Ranica Arrowsmith, Associate Editor05.23.16
Twenty years ago, the U.S. Food and Drug Administration (FDA) released a guidance document titled “Do It By Design: An Introduction to Human Factors in Medical Devices.” The document still serves as a mini-Bible for medtech companies seeking to better understand how device designs affect their use. According to the guidance, users use “expectancies” and “mental models” to interact with tools like medical devices. Expectancies refer to how people are predisposed to react to new situations according to established habits. Designers can take advantage of existing conventions—such as the color red indicating danger—in the general population, as well as the standards and conventions of the medical community. Designs consistent with ingrained habits will facilitate performance and reduce training time, while designs that conflict with such habits can lead to errors. Mental models characterize how people form abstract concepts about how complex phenomena actually work based on experience. For example, anesthesiologists form mental representations of patient status based on information about respiration, heart rate, oxygen levels, and other bodily processes. Monitors should present such information in a manner consistent with such models. There is a need for thorough assessment of how users conceptualize device operation in patient treatment and monitoring. This is a complex issue, because individuals differ in how they mentally integrate and conceptualize data that change over time.
Color, touch, feel, and appearance are the first signals to a user on how to use a medical device. As such, surface coatings and treatments on devices are an essential consideration for medical device makers, as not only do they affect function, but also usability in a more abstract sense. This is especially important for orthopedic surgical devices; whereas implants have far more functional than usability considerations. Surface is the first line between user and application—so coatings companies pay special attention to human factor interaction in their research and development.
“A popular coating for Boyd in the orthopedic medical device market is PVDF (polyvinylidene difluoride), which is most often used on surgical tools,” said Dick Buxton, application manager for Boyd Coatings Research Co. Inc. based in Hudson, Mass. “It has excellent characteristics, such as color stability and durability even through autoclave and gamma sterilization. It also comes in a wide variety of colors, which makes it ideal for color-coding instruments for identification, measurements and surgical sequence. We have 14 standard colors that are FDA approved and biocompatibility tested and can create additional colors made from those standard colors. PVDF also has great electrical insulation properties, thus preventing any potential shocks from passing to either the doctor or patient when used during surgery. And, because it has such amazing durability and is easy to clean, PVDF is an excellent coating for reusable instruments.
“We’ve also used PVDF on hand-held camera type devices used in investigative/exploratory procedures,“ Buxton continued. “We can combine properties of different materials to achieve complex requirements, for example, on one such camera which is about the size of a tennis ball with an aluminum housing. PVDF, which is insulative, is used over the entire surface of the camera housing to prevent shock while the internals are overcoated with a conductive material. Together, they form an EMI shield to prevent stray electronic signals from giving erroneous readings (i.e. false positives or negatives) while also protecting the patient and surgeon from shock. Vice versa, we can also apply a conductive coating to a non-conductive surface.
“PVDF is one of several types of fluoropolymers that we can apply, each with its own set of properties. We also have other coating types in our ‘quiver’ that are also used in medical applications. The wonderful thing about coatings is that—in addition to being decorative or informative—they can bring attributes to a substrate that it doesn’t normally have.“
Color has been of particular concern for medical device makers, as the FDA has fielded several instances of harmful color additives in plastics and device coatings. For instance, in 2003, the agency related several reports of toxicity—in some instances leading to death—of the use of FD&C Blue No. 1 in enteral feeding tubes. The dye was meant to help in the detection and/or monitoring of pulmonary aspiration in patients being fed by those tubes. No definite causal relationship was determined between the dye and the adverse events, but there were 20 cases from the scientific literature or in FDA post-marketing adverse event reports associating the use of blue dye in tube feedings with blue discoloration of body fluids and skin, as well as more serious complications. There were 12 reported deaths and one case with an unknown outcome. So, the agency warned healthcare professionals against using these blue-dyed feeding tubes.
Eleven years later, in 2014, the Food and Drug Law Journal published an article titled, “The Grays of Medical Device Color Additives,” which outlined the unclear nature of the FDA’s color additive regulations. “In order for any approach to be successful, whether it is a new twist on past practices, or an entirely new path forward, the FDA must, to the best of its ability, better understand its past medical device color additive practices (as well as the variations that have developed within the last twenty or so years), and engage in a dialogue with stakeholders on how it and the medical device industry should consider unlisted color additives currently used in marketed devices in the United States,” the article’s abstract stated. Such a niche consideration as color additives can and has easily fallen to the fringes of regulatory consideration; but, as the 2003 case illustrates, because color is usually applied on the outside surfaces of medical devices which are the sections that come into contact with the patient, it must be handled with clarity and direction by the FDA.
