Sam Brusco, Associate Editor02.08.21
This past November, Canadian medical device firm Spiderwort, which is developing novel biomaterials for regenerative medicine, was granted Breakthrough Device designation by the U.S. Food and Drug Administration (FDA) for its CelluBridge spinal cord scaffold implant. Achieving breakthrough status means development, assessment, and review are expedited to offer patients diagnosed with life-threatening or irreversibly debilitating diseases and conditions a more effective treatment.
“This designation will enable us to efficiently interact with the FDA in order to increase the speed at which we will initiate our clinical trials,” Spiderwort CEO and co-founder Charles Cuerrier commented to the press.
The firm’s revolutionary biomaterial uses a plant-based cellulose scaffolding to create a framework supporting the regeneration of healthy tissues. The biomaterial is made of microchannels that guide regenerating neurons through damaged spinal cord regions following a traumatic injury. Currently, preclinical studies are underway to demonstrate the promise of this technology to restore motor function. CelluBridge has already proven effective in stimulating motor recovery in small-animal models.
“We are pushing the limits of science every day to bring something remarkable into the world,” said Andrew E. Pelling, Spiderwort's chief science officer and co-founder told the press. “Spiderwort was born from curiosity-driven exploration, and the results have the potential to significantly improve patients’ lives.”
Orthobiologics consist of tissue and bone replacement materials used to boost healing and recovery of ligaments, tendons, muscles, and bones. These sophisticated, highly pure biomaterials are often based on calcium phosphate (hydroxyapatite) composites and other biomaterials that are typically bioengineered to mimic human bone structure and optimize bone regeneration. They are a crucial part of orthopedic surgical procedures, assisting in rapid recovery of joints, bones, and muscles following a surgery and reducing healing time.
Included in the orthobiologic arsenal are synthetic bone substitutes, bone cement, allografts, stem cells, and others. The industry is shaped by many of the same factors impacting the orthopedic market in general. Rise in the global geriatric population increases the prevalence of chronic diseases like arthritis and osteoporosis. Further, growth in sports injuries and trauma surgeries will also likely propel the orthobiologics market.
One major factor of more frequent orthobiologic use is the prevalence of osteoarthritis in the U.S.—a Centers for Disease Control survey indicated over 30 million Americans (about 10 percent of the overall population) are affected by osteoarthritis. Recently, orthobiologics have been used for newer treatment methods in spinal fusion, dental, maxillofacial, cartilage repair, knee arthroscopies, and other such disorders. However, orthobiologics is a relatively new technology and in the early stages of adoption. Limited reimbursement support for stem cells and allografts puts a strain on the global market, and the high cost of bone grafts makes reimbursement difficult.
That said, the North American orthobiologics market was valued at $2.3 billion in 2018 according to a Fortune Business Insights report. Global market value is expected to rise at a 4.5 percent CAGR to reach $8.3 billion by 2026. According to the report, Medtronic plc has emerged as the most influential player in the market. Medtronic obtained FDA clearance for its Infuse Bone Graft for spine implants in 2018.
Infuse was the standard for bone grafts for a long time, but has a pretty checkered past. The FDA approved it with Medtronic interbody fusion devices in single-level spine surgeries in 2002. But after being on the market for a couple of years, reports began to emerge that the rhBMP-2 used in the bone graft caused unwanted side effects including male sterility, infection, bone and nerve injury, urinary problems, and possible increased cancer risk. In 2008, FDA issued a public health notification warning of “life-threatening complications associated with recombinant human bone morphogenetic protein in cervical spine fusion.” Medtronic was also accused of paying off doctors to use its products, intentionally obscuring possible side effects and using deceptive marketing. A number of patients were injured after using Infuse, and Medtronic was slapped with more than a few lawsuits. In the U.S., Medtronic has paid at least $476 million in Infuse-related settlements, according to the Star Tribune.
Today Infuse is approved from ALIF and OLIF when used with specific PEEK or titanium spinal cages. Medtronic has two trials evaluating Infuse in additional indications of PLF and TLIF procedures.
Unfortunately, the bone grafts’ controversy continues—in December 2018, the Star Tribune reported a study that disappeared into Medtronic’s archives containing potentially fatal problems using Infuse during neck surgery. A review of over 1,000 injury reports that regulators publicly released found more than 100 cases with post-surgical neck problems, including multiple cases of neck swelling that could close airways or damage nerves.
