TY - JOUR
AU - Peramo, Antonio
AB - Abstract Background Surgical implants are widely used in the medical field but their long-term performance is limited due to failure of integration with tissues. This manuscript describes very well-known problems associated with implants and discusses novel solutions used in tissue engineering and regenerative medicine that can be implemented in this uncommonly discussed medical area. Sources of data General and medical literature describing modifications of medical and surgical implants, biofunctionalization, tissue engineering and regenerative medicine. Areas of agreement Procedures for surgical implantation have grown substantially in the last few decades and provided improved quality of life for patients, regardless of area of implantation and device type and purpose. Areas of controversy In general, implants fail because of lack of long-term integration with the surrounding tissues. Implant manufacturers have not addressed implant failure from the point of view of biointegration. In addition, some medical practitioners are inclined to treat implant failure by using anti-infection methods to prevent bacterial adhesion. However, both approaches are conceptually limited, as discussed in this manuscript. Growing points Implantation in the future will not be limited to medically needed procedures but also to a growing number of cosmetic body transformation procedures, which may include perceived ‘improved implant functions’ over natural tissues or organs. An additional trend is that implant procedures are being progressively performed in younger individuals. Areas timely for developing research Current implants generally do not allow the physician to have controlled long-term access to internal tissues in contact with the implants, for example to release specific compounds when medically needed to the problem area. medical device, implant interface, regenerative medicine, tissue engineering, drug delivery Introduction Medical devices and surgical implants have been technically improved in the last few decades and their use has been widely extended to a large number of patients. An example is the exo-squeletal prosthesis, which is being used by a growing number of disabled people [see for example a recently developed symbionic leg by Ossur (http://www.ossur.com; 6 December 2013, date last accessed)]. One of the reasons for the improved usability—and limited failure—of these external prostheses is that these devices are not percutaneous or permanently placed inside the body and hence a permanent, constant biointegration between both is not required. For percutaneous and totally implanted devices there is, however, an increased interest in finding solutions to provide a better long-term integration with tissues and organs. A possible way to better biointegrate implants and tissue would be to implement solutions drawn from tissue engineering and regenerative medicine directly into or around the areas in contact with the medical implants, in addition to the more normal approach of functionalizing or modifying the surgical implant itself. This paper introduces these concepts and presents some of the work that has been previously proposed in this area. However, because biointegration, as applied to the interface between an implant and a biological tissue, is a concept that is still in development, this article is in fact a mix of review article and white paper, to help disseminate ideas in the field of biointegration tissue–implant. The vast majority of surgical implants are still made of non-biodegradable materials. From hip prostheses to peritoneal catheters, the interface tissue–implant induces a well-studied foreign body response, creates an area prone to infections and, over time, is not conducive to the integration of the implant with the tissue, ending with implant failure.1–3 Since the type and number of surgical implants is staggering we will reduce the discussion of our concepts mostly to implants that present a hard, non-biodegradable, non-modifiable interface with the surrounding tissues. The implants are either completely placed inside the body, like knee replacements, or only partially, like catheters, and made of varied materials like metal, ceramic or plastics. We will not focus on a particular type of surgical implant or prothesis, since the broad concepts presented can be applicable to most of them. It must also be clear that we are not describing the use of scaffolds, biomaterials, biomolecules, cells and tissue-engineered constructs, which normally contain soft and biodegradable materials. These are typically designed for a one-time use and in the context of our discussion are not considered ‘implants’. In this manuscript, then, we will: (i) discuss the need of improving the long-term integration tissue–implant; (ii) introduce the reader to the problems created at the interface between implants and biological tissues; (iii) describe methods currently in use to modify the implants or surgical devices and (iv) describe novel ideas drawn from tissue engineering, regenerative medicine and biomedical engineering that could be implemented in future devices or implants. These methods would