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Research Article| Volume 52, SUPPLEMENT 2, S106-S111, June 2021

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The rationale behind implant coatings to promote osteointegration, bone healing or regeneration

  • Kai Borcherding
    Affiliations
    Department of Adhesive Bonding Technology and Surfaces, Fraunhofer Institute for Manufacturing Technology and Advanced Materials IFAM, Bremen, Germany
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  • Gerhard Schmidmaier
    Affiliations
    Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, HTRG - Heidelberg Trauma Research Group, Heidelberg University Hospital, Heidelberg, Germany
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  • Gunther O. Hofmann
    Affiliations
    Department of Trauma, Hand and Reconstructive Surgery, Experimental Trauma Surgery, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
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  • Britt Wildemann
    Correspondence
    Corresponding author at: Experimental Trauma Surgery, Department of Trauma, Hand and Reconstructive Surgery, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany.
    Affiliations
    Department of Trauma, Hand and Reconstructive Surgery, Experimental Trauma Surgery, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany

    Julius Wolff Institute, BIH Center for Regenerative Therapies, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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Open AccessPublished:November 20, 2020DOI:https://doi.org/10.1016/j.injury.2020.11.050

      Highlights

      • The clinical problem in orthopedic and trauma surgery and explain the four “osteos-”essential for implant integration and bone regeneration.
      • Present examples of coatings that are used in different orthopedic indications.
      • Finally raise the awareness of coating and translational requirements.

      Abstract

      Implant loosening, bone healing failure, implant-associated infections, and large bony defects remain challenges in orthopedic surgery. Implant surface modifications and coatings are being developed to promote osteointegration, prevent colonization by bacteria, and release bioactive factors. The following mini-review briefly discusses the clinical problem, explains the four “osteos”, presents examples of coatings used for different orthopedic indications, and finally raises awareness of the coating and translational requirements.

      Keywords

      Clinical problem

      Bone adapts to the mechanical requirements throughout life. It is subject to permanent modeling, which enables the repair of microfractures and the adaptation to changes in mechanical demands. In the case of degenerative or traumatic disturbance of the bone, the function of the bone is usually supported by implants, which can be permanent or temporary. In addition to metallic implants, biomaterials are also used to promote bone regeneration in the case of bony defects. The requirements for implants and materials used in trauma and orthopedic surgery differ depending on the indication:
      • 1.
        In the case of joint arthroplasty, the implants should ideally be in place for the entire life span of the patient. The implants are mainly made of metal alloys combined with a synthetic inlay. When using a non-cemented prosthesis, a direct integration into the bone stock is required to ensure strong contact.
      • 2.
        To enable fracture healing, the bone ends are repositioned and the bone is stabilized by an intramedullary nail, a plate, an external fixator, or screws. After the bone has healed, the implant is no longer needed and can be removed.
      • 3.
        If large bony defects must be treated, permanent or degradable implants are used. Defects can occur due to trauma, non-healing, or the resection of infected bone. In these cases, a degradable material for defect filling is used that is remodeled and enables the regeneration of the bone. Large defects due to the resection of tumors are frequently treated with permanent metallic mega-prostheses. The prosthesis ensures the stable bridging of the large defect or the joint replacement in the event of extensive bone loss.
      Fig. 1 summarizes the problems, needs, and coating properties for joint replacement, fracture healing, and defect healing.
      Fig. 1
      Fig. 1Summary of problems, needs and coating properties for joint replacement, fracture and defect healing. Joint replacement refers to uncemented prosthesis. The figure is made by using and modifying Servier Medical Arts. * based on
      [
      • Weber F.E.
      Reconsidering Osteoconduction in the Era of Additive Manufacturing.
      ]
      .