A whistleblower also reported last September that Medtronic was widely selling Infuse in Australia without a safety component, the titanium LT-Cage device designed to hold it in check. The company pulled Infuse off the Australian market as a result as regulators investigate. Medtronic said in a statement the withdrawal was unrelated to safety problems and denied any wrongdoing, noting the cage is sold separately from Infuse, but adding that it’s legal to do so and the decision is left to doctors.
The orthobiologics market has since blossomed into orthopedic and spine device companies large and small creating their own solution to accompany their orthopedic implants.
“We are committed to driving innovative orthobiologic solutions that meet the clinical and economic needs of surgeons, hospitals, and patients,” said Albert Cornejo, leader of Cervical and Biologics at NuVasive Inc., a San-Diego based global manufacturer of spine technology and enabling solutions. “The company first primed the orthobiologic market with Osteocel, a flagship allograft cellular bone matrix, and has since delivered Attrax, continuing to address the call for smart biomaterials and products supported by high-quality clinical evidence.”
The firm acquired the Osteocel biologics business from Osiris Therapeutics (which has since been bought by Smith+Nephew) in 2008. At the time, it was the only viable bone matrix product on the market that provided autograft’s beneficial properties of osteoconduction, osteoinduction, and osteogenesis.
“Key to our portfolio is Attrax Putty, a synthetic, bioactive, and osteoconductive bone void filler to repair bone defects,” said Cornejo. “This proprietary, advanced biomaterial features a surface microarchitecture that provides an instructive environment for bone formation without added cells or growth factors.”
NuVasive’s Attrax Putty allograft product line has been used globally since 2011 and obtained FDA clearance in 2015, launching in the U.S. a year later. Its proprietary biotextured microarchitecture promotes differentiation of mesenchymal stem cells into bone-forming osteoblasts to create bone in intramuscular defects. The putty is composed of the firm’s highly flexible alkylene oxide copolymer that is eliminated from the body within 48 hours combined with the Attrax ceramic surface. Attrax’s micropore size distribution spans 0.3 to 1.1 microns.
The Attrax Scaffold absorbent ceramic-collagen bone graft was launched in the U.S. in 2018 following its first clinical case at Columbus, Ga.’s Hughston Clinic. The Attrax biologic is delivered to the posterolateral spine to promote vertebral fusion.
“A recently published randomized controlled trial compared Attrax Putty to autograft in posterolateral lumbar fusions and concluded Attrax Putty alone demonstrated non-inferiority compared to autograft,”1 indicated Cornejo. “With this study, Attrax Putty is now the first and only ceramic bone graft substitute on the market supported by Level I evidence to demonstrate non-inferior fusion performance compared to autograft, and addresses the market requirement of data-backed solutions with strong economic value.”
The March 2020 Spine study supported FDA clearance for use of Attrax Putty as a standalone bone graft substitute for autograft. One hundred patients underwent an instrumented thoracolumbar posterolateral fusion (PLF). After randomization, one side of the spine received Attrax and local bone with iliac crest autograft was applied to the contralateral side. CT scans at one year showed 55 percent fusion rates for the Attrax side and 52 percent for the autograft side, with a 71 percent over fusion rate.
“We see a growing need for smart and advanced surface technology made for unique patient needs while meeting health systems’ need for economic solutions,” commented Cornejo. “We believe Attrax provides a true market solution for patients and surgeons that is supported by high-quality clinical evidence, and drives down procedural costs for health systems. The company remains focused on delivering this product to patients globally.”
A number of other biologic technologies made headlines last year as the sector continued to proliferate. Kuros Biosciences treated its first patient in a clinical trial evaluating its Fibrin-PTH (KUR-113) drug-biologic product for spinal fusion. An upcoming phase 2 study will evaluate it for both open and minimally invasive techniques. DiscGenics raised $50 million in a Series C funding round to support expansion and clinical trials for its allogeneic, injectable disc cell therapy for lumbar degenerative disc disease as well.