“Being both a Tier 1 and Tier 2 provider, we have found that there is more pressure than ever before from a regulatory standpoint,” noted Michael Venturini, president and CEO of Columbia City, Ind.-based DOT America Inc., a high-tech surfaces company. “We have seen the level of proof rising constantly, i.e. for OEMs, as well as notified and regulatory bodies requesting additional and more detailed reporting on starting materials, coating properties, mechanical behavior and biocompatibility, short and long term, and they are also requesting more in-depth information on validations. We expect this to intensify after the new ISO 13485:2016 becomes effective. With the FDA paying closer attention to the roles that suppliers play for the OEMs, the supply chain needs to rise to the requirements as transparently as possible.”
ISO 13485 has not been revised since 2003. Companies have three years to fully transition and comply with the new 2016 quality standard. The new revision places a greater emphasis on quality management systems (QMS) throughout the supply chain and product lifecycle, as well as device usability and postmarket surveillance requirements.1
“Further developments in regulations tend to have a positive effect on both DOT Germany and DOT America, as we are FDA registered, stay current on regulatory affairs, and are confident in our abilities to meet all changes and requirements head on,” Venturini added. “Our customer base recognizes this and has the utmost trust and confidence in our ability to meet every need from a regulatory compliance standpoint.”
Surface treatments are especially important for orthopedic implants, which very often act as bone-growth platforms. Sweden-based biomaterial company Promimic AB, makes a proprietary implant surface designed to dramatically accelerate osseointegration called HAnano Surface. The surface can be applied onto various types of substrates, including metals, ceramics and polymers. The treatment can convert any implant, regardless of its dimensions and structure, to a surface that resembles natural human bone tissue.
“In general, coatings are there to improve the integration with the bone, creating a faster anchoring of the implant restoring the lost function to the body faster than for an uncoated implant,” CEO Ulf Brogren explained to ODT. “The use of porous structures —metals as implant materials are growing. We believe the use of porous implants will result in an increased demand for new types of coatings—coatings that can be combined with porous materials. Such coatings will be based on wet chemistry without the need for line of sight; adding bone chemistry and bio-mimicking nano-structures to the implants without clogging the pores. This will create implant materials that are structured as bone and have a bone-like chemistry. This is an example of the high performing implants that will be required to meet the increasing clinical demands as more and more patients will be needing more and more implants due to poorer bone quality.
“Within the spine segment several of the leading implant companies have launched coated PEEK interbody devices at this moment,” he continued. “The reason for this is to create devices that actually integrate with bone, in order to support a better and faster fusion. For all non-titanium implants the need for a coating that improves the osseointegration will be crucial.
“In many market segments product differentiation will be key to success, since the majority of the implants currently available on the market have similar designs and functions. Also, as the market is shifting due to changing demographics and growing health problems, the demand for high performing implants is increasing. Combining novel implant designs with the right bone chemistry for better and faster integration will be one important solution to these problems, and Promimic sees an increasing demand in coatings from these marketing and clinical perspectives.”
Promimic’s existing technology includes its hydroxyapatite surface, to which it adds bone-like chemistry that attracts bone cells and accelerates integration. According to Brogren, since the coating is only 20 nanometers thin, bone will integrate with the implant, in the micro and macro roughness of the implant surface, and not into the coating itself. The Promimic coating technology can coat all kind of shapes and materials in a cost-efficient way, and the company establishes predicate devices and master files for its HAnano Surface with the FDA. Promimic has also developed an extensive portfolio of pre-clinical in vivo data, which may facilitate and support customer regulatory submissions.
Promimic also developed a unique wet chemical coating process designed for implementation anywhere an implant is produced and on any device. Through a licensing agreement, the OEM client gets full control over the coating process directly at their production line.
For customers that don’t want an in-house solution, the company has also recently signed a strategic partnership with Warsaw, Ind.-based Danco Anodizing Inc., where Danco will invest in a production line for the HAnano Surface, making it easier for U.S. customers to get to market. Danco will be the preferred process partner for Promimic in the United States and also in the Chinese medical implant market.