      Definition: the four “osteos”

      Four terms are used to describe the processes occurring during the ingrowth of a prosthesis and bone regeneration, namely osteointegration, osteoconduction, osteoinduction, and osteogenesis.
      Osteointegration describes the ingrowth of the implant into the bone, which leads to a direct bond to the bone and a firm anchorage. This is necessary for the long-term function of a joint replacement. Branemark named this process osseointegration in 1977 and today the terms are used in parallel [
      • Brånemark P.I.
      • Hansson B.O.
      • Adell R.
      • Breine U.
      • Lindström J.
      • Hallén O.
      • et al.
      Osseointegrated implants in the treatment of the edentulous jaw. Experience from a 10-year period.
      ]. The surface topography, roughness, and chemical composition of the implant influence the process of osteointegration (Fig. 2).
      Fig. 2
      Fig. 2The surface of implants can be modified to promote osteointegration. Changes in the surface roughness or the application of coatings are used for better osteointegration. Active factors, such as antibiotics or growth factors can be incorporated in the coatings. On the cellular base, osteointegration depends on the differentiation of progenitor cells to osteoblasts and finally osteocytes embedded in the mineralized matrix. The figure is made by using and modifying Servier Medical Arts.
      The following processes are required for osteointegration and bone regeneration:
      Osteoconduction describes the growth and adherence of osteoblasts to the surface of the implant [
      • Albrektsson T.
      • Johansson C.
      Osteoinduction, osteoconduction and osseointegration.
      ]. The surface and scaffold properties, porosity, and chemistry influence these processes. The term osteoconduction may be traced back to J.B. Murphy (1857–1916) [
      • Weber F.E.
      Reconsidering Osteoconduction in the Era of Additive Manufacturing.
      ,
      • Turner W.G
      The use of the bone graft in surgery.
      ]. Weber defines osteoconduction as a three-dimensional (3D) process in which the osteconductive material/scaffold serves as a guiding structure for new bone formation. While, according to his definition, osteointegration is a 2D process. The ingrowth of vessels and osteoprogenitor cells from the host tissue into the implanted material leads to the bony bridging of the defect. However, an osteoconductive surface is also important for, e.g., intramedullary nails. The attachment of osteoblasts to the surface reduces the risk of bacterial adhesion (“race for the surface” [
      • Gristina A.G.
      • Naylor P.
      • Myrvik Q
      Infections from biomaterials and implants: a race for the surface.
      ,
      • Subbiahdoss G.
      • Kuijer R.
      • Grijpma D.W.
      • van der Mei H.C.
      • Busscher H.J
      Microbial biofilm growth vs. tissue integration: “the race for the surface” experimentally studied.
      ]) and implant loosening.
      Osteoinduction describes the stimulatory effect of factors on progenitor cells to induce migration and differentiation into bone-forming osteoblasts. An important study in this context is the work from Marshal Urist, published in 1965 in Science [
      • Urist M.R
      Bone: formation by autoinduction.
      ], which later led to the identification of bone morphogenetic proteins (BMPs) [
      • Urist M.R.
      • Strates B.S
      Bone morphogenetic protein.
      ]. In addition to BMPs, other growth factors and signaling molecules can induce cell migration and osteogenic differentiation and are important for bone formation; for a review see [
      • Tsiridis E.
      • Upadhyay N.
      • Giannoudis P
      Molecular aspects of fracture healing: which are the important molecules?.
      ,
      • Hankenson K.D.
      • Gagne K.
      • Shaughnessy M
      Extracellular signaling molecules to promote fracture healing and bone regeneration.
      ].
      Osteogenesis means the differentiation of progenitor cells into osteogenic bone-forming cells. One of the early studies on osteogenesis was by Huggins in 1931 [
      • Huggins C.B
      The formation of bone under the influence of epithelium of the urinary tract.
      ]. He used several dog studies to investigate bone formation in the urinary tract. Based on his results and the literature, he concluded that “…certain other connective tissues under an altered environment may acquire osteogenic properties”. In 1920, Asami and Dock described in an experimental setting heteroplastic bone formation in the kindney, however, they did not use the term osteogenesis [
      • Asami G.
      • Dock W
      Experimental studies on heteroplastic bone formation.
      ].
      Fig. 3 summarizes the factors affecting the four “osteos”, namely the material itself and its surface chemistry, topography and biocompatibility, but also the design of the implant and its mechanics, the interface between the implant and host tissue, as well as endogenous or exogenous factors.
      Fig. 3
      Fig. 3Examples for factors affecting the performance of an implant.