apply in particular to implants that are intended to be in place for very long periods of time or, in most cases, indefinitely. Need to improve surgical implant integration with the surrounding tissues Documented attempts to solve the issues associated with modern implants date back to the early twentieth century, when Lambotte coated external fixation pins for bone repair with nickel and gold to protect the pins against rust.4 Nowadays, an incredible variety of devices using disparate materials (from plastics to metals) have been developed by researchers, constructed by the medical device industry and implanted by surgeons. But do current medical implants require substantial improvements over current technologies? Published information about the failure rates and economic impact of all medical implants sold by current manufacturers is difficult to find. In any case it is possible to find specialized reviews by implant type or disease. Failure rates and economic impact are partially available for catheters or device replacements in osteoarthritis, with knee and hip replacements the best documented areas.5,6 For instance, total combined hip and knee replacements in the USA were over 900 000 cases in 2009;7 knee replacements worldwide more than a million and 75 000 in the UK alone in 2009.5 Several hundred million intravascular catheters are placed every year in the USA while between 10 and 30% of hospitalized patients have vascular or urinary catheters in place.8,9 Economic costs of implant failure have been evaluated for certain type of implants.10 In addition, some patients require multiple device replacements and as mentioned before it is expected that the number of medical procedures with more sophisticated implants and longer periods of implantation will increase in the near future due to an aging population with several medical complications, particularly diabetes and vascular diseases.11 While in the past medical implants where mostly used by the elderly, there is also an observed increase in the number of implants in younger populations (<55 years old). By any measure, the above figures are staggering, indicating the clear necessity of improvement of the process of long-term integration tissue–implant, which may eventually lead to reductions in infections. Problems associated with medical implants Biointegration The main reason for the failure of the implants is the lack of integration between the implant and the tissue that surrounds it (which may derive in aseptic loosening and peri-implantitis12) (Table 1, Fig. 1). We define here ‘biointegration’ as the recurrent, long-term mechanical, biological and physical adjustment of the interface between the surgical implant (metal, plastic) and the surrounding tissue (biological). An alternative, but not equal term is ‘biofunctionalization’, but this expression is better used to describe some of the methodologies to improve implant performance (discussed later in this manuscript). The term biofunctionalization is also encountered in biosensor technology, in the development of coatings of implant materials or in the characterization and evaluation of implants.13–17 Table 1 Irrespective of the manner they are classified and their purpose, implant-associated problems can be seen as temporary, recurrent or permanent Simple classification of implants . Associated problems . By type of anchoring (bone or soft tissue) Temporary: infection By intended term of implantation (short, long term or permanent) Recurrent: swelling By purpose or surgical procedure Permanent: loosening leading to chronic inflammation ischemic necrosis, scars and fibrosis Simple classification of implants . Associated problems . By type of anchoring (bone or soft tissue) Temporary: infection By intended term of implantation (short, long term or permanent) Recurrent: swelling By purpose or surgical procedure Permanent: loosening leading to chronic inflammation ischemic necrosis, scars and fibrosis Some of the issues, like a temporary bacterial infection, can become permanent. For long-term and permanently implanted devices, the outcome may be surgical revision and retrieval of the implant. Open in new tab Table 1 Irrespective of the manner they are classified and their purpose, implant-associated problems can be seen as temporary, recurrent or permanent Simple classification of implants . Associated problems . By type of anchoring (bone or soft tissue) Temporary: infection By intended term of implantation (short, long term or permanent) Recurrent: swelling By purpose or surgical procedure Permanent: loosening leading to chronic inflammation ischemic necrosis, scars and fibrosis Simple classification of implants . Associated problems . By type of anchoring (bone or soft tissue) Temporary: infection By intended term of implantation (short, long term or permanent) Recurrent: swelling By purpose or surgical procedure Permanent: loosening leading to chronic inflammation ischemic necrosis, scars and fibrosis Some of the issues, like a temporary bacterial infection, can become permanent. For long-term and permanently implanted devices, the outcome may be surgical revision and retrieval of the implant. Open in new tab Fig. 