From Tim Zentz’s perspective, sales manager at Danco, it is the market’s focus on higher performance coatings for implantable devices that has provided Danco the opportunity to offer their customers the HAnano process via Promimic that allows for improved osseointegration of the implant, which ultimately improves a patient’s recovery time.
Kevin Gilbert, quality manager at Danco, draws attention to the standards and quality changes that are affecting the surfaces and coatings business. “With the changes in ISO 9001 and ISO 13485 really driving for the mitigation of risk in all the processes that are performed, it is important that the culture of the organization focuses on preventive processes,” he told ODT. “This has to be based on the correct analysis of data and not reactionary. It is imperative that enough of the correct data is collected to be able to link KPI’s (Key Performance Indicators) to the PFMEA (Process Failure Mode Effects Analysis) system. This applies to every aspect of the QMS and production process. One such example is to evaluate the communication processes between Danco and the customer base; Danco needs to communicate quality escapes from the customer that could result in quality issues within our organization. This includes everything from the accuracy of the purchase order supplied with the product, to the packaging the product is shipped to and from in, to ensure that the product is not introduced to product contact materials that would result in contamination of the product during shipment.”
Once color, coatings, materials, and every other consideration has been paid to a device, then comes considerations such as polishing. Chicago, Ill.-based Able Electropolishing Co. provides electropolishing services, as well as other finishing services such as passivation, which uses nitric or citric acid to remove free iron and other surface contaminants, restoring the material to its original mill condition; its proprietary Brite passivation, a light electropolishing process designed to clean the part surface and leave a finish superior to standard passivation; titanium finishing and anodizing; deburring; and ultracleaning.
“Electropolishing becomes an important role in the final product,” Sales Manager Scot Potter told ODT. “The electropolishing provides many benefits in one process. The process provides deburring, microfinish improvement, improved corrosion resistance, ultracleaning and a decorative finish in one operation. In addition, the laser marking allows customers to meet FDA UDI (unique device identifier) requirements. Lastly, the titanium color anodizing improves part identification by color-coding parts for product or size identification.”
Down the Coated Pipeline
“New markets have developed for titanium plasma-sprayed (TPS) coatings on PEEK for spinal applications and on ceramic substrate material for hip cups,” DOT America’s Venturini said. “Upgrades in physical vapor deposition (PVD) coating technology facilitate the production of coatings with very low roughness, thus further reducing wear. The significance of surface treatments to fight microbial infections post-operative have become fields of intensive research and development, and anti-microbial coatings for trauma and orthopedic implants based on silver or other elements have evolved. “We are excited about the growing importance of additive manufacturing in the mass production of implants, with regard to the role thin calcium phosphate (CaP) coatings can play to foster bone on-growth.
“Certainly, there are also challenges ahead: We tend to consider additive manufacturing as a potential challenge for porous coating of certain implant types in the long run. And in the trauma business, the evolution of non-metal screws, consisting of a combination of biodegradable polymers, such as polylactic acid, and hydroxyapatite, can replace certain anodized titanium screws.”
According to Parimal Bapat, research engineer at Holt, Mich.-based Orchid Orthopedics, ”Additive manufacturing (AM) is a good choice for implants with low surface to volume ratios and implants that have complex geometries which are difficult to achieve with traditional forging, casting, and machining techniques. In addition, since a variety of materials such as titanium and stainless steel, can be used in the AM process, functional prototypes can be made out of the same material as production components. This enables more rigorous testing of prototypes while decreasing the development time for new products.
” The highly popular 3D printing process is being used to build complete orthopedic implants, including the roughened surface, in one single process. The process is fast, ideal for low runs, and can create nearly production-ready implants. 3D printing utilizes a computer aided design (CAD) program to build an implant, one layer at time. Layer thickness can be controlled down to a few microns. Using the CAD software, engineers determine the desired coating specifications and build the entire implant in a single run, with minimum post processing.”2
Boyd’s Buxton sees process control becoming more and more important. “This is driving Precision Coating (and our Boyd Coatings division) to more advanced equipment to more precisely control properties, particularly thickness and friction,” he said. “As more interventional medical applications are defined, these properties are often critical to our customers’ success. The other area is in research of alternative materials in order to protect our planet through ‘green’ initiatives. Boyd has a strong engineering team working both these areas.”