Spine Wave launched the Tempest Allograft Bone Matrix, composed of cancellous and partially demineralized cortical bone. It touts osteoconductive and osteoinductive properties to boost bone growth and cellular migration. And Baxter got an FDA nod for its Altapore Share Bioactive Bone Graft for spine surgery. It can be used as either a standalone bone graft substitute or an autograft extender to fill gaps in the skeletal system.
“We will continue to explore and develop best-in-class solutions that support bone fusion, including continued investment in the Attrax product and in generating clinical evidence to drive a better understanding of the synergies of our orthobiologics and complementary fusion solutions like our novel interbody devices developed with Advanced Materials Science,” said Cornejo.
Durham, N.C.-based Bioventus provides offerings for osteoarthritis, surgical, and non-surgical bone healing. In addition to the Exogen Ultrasound Bone Healing System, the firm makes a suite of joint pain injection therapies and bone graft solutions. The joint therapies segment consists of non-surgical alternatives that work with biological processes to provide a natural joint lubricant, which helps relieve mild to moderate osteoarthritis pain. Among the bone graft products are allograft, stem cell and marrow, and synthetic grafts. The company has indicated a focus on spinal fusion surgeries.
“Hospital pricing is critical and hospitals are spending more time looking at the role of bone graft substitutes, particularly in their overall budget for spinal fusion, which is the area we primarily focus on,” commented Bioventus CEO Ken Reali.
The synthetic line includes the Interface bioactive bone graft, the Osteomatrix+ moldable bone graft substitute, and the Signafuse bioactive synthetic bone graft. The allograft line consists of the Purebone osteoconductive scaffold, the Exponent demineralized bone matrix, and the OsteoAmp tissue-based bone allograft product. Bioventus acquired this product line from Advanced Biologics in 2014. It is available in four formats and is touted as a cost-effective alternative to recombinant growth factors and allograft-derived stem cells.
OsteoAmp Select Fibers became the latest addition to the OsteoAmp line in March 2019. They are specifically processed to retain essential growth factors that support bone formation.2 The nanotextured fibers provide a conduit for cell migration. The fibers are interlocking to maintain integrity and position, have high fluid retention, and have the ability to expand. These properties all support easy molding and packing into place to conform with irregular bone voids. Bioventus plans to release the latest generation of its OsteoAmp line in a few months.
“Our OsteoAmp Flow, to be launched the middle of 2021, will address minimally invasive and interbody spinal fusions,” said Reali. “The product will stay in place and is ideally suitable for an interbody fusion cage.”
Last June, the firm launched the SignaFuse Bioactive Bone Graft in a strip format. Composed of 55 percent bioglass by weight, the strips have demonstrated higher levels of osteoblast differentiation compared to other synthetic bone graft strips, according to the company. SignaFuse’s biphasic mineral is made of 60 percent hydroxyapatite and 40 percent beta-tricalcium phosphate. The new strips hydrate rapidly and come in sizes ranging from 25 to 200 millimeters in length. The first in-patient use of the SignaFuse strips took place last September. A PLF procedure was performed using the strips in the posterolateral gutters of the patient’s spine.
“We plan on continuing to evolve with new formulations that are nonmetal-based devices,” said Reali. “We also see a lot of things in development today that may be solid acquisition targets for us.”
Cleanup and Evaluation
Like any other medical technology, orthobiologics must undergo rigorous testing, inspection, and sterilization before they are market-ready. Medical devices and products can be sterilized utilizing various terminal sterilization modalities such as ethylene oxide (EO), Gamma, E-beam, etc.—or by filtration followed by aseptic processing. But orthobiologic materials are in a class by themselves and necessitate different approaches to cleaning and evaluation.
“Most commonly used materials in orthopedic applications include viscous materials such as Hyaluronic acid, PMMA, Peptide gels, Collagen, etc.,” explained Sarath Koruprolu, CEO of MycoScience, a Willington, Conn.-based firm specializing in microbiology and regulatory compliance that provides laboratory and consulting services. “Some products made with these materials cannot withstand terminal sterilization and may break down during the process, affecting product performance and integrity. Aseptic processing is chosen as an acceptable alternative in such cases. However, aseptic processes are inherently riskier than terminally sterilizing the product due to many manipulations involved in the process.”