1 Open in new tabDownload slide This image graphically summarizes and conceptualizes the lack of integration between implants and tissues. A stainless steel fixator pin—of the same type regularly used to stabilize bone fractures—was used in an experiment to penetrate human skin specimens in an organotypic model of skin culture in vitro (as reported in Peramo A, Marcelo CL, Goldstein SA, Martin DC. Novel organotypic cultures of human skin explants with an implant-tissue biomaterial interface. Ann Biomed Eng 2009;37:401–409). After 5 days of culture of the skin with the inserted fixator pins and upon extraction the pins showed some tissue attached; in the pictures shown (A– D) fibrous tissue from the dermis; but the major part of the pin was clean, indicating lack of deposited materials and tissue attachment. To address this lack of integration some tissue engineering techniques to implement around medical implants to control and improve the interface tissue–implant are described in the text and listed in Table 3 This idea behind biological integration has been proposed by tissue engineers or biomedical engineers to describe the short-term ‘integration’ of biodegradable, soft scaffolds of varied sorts with tissues.18,19 One can consider that integration has been achieved if there is no visible physical separation between the implant and the tissue and the implant is not ‘loose’ or, in other words, that there is good tissue attachment and no scar tissue formation. This generally implies some type of cell and tissue penetration of the implant surface, requiring direct functional and structural connection between the tissue and the implant. Occasionally, loosening of the implant is due to biofilm formation on its surface, but the lack of mechanical adjustment is not always or necessarily related to device infection.20,21An additional issue is the unkonwn effect of health disorders in the tissue reaction to surgical implants.22 Device infection After implantation, if the functional and structural connection described above as biointegration fails, infection can spread to the interior of the body, particularly if the implant is percutaneous. In clinical practice, after placement of an implant, the standard of care is to allow healing of the injury to proceed solely through the body's own regenerative ability while providing daily care to prevent infection. The eventual bacterial biofilm formed on the surface of the devices is remarkably difficult to eliminate, a problem compounded by the increased bacterial resistance to antibiotics.23 In addition, the biofilm creates a physical barrier and formation of layers of tissue that prevent drug delivery to more internal tissues. Release of debris from the implant surface into the tissue, which is fairly common, may represent a more serious problem than the loosening of the implant, and can in fact be the reason for its failure.24,25 An often overlooked issue is the difference in resistance to infection between biodegradable and non-biodegradable implants, discussed recently by Daghighi et al.26 Description of methods for implant modification Most of the studies in this area have been related to implant topology, implant mechanical properties and implant material composition, including surface properties of the implant (Table 2), since it was long demonstrated that surface roughness, porosity and texture of the implants affect implant viability.27 Table 2 Implant failures have been addressed by a number of technological approaches that can be broadly related to the physical interface or their biological functionality or in some cases a combination of both Related to physical functionality . Related to biological functionality . Implant topology Mechanical properties Implant material composition Implant coatings and surface treatment Physical interface does not change over time They constitute ‘reactive interfaces’ The focus is on tissue repair Antimicrobials Drugs Regenerative materials: hydrogels, scaffolds, liquids or cell suspensions Interface change over time They constitute proactive interfaces The focus should be on tissue regeneration Related to physical functionality . Related to biological functionality . Implant topology Mechanical properties Implant material composition Implant coatings and surface treatment Physical interface does not change over time They constitute ‘reactive interfaces’ The focus is on tissue repair Antimicrobials Drugs Regenerative materials: hydrogels, scaffolds, liquids or cell suspensions Interface change over time They constitute proactive interfaces The focus should be on tissue regeneration The proposition in this manuscript is for the development of long-term access proactive interfaces focusing on the possibility to induce tissue regeneration. Open in new tab Table 2 Implant failures have been addressed by a number of technological approaches that can be broadly related to the physical interface or their biological functionality or in some cases a combination of both Related to physical functionality . Related to biological functionality . Implant topology Mechanical properties Implant material composition Implant coatings and surface treatment Physical