      Examples for coatings

      There has been intensive research into implant coatings to optimize the material properties or to release drugs locally. While not all published approaches can be discussed in this mini-review, some important aspects and developments are briefly addressed.
      Two main approaches to coatings have been explored, namely to improve the surface properties [
      • Dehghanghadikolaei A.
      • Fotovvati B.
      Coating techniques for functional enhancement of metal implants for bone replacement: a review.
      ] or to facilitate local drug delivery [
      • Nyberg E.
      • Holmes C.
      • Witham T.
      • Grayson W.L
      Growth factor-eluting technologies for bone tissue engineering.
      ]. Both approaches can be combined. The surface modifications include the deposition of hydroxyapatite (HA), metallic oxides or polymers onto the surface. Various methods are used to produce these coatings, such as plasma spraying, electrochemical deposition, the sol-gel technique, and high-velocity suspension flame-spraying, as described in detail in a recent review [
      • Dehghanghadikolaei A.
      • Fotovvati B.
      Coating techniques for functional enhancement of metal implants for bone replacement: a review.
      ]. There has been extensive research on local drug delivery systems, and Barik et al. summarize the challenges and approaches in a recent review [
      • Barik A.
      • Chakravorty N.
      Targeted drug delivery from titanium implants: a review of challenges and approaches.
      ]. Drop-casting, dipping, spraying, and polyelectrolytic deposition are the main methods used for coatings. To modify the release kinetics or protect the incorporated factors, encapsulation methods are used [
      • Goldberg M.
      • Langer R.
      • Jia X.
      Nanostructured materials for applications in drug delivery and tissue engineering.
      ]. A further optimization is the use of “smart” materials that release the incorporated factors in response to defined stimuli during healing, such as enzymes (e.g. matrix metalloproteinase), pH changes due to the healing phase, or external stimuli (e.g. ultrasound), as described in the review by Qu et al. [
      • Qu M.
      • Jiang X.
      • Zhou X.
      • Wang C.
      • Wu Q.
      • Ren L.
      • et al.
      Stimuli-responsive delivery of growth factors for tissue engineering.
      ].

      Joint replacement

      The correct implantation and osteointegration of the stem components of uncemented prostheses are important for successful joint replacement. Factors that influence osteointegration are the surface microstructure/roughness, the chemical composition, and implant corrosion. The modification of the metallic implant surface includes sandblasting or etching to increase the roughness, coatings such as sol-gel, plasma or high-velocity suspension spraying, and electrochemical processes for the incorporation of substrates such as HA to reduce corrosion and promote integration [
      • Dehghanghadikolaei A.
      • Fotovvati B.
      Coating techniques for functional enhancement of metal implants for bone replacement: a review.
      ]. Plasma spraying of HA is often used by implant manufacturers, and this process enables large-scale production at a low cost. However, this technique can result in, e.g., the structural alteration of calcium phosphate (CaP) due to the high temperature [
      • Heimann R.B
      Plasma-sprayed hydroxylapatite-based coatings: chemical, mechanical, microstructural, and biomedical properties.
      ]. Biomimetic coatings based on the precipitation of CaP from simulated body fluid (SBF) work under physiological conditions and result in crystals more similar to bone mineral than HA [
      • Koju N.
      • Sikder P.
      • Ren Y.
      • Zhou H.
      • Bhaduri S.B
      Biomimetic coating technology for orthopedic implants.
      ]. This process also enables the co-precipitation of osteoinductive growth factors and can be applied to metallic surfaces and polymeric materials. Silver coatings are used clinically to reduce the implant-related infections of tumor prostheses [
      • Schmidt-Braekling T.
      • Streitbuerger A.
      • Gosheger G.
      • Boettner F.
      • Nottrott M.
      • Ahrens H.
      • et al.
      Silver-coated megaprostheses: review of the literature.
      ]. Coatings based on, e.g., tantalum, graphite-like carbon, diamond-like carbon or titanium nitride are applied to orthopedic implants to optimize their biocompatibility and reduce wear and particle abrasion [
      • Ching H.A.
      • Choudhury D.
      • Nine M.J.
      • Abu Osman N.A
      Effects of surface coating on reducing friction and wear of orthopaedic implants.
      ].