There are a number of other aspects Koruprolu urged manufacturers of pre-filled syringes with viscous products to consider. From the materials and environmental perspective—cleaning and disinfection of mixing vessels and transfer lines, raw material sterilization, and sanitizing work surfaces, equipment, and floors is crucial. On the process side, Koruprolu urged manufacturers to pay attention to compounding and mixing, homogenization, product filtration, and fill volume accuracy.
“Process development of such viscous products into a pre-filled syringe with sufficient homogenization, proper filtration and air pocket removal, while simultaneously maximizing yield and sterility assurance has become increasingly challenging,” said Koruprolu. “The addition of novel biomaterials only adds to this challenge due to their interactions with the product affecting overall product form and delivery.”
Koruprolu pointed out a number of best practices when working on orthobiologic manufacturing projects. First is the type of mixing system: dual and triple shaft mixers are usually employed to batch moderate to high viscosity applications. Sometimes the combination of a low-speed agitator with a high shear device like a disc style disperser or high shear mixed is used. These technologies used individually or in combination assembly can be used up to 75,000 cP. For even higher viscosities, more agitators can be used to boost bulk flow, deliver material to the high-speed devices, and remove product from vessel walls for better heat transfer.
Regarding impellor types, Koruprolu indicated that a prop impeller is more effective for water-like and lower viscosities. Pitched blade and vertical blade turbines are better for mixing high viscosity materials. Very high viscosity mixing can be achieved using square blades and anchor paddles. Different types of pumps and fill nozzles are also necessary for accurate fill volume. Koruprolu also urges onsite terminal sterilization—for example, steam sterilization capabilities—to minimize the risk of contamination. Endotoxin and bioburden testing is also needed to ensure the products meet regulatory requirements while being effective.
“Manufacturers of orthobiologic technologies, like all medical device manufacturers, have an inescapable need to ensure reliability of their products,” said Elizabeth Kidd, materials scientist at BTG Labs, a materials science company based in St. Bernard, Ohio, that offers adhesion quality control for manufacturers concerned with adhesive bonding, painting, coating, printing, and cleaning. “Guaranteeing strong bonds (often between dissimilar materials) and flawless coating adhesion is critical for achieving high reliability. Instituting process controls that verify the surface readiness for adhesion on 100 percent of products at critical control points throughout the manufacturing process fulfills FDA requirements for process verification inspection and ensures every assembly conforms to quality requirements laid out at the process design stage. This degree of inspection is possible with rapid, quantitative, accurate testing done on a production level using smart sensors that communicate critical quality data manufacturers can use to optimize their cleaning processes for defectless adhesion.”
Regulatory authorities expect all risks to health associated with the use of bone cement or bone graft materials—like ineffective bone formation or adverse tissue reaction—are addressed through extensive materials characterization, in-vitro studies, and stability studies. Complete chemical composition (including elemental analysis and inorganic material analysis) should be performed, including determination of all additives and trace impurities.
For physical property determination, microscopy studies often use optical and electron microscopy image acquisition. This depicts particle size, shape, and porosity. Surface area and volumetric porosity measurements can be calculated using an ET technique and dynamic light scattering to obtain particle size distribution information. X-ray powder diffraction can be employed to study phase composition, crystal structure, and morphology of bone graft materials. This is used to determine phase purity—the relative mass percentages of crystalline and amorphous phases. To acquire further structural and microstructural info, spectroscopy methods like infrared and Raman combined with transmission electron microscopy may be used.
In-vitro studies are conducted in simulated body fluid to help verify formation of apatite layer on surfaces. Such studies observe calcium and phosphorus deposition onto surfaces, with techniques like scanning electron microscopy used to confirm formation of the bone-like apatite later on the bone graft materials’ surface. Stability testing involves controlled stability storage and regulatory complaint testing programs. Such programs encompass weight loss by thermogravimetric analysis, pH, elemental composition, and calcium deposition.
“Working with partners requires the use of a common data-driven language based on analytics that translate seamlessly from R&D laboratories to production, from part suppliers to manufacturers, and from production technicians to management,” said Kidd. “Developing this common language between partnering organizations at the beginning of the product life cycle affords manufacturers insight into the treatment of an invisible layer—the surface. This type of inspection provides fulfillment of FDA process verification requirements and a troubleshooting mechanism for surface treatment inconsistencies (e.g., inconsistent surface activation due to an unoptimized plasma treatment system).”