One must not forget the dental market either. Increasingly, the dental and orthopedic markets are cross-pollinating ideas and techniques. This year, Elsevier’s Biomaterials journal published an article detailing the design of an engineered, elastin-like protein (ELP) that is chemically modified to enable stable coatings on the surfaces of titanium-based dental and orthopedic implants by novel photocrosslinking and solution processing steps.3
References
Color, touch, feel, and appearance are the first signals to a user on how to use a medical device. As such, surface coatings and treatments on devices are an essential consideration for medical device makers, as not only do they affect function, but also usability in a more abstract sense. This is especially important for orthopedic surgical devices; whereas implants have far more functional than usability considerations. Surface is the first line between user and application—so coatings companies pay special attention to human factor interaction in their research and development.
“A popular coating for Boyd in the orthopedic medical device market is PVDF (polyvinylidene difluoride), which is most often used on surgical tools,” said Dick Buxton, application manager for Boyd Coatings Research Co. Inc. based in Hudson, Mass. “It has excellent characteristics, such as color stability and durability even through autoclave and gamma sterilization. It also comes in a wide variety of colors, which makes it ideal for color-coding instruments for identification, measurements and surgical sequence. We have 14 standard colors that are FDA approved and biocompatibility tested and can create additional colors made from those standard colors. PVDF also has great electrical insulation properties, thus preventing any potential shocks from passing to either the doctor or patient when used during surgery. And, because it has such amazing durability and is easy to clean, PVDF is an excellent coating for reusable instruments.
“We’ve also used PVDF on hand-held camera type devices used in investigative/exploratory procedures,“ Buxton continued. “We can combine properties of different materials to achieve complex requirements, for example, on one such camera which is about the size of a tennis ball with an aluminum housing. PVDF, which is insulative, is used over the entire surface of the camera housing to prevent shock while the internals are overcoated with a conductive material. Together, they form an EMI shield to prevent stray electronic signals from giving erroneous readings (i.e. false positives or negatives) while also protecting the patient and surgeon from shock. Vice versa, we can also apply a conductive coating to a non-conductive surface.
“PVDF is one of several types of fluoropolymers that we can apply, each with its own set of properties. We also have other coating types in our ‘quiver’ that are also used in medical applications. The wonderful thing about coatings is that—in addition to being decorative or informative—they can bring attributes to a substrate that it doesn’t normally have.“
Color has been of particular concern for medical device makers, as the FDA has fielded several instances of harmful color additives in plastics and device coatings. For instance, in 2003, the agency related several reports of toxicity—in some instances leading to death—of the use of FD&C Blue No. 1 in enteral feeding tubes. The dye was meant to help in the detection and/or monitoring of pulmonary aspiration in patients being fed by those tubes. No definite causal relationship was determined between the dye and the adverse events, but there were 20 cases from the scientific literature or in FDA post-marketing adverse event reports associating the use of blue dye in tube feedings with blue discoloration of body fluids and skin, as well as more serious complications. There were 12 reported deaths and one case with an unknown outcome. So, the agency warned healthcare professionals against using these blue-dyed feeding tubes.
Eleven years later, in 2014, the Food and Drug Law Journal published an article titled, “The Grays of Medical Device Color Additives,” which outlined the unclear nature of the FDA’s color additive regulations. “In order for any approach to be successful, whether it is a new twist on past practices, or an entirely new path forward, the FDA must, to the best of its ability, better understand its past medical device color additive practices (as well as the variations that have developed within the last twenty or so years), and engage in a dialogue with stakeholders on how it and the medical device industry should consider unlisted color additives currently used in marketed devices in the United States,” the article’s abstract stated. Such a niche consideration as color additives can and has easily fallen to the fringes of regulatory consideration; but, as the 2003 case illustrates, because color is usually applied on the outside surfaces of medical devices which are the sections that come into contact with the patient, it must be handled with clarity and direction by the FDA.
“Being both a Tier 1 and Tier 2 provider, we have found that there is more pressure than ever before from a regulatory standpoint,” noted Michael Venturini, president and CEO of Columbia City, Ind.-based DOT America Inc., a high-tech surfaces company. “We have seen the level of proof rising constantly, i.e. for OEMs, as well as notified and regulatory bodies requesting additional and more detailed reporting on starting materials, coating properties, mechanical behavior and biocompatibility, short and long term, and they are also requesting more in-depth information on validations. We expect this to intensify after the new ISO 13485:2016 becomes effective. With the FDA paying closer attention to the roles that suppliers play for the OEMs, the supply chain needs to rise to the requirements as transparently as possible.”