      Fracture healing

      Bone heals under optimal conditions with restitutio ad integrum. In addition to restoring the mechanical stability of the fractured bone, the revascularization and differentiation of the cells are both important for successful healing, and both processes are triggered by a large number of growth factors [
      • Giannoudis P.V.
      • Einhorn T.A.
      • Schmidmaier G.
      • Marsh D
      The diamond concept–open questions.
      ,
      • Martino M.M.
      • Briquez P.S.
      • Maruyama K.
      • Hubbell J.A
      Extracellular matrix-inspired growth factor delivery systems for bone regeneration.
      ,
      • Glatt V.
      • Evans C.H.
      • Tetsworth K.
      A concert between biology and biomechanics: the influence of the mechanical environment on bone healing.
      ]. The coating of implants with growth factors to stimulate bone healing has been investigated intensively. Carriers used are [
      • Begam H.
      • Nandi S.K.
      • Kundu B.
      • Chanda A
      Strategies for delivering bone morphogenetic protein for bone healing.
      ]:
      • Biomimetic coatings (ceramics based on CaP)
      • Synthetic polymers, e.g. polycaprolactone, polylactide, polyethylene glycol
      • Natural polymers, e.g. collagen and alginate
      • Micro- and nanoparticles
      In addition to the mechanical stability of the coating during the insertion process, the following aspects must be taken into account when delivering drugs locally: the characteristics of the growth factors, the stability of the growth factors (e.g. selection of the coating material and procedure based on the temperature sensitivity of the factor), half-life of the growth factor, material properties and degradation time, and the release kinetics of the growth factor [
      • Caballero Aguilar L.M.
      • Silva S.M.
      • Moulton S.E
      Growth factor delivery: defining the next generation platforms for tissue engineering.
      ].

      Defect healing

      Large bony defects cannot be healed by the body and the regeneration must be supported by a graft or scaffold. Materials used for tissue regeneration should fulfill the following criteria (adapted from Sokolsky-Papkov 2007 [
      • Sokolsky-Papkov M.
      • Agashi K.
      • Olaye A.
      • Shakesheff K.
      • Domb A.J
      Polymer carriers for drug delivery in tissue engineering.
      ]):
      • Match the mechanical properties of the implantation site or protect cells from inadequate mechanical loading/shielding
      • Be biocompatible
      • Mimic the extracellular matrix
      • Provide the cells with signals that enable homing and differentiation
      • The degradation should be in balance with the regeneration of the tissue.
      Further optimization of scaffolds can be done using coatings to enhance the biocompatibility and promote new bone formation. It was recently shown that coating a polycaprolactone-co-lactide scaffold with artificial components of the extracellular matrix, especially glycosaminoglycan derivates, promoted bone regeneration in a small animal model [
      • Förster Y.
      • Schulze S.
      • Penk A.
      • Neuber C.
      • Möller S.
      • Hintze V.
      • et al.
      The influence of different artificial extracellular matrix implant coatings on the regeneration of a critical size femur defect in rats.
      ]. Enhanced vascularization and bone formation were seen after the implantation of a vascular endothelial growth factor-releasing poly(lactide-co-glycolide) scaffold that was coated with bioglass [
      • Leach J.K.
      • Kaigler D.
      • Wang Z.
      • Krebsbach P.H.
      • Mooney D.J
      Coating of VEGF-releasing scaffolds with bioactive glass for angiogenesis and bone regeneration.
      ]. Biomimetic coatings based on calcium phosphate are also being developed for local drug delivery to improve the properties of the grafting material [
      • Liu Y.
      • Wu G.
      • de Groot K
      Biomimetic coatings for bone tissue engineering of critical-sized defects.
      ].