References
“This designation will enable us to efficiently interact with the FDA in order to increase the speed at which we will initiate our clinical trials,” Spiderwort CEO and co-founder Charles Cuerrier commented to the press.
The firm’s revolutionary biomaterial uses a plant-based cellulose scaffolding to create a framework supporting the regeneration of healthy tissues. The biomaterial is made of microchannels that guide regenerating neurons through damaged spinal cord regions following a traumatic injury. Currently, preclinical studies are underway to demonstrate the promise of this technology to restore motor function. CelluBridge has already proven effective in stimulating motor recovery in small-animal models.
“We are pushing the limits of science every day to bring something remarkable into the world,” said Andrew E. Pelling, Spiderwort's chief science officer and co-founder told the press. “Spiderwort was born from curiosity-driven exploration, and the results have the potential to significantly improve patients’ lives.”
Orthobiologics consist of tissue and bone replacement materials used to boost healing and recovery of ligaments, tendons, muscles, and bones. These sophisticated, highly pure biomaterials are often based on calcium phosphate (hydroxyapatite) composites and other biomaterials that are typically bioengineered to mimic human bone structure and optimize bone regeneration. They are a crucial part of orthopedic surgical procedures, assisting in rapid recovery of joints, bones, and muscles following a surgery and reducing healing time.
Included in the orthobiologic arsenal are synthetic bone substitutes, bone cement, allografts, stem cells, and others. The industry is shaped by many of the same factors impacting the orthopedic market in general. Rise in the global geriatric population increases the prevalence of chronic diseases like arthritis and osteoporosis. Further, growth in sports injuries and trauma surgeries will also likely propel the orthobiologics market.
One major factor of more frequent orthobiologic use is the prevalence of osteoarthritis in the U.S.—a Centers for Disease Control survey indicated over 30 million Americans (about 10 percent of the overall population) are affected by osteoarthritis. Recently, orthobiologics have been used for newer treatment methods in spinal fusion, dental, maxillofacial, cartilage repair, knee arthroscopies, and other such disorders. However, orthobiologics is a relatively new technology and in the early stages of adoption. Limited reimbursement support for stem cells and allografts puts a strain on the global market, and the high cost of bone grafts makes reimbursement difficult.
That said, the North American orthobiologics market was valued at $2.3 billion in 2018 according to a Fortune Business Insights report. Global market value is expected to rise at a 4.5 percent CAGR to reach $8.3 billion by 2026. According to the report, Medtronic plc has emerged as the most influential player in the market. Medtronic obtained FDA clearance for its Infuse Bone Graft for spine implants in 2018.
Infuse was the standard for bone grafts for a long time, but has a pretty checkered past. The FDA approved it with Medtronic interbody fusion devices in single-level spine surgeries in 2002. But after being on the market for a couple of years, reports began to emerge that the rhBMP-2 used in the bone graft caused unwanted side effects including male sterility, infection, bone and nerve injury, urinary problems, and possible increased cancer risk. In 2008, FDA issued a public health notification warning of “life-threatening complications associated with recombinant human bone morphogenetic protein in cervical spine fusion.” Medtronic was also accused of paying off doctors to use its products, intentionally obscuring possible side effects and using deceptive marketing. A number of patients were injured after using Infuse, and Medtronic was slapped with more than a few lawsuits. In the U.S., Medtronic has paid at least $476 million in Infuse-related settlements, according to the Star Tribune.
Today Infuse is approved from ALIF and OLIF when used with specific PEEK or titanium spinal cages. Medtronic has two trials evaluating Infuse in additional indications of PLF and TLIF procedures.
Unfortunately, the bone grafts’ controversy continues—in December 2018, the Star Tribune reported a study that disappeared into Medtronic’s archives containing potentially fatal problems using Infuse during neck surgery. A review of over 1,000 injury reports that regulators publicly released found more than 100 cases with post-surgical neck problems, including multiple cases of neck swelling that could close airways or damage nerves.
A whistleblower also reported last September that Medtronic was widely selling Infuse in Australia without a safety component, the titanium LT-Cage device designed to hold it in check. The company pulled Infuse off the Australian market as a result as regulators investigate. Medtronic said in a statement the withdrawal was unrelated to safety problems and denied any wrongdoing, noting the cage is sold separately from Infuse, but adding that it’s legal to do so and the decision is left to doctors.