interface does not change over time They constitute ‘reactive interfaces’ The focus is on tissue repair Antimicrobials Drugs Regenerative materials: hydrogels, scaffolds, liquids or cell suspensions Interface change over time They constitute proactive interfaces The focus should be on tissue regeneration Related to physical functionality . Related to biological functionality . Implant topology Mechanical properties Implant material composition Implant coatings and surface treatment Physical interface does not change over time They constitute ‘reactive interfaces’ The focus is on tissue repair Antimicrobials Drugs Regenerative materials: hydrogels, scaffolds, liquids or cell suspensions Interface change over time They constitute proactive interfaces The focus should be on tissue regeneration The proposition in this manuscript is for the development of long-term access proactive interfaces focusing on the possibility to induce tissue regeneration. Open in new tab The techniques presented below are not an exhaustive list but provide an overview of the research on implant modification. These methods are: biofunctionalizing the surface of the implant with biomolecules of other materials; modification of the implant to improve mechanical properties and use of temporary films (sometimes identified as scaffolds) for the release of cells or drugs from the modified implant surface. In most cases, the modification of the implant technique is in fact a combination of these methods. Some of the limitations of these techniques have been described elsewhere28 and will be discussed in the section “Implementing tissue engineering techniques around medical implants”. Biofunctionalization The main purpose of biofunctionalization is to achieve a surface that can drive the interaction of tissue–implant, at least for some period of time. Modification of the surface of the device, which will typically be of a monolayer thick, can be done by mechanical, physical or chemical treatments, most of them reviewed by Liu et al.29 In some cases the molecules are physisorbed but in others they are covalently attached to the surface of the implant.30,31 The performance of these biofunctional coatings have been studied extensively, with several reports focusing on titanium, gold, glass, alloys and ceramic surface modification32–35 with an increased trend towards nanostructured surface modification.28,36 Particular interest has been put in using extracellular matrix materials in implant surface functionalization37,38 but also using natural and synthetic peptides to improve biocompatibility or for their antimicrobial effects.39–41 Mechanical improvement While the mechanical properties of the implants, their topology and their composition are important elements that need further study, they have the limitation that they cannot be easily changed or replaced after implantation. The progressive mechanical deterioration and loosening of the tissue–implant interface induces the formation of scars and fibrous tissue and in some cases requires implant retrieval.42 Alterations of the structural and topological characteristics of the implants with the use of different porous materials with designs like flanges have also been implemented.43 Modifying the porosity of the materials to change mechanical properties is also important in soft tissue attachment to the implants, which has been less studied compared with bone.44,45 An additional aspect that is being considered in novel designs is to reduce the surface area in contact with the tissue,46 which can minimize foreign body responses, as well as methods to predict biointerface remodeling based on the mechanical properties of the implants.47 Other methods that have been reported are changes in the elastic modulus by modifying the morphology of the surface of the implants with biomolecules.48 Scaffolds and material delivery and elution It is possible to apply or deposit structured coatings in biomedical implants as a strategy to enhance biocompatibility and also deliver therapeutic agents. These techniques are similar to surface biofunctionalization but the main difference is that the structural patterns of the coatings and their thickness makes them more similar to scaffolds, which can hold substances for sustained release for longer periods of time. There are multiple examples of device modification in this manner. Among them are the release of biomolecules in drug-eluting stents;49 the deposition of multilayered films;50 modification with polymers that allow sustained release of drugs or other compounds like nitric oxide;51 cell sheets;52 scaffolding with nanoparticle films53 or nanotubes,54 as well as the use of natural biopolymers.55 Implementing tissue engineering techniques around medical implants General approach There are two main limitations with the methods described in the section “Description of methods for implant modification”: they act temporarily and they are non-repetitive. Those methods provide temporary solutions since the release of the compounds to the interface, for example, is limited in time or amount by the physical dimensions of the scaffold or films. In current tissue engineering and regenerative