      Implant associated infection

      All materials implanted in the human body are at high risk of bacterial colonization. If the immune system of the body cannot eliminate the bacteria, these will form a biofilm. Bacteria in a biofilm have a higher tolerance to antibiotics and are protected from the endogenous immune system. The eradication of the bacteria is, therefore, a challenge and in most cases the explantation of the implant and aggressive debridement are necessary. In addition to the enormous burden for the patient, implant-associated infections also have significant economic and social impacts [
      • Romanò C.L.
      • Tsuchiya H.
      • Morelli I.
      • Battaglia A.G.
      • Drago L
      Antibacterial coating of implants: are we missing something?.
      ].
      Various approaches are being followed to reduce bacterial adhesion and promote osteointegration. These can be divided into two main approaches: 1. pure surface modification to reduce bacterial adhesion and promote osteointegration, and 2. the local release of anti-infective factors or drugs to kill bacteria [
      • Wang M.
      • Tang T.
      Surface treatment strategies to combat implant-related infection from the beginning.
      ]. The combination of both approaches seems promising and leads to a reduction in bacterial adhesion and better integration. A hybrid surface that has a porous titanium structure, silver particles in the titanium dioxide layer, and is loaded with gentamicin has shown good cytocompatibility and antimicrobial activity in vitro [
      • Borcherding K.
      • Marx D.
      • Gätjen L.
      • Bormann N.
      • Wildemann B.
      • Specht U.
      • et al.
      Burst release of antibiotics combined with long-term release of silver targeting implant-associated infections: design, characterization and in vitro evaluation of novel implant hybrid surface.
      ]. A gentamicin-coated tibia nail has been approved for human use to prevent implant-associated infections [
      • Schmidmaier G.
      • Kerstan M.
      • Schwabe P.
      • Sudkamp N.
      • Raschke M
      Clinical experiences in the use of a gentamicin-coated titanium nail in tibia fractures.
      ]. The use of a defensive antibacterial coating to treat peri‑prosthetic joint infections in a one-stage exchange provided similar reults as a two-stage exchange [
      • Capuano N.
      • Logoluso N.
      • Gallazzi E.
      • Drago L.
      • Romanò C.L
      One-stage exchange with antibacterial hydrogel coated implants provides similar results to two-stage revision, without the coating, for the treatment of peri-prosthetic infection.
      ].