ISO 13485 has not been revised since 2003. Companies have three years to fully transition and comply with the new 2016 quality standard. The new revision places a greater emphasis on quality management systems (QMS) throughout the supply chain and product lifecycle, as well as device usability and postmarket surveillance requirements.1
“Further developments in regulations tend to have a positive effect on both DOT Germany and DOT America, as we are FDA registered, stay current on regulatory affairs, and are confident in our abilities to meet all changes and requirements head on,” Venturini added. “Our customer base recognizes this and has the utmost trust and confidence in our ability to meet every need from a regulatory compliance standpoint.”
Surface treatments are especially important for orthopedic implants, which very often act as bone-growth platforms. Sweden-based biomaterial company Promimic AB, makes a proprietary implant surface designed to dramatically accelerate osseointegration called HAnano Surface. The surface can be applied onto various types of substrates, including metals, ceramics and polymers. The treatment can convert any implant, regardless of its dimensions and structure, to a surface that resembles natural human bone tissue.
“In general, coatings are there to improve the integration with the bone, creating a faster anchoring of the implant restoring the lost function to the body faster than for an uncoated implant,” CEO Ulf Brogren explained to ODT. “The use of porous structures —metals as implant materials are growing. We believe the use of porous implants will result in an increased demand for new types of coatings—coatings that can be combined with porous materials. Such coatings will be based on wet chemistry without the need for line of sight; adding bone chemistry and bio-mimicking nano-structures to the implants without clogging the pores. This will create implant materials that are structured as bone and have a bone-like chemistry. This is an example of the high performing implants that will be required to meet the increasing clinical demands as more and more patients will be needing more and more implants due to poorer bone quality.
“Within the spine segment several of the leading implant companies have launched coated PEEK interbody devices at this moment,” he continued. “The reason for this is to create devices that actually integrate with bone, in order to support a better and faster fusion. For all non-titanium implants the need for a coating that improves the osseointegration will be crucial.
“In many market segments product differentiation will be key to success, since the majority of the implants currently available on the market have similar designs and functions. Also, as the market is shifting due to changing demographics and growing health problems, the demand for high performing implants is increasing. Combining novel implant designs with the right bone chemistry for better and faster integration will be one important solution to these problems, and Promimic sees an increasing demand in coatings from these marketing and clinical perspectives.”
Promimic’s existing technology includes its hydroxyapatite surface, to which it adds bone-like chemistry that attracts bone cells and accelerates integration. According to Brogren, since the coating is only 20 nanometers thin, bone will integrate with the implant, in the micro and macro roughness of the implant surface, and not into the coating itself. The Promimic coating technology can coat all kind of shapes and materials in a cost-efficient way, and the company establishes predicate devices and master files for its HAnano Surface with the FDA. Promimic has also developed an extensive portfolio of pre-clinical in vivo data, which may facilitate and support customer regulatory submissions.
Promimic also developed a unique wet chemical coating process designed for implementation anywhere an implant is produced and on any device. Through a licensing agreement, the OEM client gets full control over the coating process directly at their production line.
For customers that don’t want an in-house solution, the company has also recently signed a strategic partnership with Warsaw, Ind.-based Danco Anodizing Inc., where Danco will invest in a production line for the HAnano Surface, making it easier for U.S. customers to get to market. Danco will be the preferred process partner for Promimic in the United States and also in the Chinese medical implant market.
From Tim Zentz’s perspective, sales manager at Danco, it is the market’s focus on higher performance coatings for implantable devices that has provided Danco the opportunity to offer their customers the HAnano process via Promimic that allows for improved osseointegration of the implant, which ultimately improves a patient’s recovery time.
Kevin Gilbert, quality manager at Danco, draws attention to the standards and quality changes that are affecting the surfaces and coatings business. “With the changes in ISO 9001 and ISO 13485 really driving for the mitigation of risk in all the processes that are performed, it is important that the culture of the organization focuses on preventive processes,” he told ODT. “This has to be based on the correct analysis of data and not reactionary. It is imperative that enough of the correct data is collected to be able to link KPI’s (Key Performance Indicators) to the PFMEA (Process Failure Mode Effects Analysis) system. This applies to every aspect of the QMS and production process. One such example is to evaluate the communication processes between Danco and the customer base; Danco needs to communicate quality escapes from the customer that could result in quality issues within our organization. This includes everything from the accuracy of the purchase order supplied with the product, to the packaging the product is shipped to and from in, to ensure that the product is not introduced to product contact materials that would result in contamination of the product during shipment.”