medicine scaffolds or drug delivery systems have been designed to address tissue repair and tissue defects one at a time and they are not meant to be ‘deployed’ at the interface implant–tissue on a recurrent basis. It is true that some polymers can now locally sustain long drug delivery periods.56 Sustained delivery of materials into the local microenvironment of the implants may have the great benefit of eliminating systemic side effects. However, these systems cannot be replaced, changed, manipulated or replenished after implantation, limiting the ability of the physician to monitor the evolution of the implant over time and not permitting subsequent or different treatments. In general, the ability to change the biointerface host–implant at the microscopic level is currently very limited. This limitation is the reason to suggest the implementation of novel approaches currently in development in biomedical engineering and tissue engineering that may positively impact implant viability. Our proposition is to describe techniques to modify the interface tissue–implant and surgical implant access by making them smart, intelligent and responsive, listed in Table 3. Conversion of a surgical implant into a dual purpose device allowing the controlled, timed, on-demand, repetitive local delivery of cells, regenerative materials, drugs and anti-microbials from the implant itself to the surrounding tissues can help in reducing implant failure. We will discuss some of these novel approaches in this section and they are conceptually presented in Figure 2. Table 3 Suggested techniques to implement around medical implants to control and improve the biointerface tissue–implant, locally and remotely Technique . Comments and examples . References . Biosensors Whole-cell biochips for bio-sensing 57 Polypeptide nanotubes for optical biosensing 58 Biomaterials based and organic bioelectronics 59–63 Implant coatings and surface modifications, including cell encapsulation Multifunctional implant coatings and slow release 64,65 Structured nanocoatings 66–68 Multilayered coatings 69,70 Stimuli responsive and shape memory materials 71–77 Patterns for guided regeneration 78,79 Pore gradients 66,70,80 Controlled drug release 81–85 Cell encapsulation and release 86–89 Use of multiple materials and molecules To replicate ECM microenvironment 90 With polyelectrolytes 69,70,91 Telemetric systems, imaging and wireless tracking of implant conditions Wireless bio-MEMS 92,93 Tomography of cartilage and metal implants 94 Non-invasive monitoring of soft tissue wound healing 95 Optical and mCT imaging in implant infection 96,97 Other in vivo monitoring In vivo fluorescence 98 pH luminiscent probes, other probes 99 In situ self-assembly, biofabrication Biofabrication 18,100 In situ injectable materials 101–105 Technique . Comments and examples . References . Biosensors Whole-cell biochips for bio-sensing 57 Polypeptide nanotubes for optical biosensing 58 Biomaterials based and organic bioelectronics 59–63 Implant coatings and surface modifications, including cell encapsulation Multifunctional implant coatings and slow release 64,65 Structured nanocoatings 66–68 Multilayered coatings 69,70 Stimuli responsive and shape memory materials 71–77 Patterns for guided regeneration 78,79 Pore gradients 66,70,80 Controlled drug release 81–85 Cell encapsulation and release 86–89 Use of multiple materials and molecules To replicate ECM microenvironment 90 With polyelectrolytes 69,70,91 Telemetric systems, imaging and wireless tracking of implant conditions Wireless bio-MEMS 92,93 Tomography of cartilage and metal implants 94 Non-invasive monitoring of soft tissue wound healing 95 Optical and mCT imaging in implant infection 96,97 Other in vivo monitoring In vivo fluorescence 98 pH luminiscent probes, other probes 99 In situ self-assembly, biofabrication Biofabrication 18,100 In situ injectable materials 101–105 The list includes a number of implant surface modifications; use of biosensors for remote sensing; in vivo monitoring with varied probes and in situ self-assembly and biofabrication. Open in new tab Table 3 Suggested techniques to implement around medical implants to control and improve the biointerface tissue–implant, locally and remotely Technique . Comments and examples . References . Biosensors Whole-cell biochips for bio-sensing 57 Polypeptide nanotubes for optical biosensing 58 Biomaterials based and organic bioelectronics 59–63 Implant coatings and surface modifications, including cell encapsulation Multifunctional implant coatings and slow release 64,65 Structured nanocoatings 66–68 Multilayered coatings 69,70 Stimuli responsive and shape memory materials 71–77 Patterns for guided regeneration 78,79 Pore gradients 66,70,80 Controlled drug release 81–85 Cell encapsulation and release 86–89 Use of multiple materials and molecules To replicate ECM microenvironment 90 With polyelectrolytes 69,70,91 Telemetric systems, imaging and wireless tracking of implant conditions Wireless bio-MEMS 92,93 Tomography of cartilage and metal implants 94 Non-invasive monitoring of soft tissue wound healing 95 Optical and mCT imaging in implant infection 96,97 Other in vivo monitoring In vivo