      Requirements for coatings/translation

      In addition to the optimal shape (design) of an implant, its material, surface topography and chemistry are associated with the principle of bone on-growth or in-growth [
      • Lewallen E.A.
      • Riester S.M.
      • Bonin C.A.
      • Kremers H.M.
      • Dudakovic A.
      • Kakar S.
      • et al.
      Biological strategies for improved osseointegration and osteoinduction of porous metal orthopedic implants.
      ]. Stainless steel and titanium (alloys), the materials primarily used for orthopedic implants, both have differences or rather advantages in strength, ductility, stiffness or cell response; and have to be considered according to the medical need [
      • Hayes J.S.
      • Richards R.G.
      The use of titanium and stainless steel in fracture fixation.
      ,
      • Perren S.M.
      • Regazzoni P.
      • Fernandez A.A
      How to choose between the implant materials steel and titanium in orthopedic trauma surgery: part 1 - mechanical aspects.
      ]. The design of the implant can compensate mechanical disadvantages, but the response of host cells and bacteria to the material differ. Based on preclinical research and clinical experience, the disadvantages of electropolished steel (smooth surface) are imaging artifacts, possible implant migration, release of toxic/allergic ions such as cobalt, chromium, nickel and higher infection risk, while the disadvantages of rougher titanium implants are removal complications due to the better osteointegration. Polymers, for instance PEEKs (polyetheretherketone), are mainly used in the field of spinal surgery as an radiolucent alternative to metallic implants [
      • Kurtz S.M.
      • Devine J.N.
      PEEK biomaterials in trauma, orthopedic, and spinal implants.
      ], but a general usage has not been established due to biomechanical limitations compared to titanium or stainless steel [
      • Mugnai R.
      • Tarallo L.
      • Capra F.
      • Catani F
      Biomechanical comparison between stainless steel, titanium and carbon-fiber reinforced polyetheretherketone volar locking plates for distal radius fractures.
      ]. Solid metal implants, especially made of cobalt-chrome or steel, can be removed more easily (temporary implants) due to the lesser degree of osteointegration than pure titanium, zirconium and/or titanium-based coatings [
      • Plecko M.
      • Sievert C.
      • Andermatt D.
      • Frigg R.
      • Kronen P.
      • Klein K.
      • et al.
      Osseointegration and biocompatibility of different metal implants–a comparative experimental investigation in sheep.
      ]. In addition to the requirement for the biological compatibility of the material itself, the surface chemistry (hydrophilic vs. hydrophobic) and the surface topography, more specifically the roughness [
      • Moroni A.
      • Faldini C.
      • Chilò V.
      • Rocca M.
      • Stea S.
      • Giannini S.
      The effect of surface material and roughness on bone screw stability.
      ], are the dominant factors affecting osteointegration. Specific material selection, surface modification or additional coatings are required if osteointegration is to be promoted (permanent implants). The main requirements for this purpose are of a chemical, physical and biological nature. Biocompatibility is an obvious requirement for an implant coating to promote osteointegration. Although different materials and surface modifications are used to optimize implants, there is still a lack of comparative studies demonstrating the evidence for “the best” material and surface condition or the best coating [
      • Barfeie A.
      • Wilson J.
      • Rees J.
      Implant surface characteristics and their effect on osseointegration.
      ]. Another requirement is that the material characteristics are retained during use and that the biological interaction in the body does not have any negative effects. In particular, the tendency of wear and corrosion in an in vivo environment, which can lead to loosening of particles or the release of toxic elements, can be addressed by coatings [
      • Ching H.A.
      • Choudhury D.
      • Nine M.J.
      • Abu Osman N.A
      Effects of surface coating on reducing friction and wear of orthopaedic implants.
      ]. Implant derived wear particles trigger cells from the innate and adaptive immune system e.g. macrophages and lymphocytes, resulting in an inflammatory reaction characterized by the secretion of cytokines, chemokines and growth factors, which can result in osteolysis and bone loss due to enhanced osteoclast activity and necrosis [
      • Athanasou N.A.
      The pathobiology and pathology of aseptic implant failure.
      ,
      • Eger M.
      • Hiram-Bab S.
      • Liron T.
      • Sterer N.
      • Carmi Y.
      • Kohavi D.
      • et al.
      Mechanism and prevention of titanium particle-induced inflammation and osteolysis.
      ]. This interaction of the material in vivo has to be taken into account in the development of new coatings or the translation of approved coatings into new applications. A further obligatory requirement is that the coating adheres to the surface at least until it reaches its final destination and can fulfill its purpose.
      A requirement from the production point of view is the temperature resistance of the implant material to the temperature introduced during the coating or surface-structuring process. For example, the temperature during a plasma spray process for HA can exceed 500 °C, while for calcium phosphates it can reach above 1000 °C [
      • Yang Y.
      • Kim K.H.
      • Agrawal C.M.
      • Ong J.L
      Interaction of hydroxyapatite-titanium at elevated temperature in vacuum environment.