The orthobiologics market has since blossomed into orthopedic and spine device companies large and small creating their own solution to accompany their orthopedic implants.
“We are committed to driving innovative orthobiologic solutions that meet the clinical and economic needs of surgeons, hospitals, and patients,” said Albert Cornejo, leader of Cervical and Biologics at NuVasive Inc., a San-Diego based global manufacturer of spine technology and enabling solutions. “The company first primed the orthobiologic market with Osteocel, a flagship allograft cellular bone matrix, and has since delivered Attrax, continuing to address the call for smart biomaterials and products supported by high-quality clinical evidence.”
The firm acquired the Osteocel biologics business from Osiris Therapeutics (which has since been bought by Smith+Nephew) in 2008. At the time, it was the only viable bone matrix product on the market that provided autograft’s beneficial properties of osteoconduction, osteoinduction, and osteogenesis.
“Key to our portfolio is Attrax Putty, a synthetic, bioactive, and osteoconductive bone void filler to repair bone defects,” said Cornejo. “This proprietary, advanced biomaterial features a surface microarchitecture that provides an instructive environment for bone formation without added cells or growth factors.”
NuVasive’s Attrax Putty allograft product line has been used globally since 2011 and obtained FDA clearance in 2015, launching in the U.S. a year later. Its proprietary biotextured microarchitecture promotes differentiation of mesenchymal stem cells into bone-forming osteoblasts to create bone in intramuscular defects. The putty is composed of the firm’s highly flexible alkylene oxide copolymer that is eliminated from the body within 48 hours combined with the Attrax ceramic surface. Attrax’s micropore size distribution spans 0.3 to 1.1 microns.
The Attrax Scaffold absorbent ceramic-collagen bone graft was launched in the U.S. in 2018 following its first clinical case at Columbus, Ga.’s Hughston Clinic. The Attrax biologic is delivered to the posterolateral spine to promote vertebral fusion.
“A recently published randomized controlled trial compared Attrax Putty to autograft in posterolateral lumbar fusions and concluded Attrax Putty alone demonstrated non-inferiority compared to autograft,”1 indicated Cornejo. “With this study, Attrax Putty is now the first and only ceramic bone graft substitute on the market supported by Level I evidence to demonstrate non-inferior fusion performance compared to autograft, and addresses the market requirement of data-backed solutions with strong economic value.”
The March 2020 Spine study supported FDA clearance for use of Attrax Putty as a standalone bone graft substitute for autograft. One hundred patients underwent an instrumented thoracolumbar posterolateral fusion (PLF). After randomization, one side of the spine received Attrax and local bone with iliac crest autograft was applied to the contralateral side. CT scans at one year showed 55 percent fusion rates for the Attrax side and 52 percent for the autograft side, with a 71 percent over fusion rate.
“We see a growing need for smart and advanced surface technology made for unique patient needs while meeting health systems’ need for economic solutions,” commented Cornejo. “We believe Attrax provides a true market solution for patients and surgeons that is supported by high-quality clinical evidence, and drives down procedural costs for health systems. The company remains focused on delivering this product to patients globally.”
A number of other biologic technologies made headlines last year as the sector continued to proliferate. Kuros Biosciences treated its first patient in a clinical trial evaluating its Fibrin-PTH (KUR-113) drug-biologic product for spinal fusion. An upcoming phase 2 study will evaluate it for both open and minimally invasive techniques. DiscGenics raised $50 million in a Series C funding round to support expansion and clinical trials for its allogeneic, injectable disc cell therapy for lumbar degenerative disc disease as well.
Spine Wave launched the Tempest Allograft Bone Matrix, composed of cancellous and partially demineralized cortical bone. It touts osteoconductive and osteoinductive properties to boost bone growth and cellular migration. And Baxter got an FDA nod for its Altapore Share Bioactive Bone Graft for spine surgery. It can be used as either a standalone bone graft substitute or an autograft extender to fill gaps in the skeletal system.
“We will continue to explore and develop best-in-class solutions that support bone fusion, including continued investment in the Attrax product and in generating clinical evidence to drive a better understanding of the synergies of our orthobiologics and complementary fusion solutions like our novel interbody devices developed with Advanced Materials Science,” said Cornejo.