Once color, coatings, materials, and every other consideration has been paid to a device, then comes considerations such as polishing. Chicago, Ill.-based Able Electropolishing Co. provides electropolishing services, as well as other finishing services such as passivation, which uses nitric or citric acid to remove free iron and other surface contaminants, restoring the material to its original mill condition; its proprietary Brite passivation, a light electropolishing process designed to clean the part surface and leave a finish superior to standard passivation; titanium finishing and anodizing; deburring; and ultracleaning.
“Electropolishing becomes an important role in the final product,” Sales Manager Scot Potter told ODT. “The electropolishing provides many benefits in one process. The process provides deburring, microfinish improvement, improved corrosion resistance, ultracleaning and a decorative finish in one operation. In addition, the laser marking allows customers to meet FDA UDI (unique device identifier) requirements. Lastly, the titanium color anodizing improves part identification by color-coding parts for product or size identification.”
Down the Coated Pipeline
“New markets have developed for titanium plasma-sprayed (TPS) coatings on PEEK for spinal applications and on ceramic substrate material for hip cups,” DOT America’s Venturini said. “Upgrades in physical vapor deposition (PVD) coating technology facilitate the production of coatings with very low roughness, thus further reducing wear. The significance of surface treatments to fight microbial infections post-operative have become fields of intensive research and development, and anti-microbial coatings for trauma and orthopedic implants based on silver or other elements have evolved. “We are excited about the growing importance of additive manufacturing in the mass production of implants, with regard to the role thin calcium phosphate (CaP) coatings can play to foster bone on-growth.
“Certainly, there are also challenges ahead: We tend to consider additive manufacturing as a potential challenge for porous coating of certain implant types in the long run. And in the trauma business, the evolution of non-metal screws, consisting of a combination of biodegradable polymers, such as polylactic acid, and hydroxyapatite, can replace certain anodized titanium screws.”
According to Parimal Bapat, research engineer at Holt, Mich.-based Orchid Orthopedics, ”Additive manufacturing (AM) is a good choice for implants with low surface to volume ratios and implants that have complex geometries which are difficult to achieve with traditional forging, casting, and machining techniques. In addition, since a variety of materials such as titanium and stainless steel, can be used in the AM process, functional prototypes can be made out of the same material as production components. This enables more rigorous testing of prototypes while decreasing the development time for new products.
” The highly popular 3D printing process is being used to build complete orthopedic implants, including the roughened surface, in one single process. The process is fast, ideal for low runs, and can create nearly production-ready implants. 3D printing utilizes a computer aided design (CAD) program to build an implant, one layer at time. Layer thickness can be controlled down to a few microns. Using the CAD software, engineers determine the desired coating specifications and build the entire implant in a single run, with minimum post processing.”2
Boyd’s Buxton sees process control becoming more and more important. “This is driving Precision Coating (and our Boyd Coatings division) to more advanced equipment to more precisely control properties, particularly thickness and friction,” he said. “As more interventional medical applications are defined, these properties are often critical to our customers’ success. The other area is in research of alternative materials in order to protect our planet through ‘green’ initiatives. Boyd has a strong engineering team working both these areas.”
One must not forget the dental market either. Increasingly, the dental and orthopedic markets are cross-pollinating ideas and techniques. This year, Elsevier’s Biomaterials journal published an article detailing the design of an engineered, elastin-like protein (ELP) that is chemically modified to enable stable coatings on the surfaces of titanium-based dental and orthopedic implants by novel photocrosslinking and solution processing steps.3
References
- http://www.raps.org/Regulatory-Focus/News/2016/03/01/24443/New-ISO-13485-Device-Companies-Have-Three-Years-to-Transition/
- http://www.orchid-ortho.com/_blog/Orchid_Blog/post/new-trends-in-orthopedic-implant-coatings/
- http://web.stanford.edu/group/heilshorn/publications/2016/2016_RaphelLindsayHaughHeilshorn.pdf