      ,
      • Radin S.R.
      • Ducheyne P.
      Plasma spraying induced changes of calcium phosphate ceramic characteristics and the effect onin vitro stability.
      ]. Laser structuring introduces a temperature into the surface that can be far above the substrate boiling point (e.g. 3260 °C for titanium). Particularly for metallic implants, the influence of temperature can trigger metallurgical changes, and thus, further biomechanical consequences have to be reviewed. Surface modification (blasting, etching) [
      • Pazos L.
      • Corengia P.
      • Svoboda H.
      Effect of surface treatments on the fatigue life of titanium for biomedical applications.
      ] and porous coatings also have the potential for crack initiation [
      • Yue S.
      • Pilliar R.M.
      • Weatherly G.C
      The fatigue strength of porous-coated Ti–6% Al–4% V implant alloy.
      ], which is known to influence biomechanical requirements regarding fatigue and bending strength. Other evident requirements are that the final implant can still be sterilized without any negative effects and that the required shelf life can subsequently be met without negative changes to the characteristics over time.
      The prerequisite for the translation, market access, and success of an innovative coating is tackling the major hurdles from bench to bedside. The research starts with a clinical need, continues with the evidence from in vitro and in vivo testing to the first implant in the patient and subsequent purposefully designed clinical trials to gain market access [
      • Keramaris N.C.
      • Kanakaris N.K.
      • Tzioupis C.
      • Kontakis G.
      • Giannoudis P.V
      Translational research: from benchside to bedside.
      ]. In particular, the launch costs of “just” adding a coating to already approved implants should not be underestimated, even when the main intended use remains the same, e.g., the use of an intramedullary nail for treatment of a tibia fracture. A coating, for example against an increased risk of local bone infection, must not only be developed with regard to its effectiveness against microorganisms and its biocompatibility, but also with regard to the interaction with the intended use, the material and all the production steps, including packaging, sterilization, storage and shelf life.
      In particular, the lack of cooperation between the different stakeholders (academia, clinical users, manufacturers, regulatory body's, health insurances and policy makers) can cause substantial obstacles in the development and translation for innovative and needed products or end in a deadlock [
      • Busscher H.J.
      • Alt V.
      • van der Mei H.C.
      • Fagette P.H.
      • Zimmerli W.
      • Moriarty T.F.
      • et al.
      A Trans-atlantic perspective on stagnation in clinical translation of antimicrobial strategies for the control of biomaterial-implant-associated infection.
      ].
      Moreover, the regulatory requirements increase with the duration of the implant-to-body contact time (limited <24 h, prolonged >24 h to 30 d or permanent > 30 d) and the product classification [
      • Boutrand J.P.
      Biocompatibility and performance of medical devices..
      ]. Especially the combination of a medical device (e.g. an implant) with drugs for therapeutic purposes can increase the regulatory complexity, which would be increased even further using advanced therapy medicinal products (based on genes, tissues or cells) as described for cell-based therapies [
      • Spinner D.S.
      • Faulkner E.C.
      • Carroll M.C.
      • Ringo M.C.
      • Joines J.W
      Regenerative Medicine and Cell Therapy in Orthopedics—Health Policy, Regulatory and Clinical Development, and Market Access.
      ]. Furthermore, due to country-specific legislation and individual local requirements, simple worldwide market access is not feasible.
      A recently published article highlighted the need for medical antibiotic implant coatings with the expected financial savings when preventing implant-associated infections [
      • Romanò C.L.
      • Tsuchiya H.
      • Morelli I.
      • Battaglia A.G.
      • Drago L
      Antibacterial coating of implants: are we missing something?.
      ]. They concluded that, despite the benefits given, there is still a lack of awareness on the part of health care providers, as well as uncertainties about regulation and reimbursement.

      Future perspectives

      Research into methods to optimize implant integration and bone healing or to reduce implant-associated infections has increased dramatically in recent decades. Various implant coatings have been developed, some with a very high complexity of the coatings and local drug delivery systems. However, feasibility must be taken into account in the clinical translation. In addition to good biocompatibility and effectiveness, the following aspects should be considered when developing a new implant modification: 1. the materials used should be approved or have the potential to be approved for human use; 2. the production should be simple, standardized, reproducible and up-scalable; and 3. the packaging, storage, and shelf-life can be affected by the coating and need to be adapted.

      Declaration of Competing Interest

      Gerhard Schmidmaier holds a patent on an implant coating.
      The other authors have no conflict of interest related to the submitted review.

      Acknowledgments

      This work was supported by the Federal Ministry of Education and Research, Germany, under grant number 03VP03681 and 03VP03682. We thank Laura Davies for English proof-reading.

      Appendix. Supplementary materials

      References

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