fluorescence 98 pH luminiscent probes, other probes 99 In situ self-assembly, biofabrication Biofabrication 18,100 In situ injectable materials 101–105 Technique . Comments and examples . References . Biosensors Whole-cell biochips for bio-sensing 57 Polypeptide nanotubes for optical biosensing 58 Biomaterials based and organic bioelectronics 59–63 Implant coatings and surface modifications, including cell encapsulation Multifunctional implant coatings and slow release 64,65 Structured nanocoatings 66–68 Multilayered coatings 69,70 Stimuli responsive and shape memory materials 71–77 Patterns for guided regeneration 78,79 Pore gradients 66,70,80 Controlled drug release 81–85 Cell encapsulation and release 86–89 Use of multiple materials and molecules To replicate ECM microenvironment 90 With polyelectrolytes 69,70,91 Telemetric systems, imaging and wireless tracking of implant conditions Wireless bio-MEMS 92,93 Tomography of cartilage and metal implants 94 Non-invasive monitoring of soft tissue wound healing 95 Optical and mCT imaging in implant infection 96,97 Other in vivo monitoring In vivo fluorescence 98 pH luminiscent probes, other probes 99 In situ self-assembly, biofabrication Biofabrication 18,100 In situ injectable materials 101–105 The list includes a number of implant surface modifications; use of biosensors for remote sensing; in vivo monitoring with varied probes and in situ self-assembly and biofabrication. Open in new tab Fig. 2 Open in new tabDownload slide Combining current methods of implant surface modification with tissue engineering methods can address the issues associated with the biointerface tissue–implant. Some of the modifications and techniques presented in the text and summarized in this image are not mutually exclusive and can be combined. Of particular interest is the idea of implant modification by zones, with focus on matching mechanical and biological properties of the varied tissues along the path of the implant (i.e. skin, muscle, bone). The other idea is to have long-term access to the interface in varied ways (for example using telemetry systems) and implementing recurrent external/internal delivery systems. These combined systems will create ‘dynamic’ biointerfaces tissue–implants for better long-term management of the implant Biosensors and smart biointerfaces tissue–implant: response to external stimuli and control An excellent approach is to make the tissue–implant interface responsive to external guidance and control, using biosensors and stimuli responsive polymers. Some suggestions are listed in Table 3. For example, we suggest the use of miniaturized delivery systems (at the nano and mesoscopic levels using refillable reservoirs for chronic delivery, as in totally implanted intrathecal drug delivery pumps64) connected to sensors with control electronics. These interfacial systems will give the physician the opportunity to dynamically release drugs or antibiotics on demand at specified rates/amounts at the precise biointerface. Biochips for bio-sensing have been proposed in the development of functional cell-based devices or hybrid cell–device interfaces that could be implemented around implants.57 These electronically assisted devices like bio-MEMS92,93 could be engineered inside, around or as part of the surgical implant containing micro-pumps, micro-valves and reservoirs that can be directed at a distance (wireless), loaded with materials that can be released on-demand. These telemetric systems for monitoring have been employed for different applications: an example is the possible early detection and monitoring of osteoarthritis;94,106 monitoring fracture healing;107 soft tissue wound healing71,95 or orthopedic implant infections.96,97 In the same manner these intelligent micro-implants could be used for the purpose of tissue regeneration or observation of cellular apoptosis98 around the surgical implant. Natural biopolymers (DNA, antibodies, polypeptides) have been suggested as base or intermediate materials for biosensors.58,59 Several of these devices can be implemented on the surface of the implant using materials as organic conductors60 using organic bioelectronics that could be better adapted to biological interfaces than normal silicon-based electronics. In particular, this has been suggested previously to help in regeneration of cardiac tissues and for nerve repair and control of prosthetic devices61,62 and in neural interfaces.63 Finally, smart tissue–implant interfaces can be developed with the use of stimuli-responsive materials. Materials are stimuli responsive when they can be induced to change by changes in the environmental conditions (temperature, pH).72,99 Examples are tunable substrates73 that can respond to the cellular environment at the tissue–implant interface to induce regeneration74,75 or for external activation of drug and protein delivery.76 Surface-reactive coatings applied to medical implants can be adjusted to match the biological properties of the surrounding tissues108 and can drive cell behavior.77 A recent review on shaping tissues with stimuli-responsive materials was presented by Huang et al.71 Biofabrication for improved functional and mechanical