necrosis by delaying healing.
- Low elastic modulus: Low Mg elastic modulus (41-45 GPa) is useful for stress shielding but it requires special engineering to adjust the mechanical properties to each clinically relevant indication.1-5
FDA Regulatory Challenges
In the late 1800s, Mg alloys were developed for vascular and orthopedic applications but their fast corrosion and significant hydrogen generation, and the resulting loss of biomechanical properties made them less than desirable for implantation. In the late 20th century, progress in alloying, surface treatment and coating technology, and advanced manufacturing techniques have helped optimize the material’s alloy properties and corrosion behavior, leading to their reintroduction to resorbable biomedical applications. However, the progress of Mg alloy implants in orthopedics is still hampered by their unpredictable biomechanical properties (mostly from a complicated corrosion profile), and safety concerns.A growing body of clinical evidence supports Mg alloy use for orthopedic, dental, and sports medicine applications based on devices currently approved. In Europe, the MAGNEZIX Compression Screw received CE mark approval in 2013. Next up—expected later this year—is the RemeOs Screw from Bioretec. The Finnish firm received U.S. Food and Drug Administration (FDA) Breakthrough Device Designation for its screw in 2021 and De Novo marketing approval. The RemeOs Screw LAG Solid is the only approved Mg-based orthopedic screw designed for fracture and osteotomy repair as well as deformity or malalignment correction. FDA has also granted German manufacturer Medical Magnesium GmbH Breakthrough Device status for its orthopedic and trauma care plate system but this device has not yet been cleared/approved.
There seemingly are only two non-prosthetic Mg-based orthopedic implants. The first is OSTEOREVIVE developed by Bone Solutions Inc. and cleared by the FDA in 2023. OSTEOREVIVE is a bone void filler for bony voids or defects in the extremities, posterolateral spine, and pelvis. This product used OsteoCrete Mg-based bone void filler (FDA cleared in 2009) as a primary predicate.
Thankfully, FDA does not believe that Mg contributes to any osteogenic activity (drug action) for conventional bone growth. However, the agency still requires significant pre-clinical Special Controls (testing) for Mg-based orthopedic devices. Some of the regulatory challenges for Mg-based prosthetic orthopedic devices include:
- In vitro degradation profile: This study aims to characterize the in-vitro corrosion rate on the worst-case subject device. The FDA’s expectation for Mg degradation is vague, as the agency requires degradation to be measured over time based on both volume and mass loss. Based on ISO 10993-16, biodegradation can be modeled by in-vitro tests. An in-vitro degradation study or “immersion test” is recommended in ISO 10993-15 and ASTM F3268, and framework recommended in ISO 10993-9 outlines the processes used to chemically degrade test material to generate degradation products for analysis.
- Hydrogen evolution: FDA requires that H2 gas generation be recorded over time (usually at the same timepoints as material loss). The sponsor is expected to report the correlation between hydrogen generation and device degradation rate.
- In vivo degradation profile: FDA recommends a functional animal model to demonstrate the effectiveness (e.g., bone healing endpoint) until complete implant absorption. This may extend the duration (late time point) of an animal study significantly since it may be challenging to demonstrate the steady-state biological tissue response to the Mg implant has been achieved. The other challenging part regarding this animal study is to determine the suitable timeframe for covering short-term (one to four weeks), mid, and late time points. Moreover, the sponsor should investigate the in vivo corrosion profile and establish in-vitro to in vivo correlation (IVIVC); the correlation is a statistically rigorous worst-case ratio that considers both variability in the in-vitro and in vivo test results, and assesses any non-linearities observed in the degradation behavior over time. IVIVC is also used to support preconditioning timeframes for mechanical testing, and to support ending the implantation study before complete absorption.
- Corrosion under mechanical testing: Some implants may be required to show the corrosion rate under specific biomechanical loading (e.g., post-surgical rehabilitation) such as shear, tension, compression, or bending and fatigue testing.
- Biocompatibility: FDA considers any orthopedic Mg-based implants as permanent (>30 d) devices in contact with bone/tissue to be assessed in accordance with Table A.1 of its guidance document “Use of International Standard ISO 10993-1, Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process.“ The sponsor should address both local (cytotoxicity, sensitization, irritation, material-mediated pyrogenicity, and implantation endpoints) and systemic toxicity (acute, subacute/subchronic, chronic, genotoxicity, and carcinogenicity endpoints). However, since Mg is an absorbable material, providing justification for required extract adjustments (particulate filtering, pH/osmolality adjustment) can be challenging. In addition, the agency may recommend a biological assessment to evaluate both short-term and long-term effects of the test article, especially if the device surface has different chemistry (e.g., oxide or HA coating) than the implant’s core. Accordingly, FDA may ask for a biocompatibility evaluation on the “final finished device” and “aged” samples. Another challenge is that FDA requires the systemic toxicity endpoints addressed via animal study to include the worst-case dose (i.e., highest device volume including largest size, largest number of possible components).
- Chemical characterization: FDA agrees the Extractables and Leachables (E&L) study and Toxicological Risk Assessment (TRA) can be leveraged to justify systemic toxicity endpoints. The sample preparation for the extractables study should be based on the worst case scenario (exhaustive extraction conditions). It is recommended that extraction be conducted in polar, semi-polar, and non-polar solvents. However, reaching exhaustivity (the amount of material extracted is less than 10% of the initial extraction) for biodegradable materials (i.e., Mg) is challenging.
References
- Waizy, H., Seitz, JM., Reifenrath, J. et al. Biodegradable magnesium implants for orthopedic applications. J Mater Sci 48, 39–50 (2013).
- Mark P. Staiger, Alexis M. Pietak, Jerawala Huadmai, George Dias, Magnesium and its alloys as orthopedic biomaterials: A review, Biomaterials, 27, 1728-1734 (2006).
- Walker J, Shadanbaz S, Woodfield TB, Staiger MP, Dias GJ. Magnesium biomaterials for orthopedic application: a review from a biological perspective. J Biomed Mater Res B Appl Biomater, 102(6), 1316-31 (2014).
- Wang JL, Xu JK, Hopkins C, Chow DH, Qin L. Biodegradable Magnesium-Based Implants in Orthopedics-A General Review and Perspectives. Adv Sci (Weinh). 28;7(8) (2020)
- Nasr Azadani M, Zahedi A, Bowoto OK, Oladapo BI. A review of current challenges and prospects of magnesium and its alloy for bone implant applications. Prog Biomater. 11(1):1-26 (2022)
Dr. Kazemzadeh-Narbat is a former FDA medical device reviewer who joined MCRA in 2020. He has worked on a wide range of products through hundreds of FDA reviews and numerous engagements at MCRA. Dr. Kazemzadeh-Narbat is a biomedical engineer with five years of FDA experience in medical device regulation. At MCRA, Dr. Kazemzadeh-Narbat provides guidance on regulatory strategies and submissions development across various therapies including orthopedic, general hospital, cardiovascular, neurologic, and as well as antimicrobial devices, drugs, and combination products.