Durham, N.C.-based Bioventus provides offerings for osteoarthritis, surgical, and non-surgical bone healing. In addition to the Exogen Ultrasound Bone Healing System, the firm makes a suite of joint pain injection therapies and bone graft solutions. The joint therapies segment consists of non-surgical alternatives that work with biological processes to provide a natural joint lubricant, which helps relieve mild to moderate osteoarthritis pain. Among the bone graft products are allograft, stem cell and marrow, and synthetic grafts. The company has indicated a focus on spinal fusion surgeries.
“Hospital pricing is critical and hospitals are spending more time looking at the role of bone graft substitutes, particularly in their overall budget for spinal fusion, which is the area we primarily focus on,” commented Bioventus CEO Ken Reali.
The synthetic line includes the Interface bioactive bone graft, the Osteomatrix+ moldable bone graft substitute, and the Signafuse bioactive synthetic bone graft. The allograft line consists of the Purebone osteoconductive scaffold, the Exponent demineralized bone matrix, and the OsteoAmp tissue-based bone allograft product. Bioventus acquired this product line from Advanced Biologics in 2014. It is available in four formats and is touted as a cost-effective alternative to recombinant growth factors and allograft-derived stem cells.
OsteoAmp Select Fibers became the latest addition to the OsteoAmp line in March 2019. They are specifically processed to retain essential growth factors that support bone formation.2 The nanotextured fibers provide a conduit for cell migration. The fibers are interlocking to maintain integrity and position, have high fluid retention, and have the ability to expand. These properties all support easy molding and packing into place to conform with irregular bone voids. Bioventus plans to release the latest generation of its OsteoAmp line in a few months.
“Our OsteoAmp Flow, to be launched the middle of 2021, will address minimally invasive and interbody spinal fusions,” said Reali. “The product will stay in place and is ideally suitable for an interbody fusion cage.”
Last June, the firm launched the SignaFuse Bioactive Bone Graft in a strip format. Composed of 55 percent bioglass by weight, the strips have demonstrated higher levels of osteoblast differentiation compared to other synthetic bone graft strips, according to the company. SignaFuse’s biphasic mineral is made of 60 percent hydroxyapatite and 40 percent beta-tricalcium phosphate. The new strips hydrate rapidly and come in sizes ranging from 25 to 200 millimeters in length. The first in-patient use of the SignaFuse strips took place last September. A PLF procedure was performed using the strips in the posterolateral gutters of the patient’s spine.
“We plan on continuing to evolve with new formulations that are nonmetal-based devices,” said Reali. “We also see a lot of things in development today that may be solid acquisition targets for us.”
Cleanup and Evaluation
Like any other medical technology, orthobiologics must undergo rigorous testing, inspection, and sterilization before they are market-ready. Medical devices and products can be sterilized utilizing various terminal sterilization modalities such as ethylene oxide (EO), Gamma, E-beam, etc.—or by filtration followed by aseptic processing. But orthobiologic materials are in a class by themselves and necessitate different approaches to cleaning and evaluation.
“Most commonly used materials in orthopedic applications include viscous materials such as Hyaluronic acid, PMMA, Peptide gels, Collagen, etc.,” explained Sarath Koruprolu, CEO of MycoScience, a Willington, Conn.-based firm specializing in microbiology and regulatory compliance that provides laboratory and consulting services. “Some products made with these materials cannot withstand terminal sterilization and may break down during the process, affecting product performance and integrity. Aseptic processing is chosen as an acceptable alternative in such cases. However, aseptic processes are inherently riskier than terminally sterilizing the product due to many manipulations involved in the process.”
There are a number of other aspects Koruprolu urged manufacturers of pre-filled syringes with viscous products to consider. From the materials and environmental perspective—cleaning and disinfection of mixing vessels and transfer lines, raw material sterilization, and sanitizing work surfaces, equipment, and floors is crucial. On the process side, Koruprolu urged manufacturers to pay attention to compounding and mixing, homogenization, product filtration, and fill volume accuracy.
“Process development of such viscous products into a pre-filled syringe with sufficient homogenization, proper filtration and air pocket removal, while simultaneously maximizing yield and sterility assurance has become increasingly challenging,” said Koruprolu. “The addition of novel biomaterials only adds to this challenge due to their interactions with the product affecting overall product form and delivery.”