biointerfaces tissue–implant A possible approach to better the tissue–implant interface may be to separate the fabrication, design and implantation procedure with the functionalization of the implant and so the interface becomes reusable, allowing regeneration therapies to be implemented on a recurrent basis. A number of biofabrication techniques can then be incorporated into the implants.100 A trend that has been growing is the fabrication of modified implants containing nano-structured and micropatterned surfaces for better biocompatibility and adjustment of mechanical properties.66,78,79 Examples are the simulation of an extracellular matrix microenvironment on titanium surfaces;90 the fabrication of gradient and multi-layered surfaces;69,70,80,91 the suggestion that the surface modification can be done by areas or zones of the implant—instead of equally changing the surface all over the implant—to incorporate biofunctional cues better matching the local tissue properties77 or the concept of fabricating scaffolds for simultaneous cell growth and drug delivery.109 Internal in situ formation and use of polymer matrices containing drugs that will be released over time is not a new application on itself, as there are a multitude of examples of smart polymer delivery systems,101–103 but this concept has not been explored around surgical implants. The idea would be to do in situ surface nano-functionalization after implantation which would allow biointerface tissue–implant formation and re-formation. In this concept, a localized implant can be reproduced and implanted constituting anew delivery systems. This has been shown for example with the delivery of anti-HIV therapies lasting 6 months.104 Another problem is how to match the mechanical properties of the tissues with those of the implants because tissue mechanical properties are dynamic, they change with age and tissue region and because the implants are normally in contact with more than one type of tissue in the longitudinal direction. For example, titanium implants have closer elastic modulus and tensile strength to those of bone than other tissues with which they are in contact. Thus, the design and use of the implants not only should take into consideration the different mechanical properties of the materials in the perpendicular direction but also in the longitudinal direction. This concept is exemplified in Figure 2. Mechanical properties of the implants should be matched by using devices that can—transversally and longitudinally—integrate with hard and soft tissues.18,45 Materials that could possibly be implemented are structured porous inorganic materials,66 which have been used as bioceramics or bioglasses in bone repair because they allow some control of pore size, surface area and symmetry.67,68 New research, specifically addressing the mechanical characteristics of the skin–implant interface45 may help in developing novel implant materials. Other aspect that needs to be studied is that mechanical properties are examined at load rates or in directions that are not of critical importance at the interface during normal life movement and ambulation.110 Controlled release of cells and suspensions to the biointerface tissue–implant The concept of drug-controlled release has been around for a long time and is being continually advanced in the literature.81–83 When referring to drug release and implants, this is commonly understood as release from the implant to the surrounding area, but almost always with the purpose of controlling pain or infection.84,85 Our proposition is to apply the same concept—using the engineering concepts described in the section “General approach”—to improve and regenerate the tissue–implant interface, using what has been called ‘therapeutic cell delivery for in situ regenerative medicine’86,87 but around surgical implants. This will have the additional advantage that the efficacy may be improved and the side effects reduced,111 since they will be released or at a specified time, location and dosage rather than through oral ingestion or injection. Attracting or delivering stem cells, growth factors112 and other materials to the implant site can include the use of nanomaterials for in situ cell delivery and regeneration,88 cell transplantation therapy, combination therapies of cells and materials or isolated specific molecules.65,89,105,113,114 It may also be possible to do localized gene therapy at the tissue–implant interface.115 Varied cell types have been used or evaluated for use in bioartificial scaffolds;116 it may be also possible to deliver them from synthetic surgical prosthesis and devices, including stem cells.117,118 Other concepts are the extended use of magnetic implants119 that can be modified for long-term use in surgical implants. The concept of dynamic biointerfaces at the tissue–implant interface Engineering one of more of the strategies described in the section “General approach” would effectively create what we termed dynamic biointerfaces. These tissue-engineered modifications of the surgical implants are not meant to store biomaterials or cells inside the implants for long periods of time, although it must be said that some