Koruprolu pointed out a number of best practices when working on orthobiologic manufacturing projects. First is the type of mixing system: dual and triple shaft mixers are usually employed to batch moderate to high viscosity applications. Sometimes the combination of a low-speed agitator with a high shear device like a disc style disperser or high shear mixed is used. These technologies used individually or in combination assembly can be used up to 75,000 cP. For even higher viscosities, more agitators can be used to boost bulk flow, deliver material to the high-speed devices, and remove product from vessel walls for better heat transfer.
Regarding impellor types, Koruprolu indicated that a prop impeller is more effective for water-like and lower viscosities. Pitched blade and vertical blade turbines are better for mixing high viscosity materials. Very high viscosity mixing can be achieved using square blades and anchor paddles. Different types of pumps and fill nozzles are also necessary for accurate fill volume. Koruprolu also urges onsite terminal sterilization—for example, steam sterilization capabilities—to minimize the risk of contamination. Endotoxin and bioburden testing is also needed to ensure the products meet regulatory requirements while being effective.
“Manufacturers of orthobiologic technologies, like all medical device manufacturers, have an inescapable need to ensure reliability of their products,” said Elizabeth Kidd, materials scientist at BTG Labs, a materials science company based in St. Bernard, Ohio, that offers adhesion quality control for manufacturers concerned with adhesive bonding, painting, coating, printing, and cleaning. “Guaranteeing strong bonds (often between dissimilar materials) and flawless coating adhesion is critical for achieving high reliability. Instituting process controls that verify the surface readiness for adhesion on 100 percent of products at critical control points throughout the manufacturing process fulfills FDA requirements for process verification inspection and ensures every assembly conforms to quality requirements laid out at the process design stage. This degree of inspection is possible with rapid, quantitative, accurate testing done on a production level using smart sensors that communicate critical quality data manufacturers can use to optimize their cleaning processes for defectless adhesion.”
Regulatory authorities expect all risks to health associated with the use of bone cement or bone graft materials—like ineffective bone formation or adverse tissue reaction—are addressed through extensive materials characterization, in-vitro studies, and stability studies. Complete chemical composition (including elemental analysis and inorganic material analysis) should be performed, including determination of all additives and trace impurities.
For physical property determination, microscopy studies often use optical and electron microscopy image acquisition. This depicts particle size, shape, and porosity. Surface area and volumetric porosity measurements can be calculated using an ET technique and dynamic light scattering to obtain particle size distribution information. X-ray powder diffraction can be employed to study phase composition, crystal structure, and morphology of bone graft materials. This is used to determine phase purity—the relative mass percentages of crystalline and amorphous phases. To acquire further structural and microstructural info, spectroscopy methods like infrared and Raman combined with transmission electron microscopy may be used.
In-vitro studies are conducted in simulated body fluid to help verify formation of apatite layer on surfaces. Such studies observe calcium and phosphorus deposition onto surfaces, with techniques like scanning electron microscopy used to confirm formation of the bone-like apatite later on the bone graft materials’ surface. Stability testing involves controlled stability storage and regulatory complaint testing programs. Such programs encompass weight loss by thermogravimetric analysis, pH, elemental composition, and calcium deposition.
“Working with partners requires the use of a common data-driven language based on analytics that translate seamlessly from R&D laboratories to production, from part suppliers to manufacturers, and from production technicians to management,” said Kidd. “Developing this common language between partnering organizations at the beginning of the product life cycle affords manufacturers insight into the treatment of an invisible layer—the surface. This type of inspection provides fulfillment of FDA process verification requirements and a troubleshooting mechanism for surface treatment inconsistencies (e.g., inconsistent surface activation due to an unoptimized plasma treatment system).”
References
- Lehr M, Oner C, Delawi D, et al. Efficacy of a standalone microporous ceramic vs. autograft in instrumented posterolateral spinal fusion; a multicenter, randomized, intra-patient controlled, non-inferiority trial. Spine 2020;45(14):944-51.
- Tidwell JL., Seaman SA, Vanderploeg EJ, Tom S. In vitro and in vivo characterization of OSTEOAMP allogenic morphogentic proteins. Data on file. Bioventus white paper, 2017.