solutions have been proposed for the long-term maintenance of cells in the development of functional cell-based devices or hybrid cell–device interfaces.57 Rather, these dynamic biointerfaces at the implant surface or interior would act as a reservoir, conduit or delivery system that can be used when needed. Another particularly compelling case to implement this dynamic biointerface can be made to address osteolysis caused by the release of debris from the implant surface into the tissue. As commented by Liu et al.,120 at present there is no approved nonoperative treatments for periprosthetic osteolysis. They suggested that intra-articular injection of some proteins or antibodies to block the TNF-like weak inducer of apoptosis (TWEAK) binding FGF-inducible molecule 14 (Fn14) signaling inhibition can diminish joint inflammation. A dynamic system for repeat delivery of such proteins or antibodies will be more compelling than repeat injections, as will be for treatment of periprosthetic infections in total joint replacements121 where daily doses of antibiotics are delivered through percutaneous silicone catheters directly into the intramedullary canal. An obvious advantage of having access to the interface tissue–implant is that regenerative strategies controlling and addressing mesenchymal–epithelial interactions122 can be implemented. These strategies have never been implemented in surgical devices and can be important in tissue remodelation around the implant. A hurdle for the implementation of these techniques is related to the position regulatory authorities take on ‘combination products’ because of concerns with products blurring the differences between drugs and devices. There are a number of good reasons for the implementation of dynamic biointerfaces and regenerative strategies around the implants:123 the possibility that the material or cell suspension would reduce the inflammatory response of the tissue to the device (possibly inhibiting dendritic cell maturation); reduce or eliminate recurrent scarring; eliminate or reduce acellular and avascular areas; reduce sensor biofouling (if biosensors are present); induce tissue regeneration or control stem cell differentiation if stem cells are delivered through the implant.124 The ability to do this is more important in long-term implantation because of repetitive periods of microinjury/repair with recurrent break down of the tissue, hypertrophic scarring and fibrosis. A particularly interesting attempt to reduce scarring and fibrosis using a locally implanted device has been presented recently.125 The authors used a PEG-based hydrogel release matrix implanted in animals to release a drug with the objective of reducing fibrosis. While the authors did not attempt to modify a surgical device, they showed a promising idea attempting to use hydrogels as a preliminary step to reduce scarring in implanted materials. The interest is to explore whether the hydrogels can be gelated around implanted surgical materials. Clinical trials We searched www.clinicaltrials.gov (6 December 2013, date last accessed) for a list of ongoing human clinical trials using general broad terms, listed in the first column of Table 4. We have included a summary of the search results in Table 4, but it should be noted that most of the search results, listed as ‘number of studies found’, do not directly implicate studies relating tissue engineering or regenerative medicine and medical implants. Several keywords used, for example biofabrication, biointegration, biointerface or biofunctionalization provided no results, indicating that several ideas and techniques have not yet reached the clinical trial phase or that investigators do not include them in their description of the study. Table 4 List of ongoing human clinical trials where some of the techniques described in this review are currently being investigated Technique, keywords . Studies found . Example(s) . Comments or results . Biosensor 22 Second generation drug-eluting stents with everolimus-eluting stent Several trials are related to drug-eluting stents, which have shown benefits compared with bare metals Biochips or biosensing or whole-cell biochips 2 A biochip for rapid diagnosis of complicated urinary tract infection Not strictly related to tissue engineering and surgical implants Bioelectronics or organic electronics or conductive polymers 7 Neuromuscular electrical stimulation versus intermittent pneumatic compression for blood flow Unrelated to tissue engineering and surgical implants Cell delivery 6 Stem cell therapy in patients with severe heart failure and undergoing left ventricular assist device placement This study is designed to determine whether the delivery of cells just after implantation of left ventricular assist device will help to improve the pumping function of your heart Guided regeneration 20 Evaluation of the safety and efficacy of a guided bone regeneration membrane for the treatment of femoral fractures Some studies relate tissue regeneration with surgical implant, particularly for bones in dental procedures using membranes Implant coating or surface coating 6 Clinical assessment of a new catheter surface coating with antimicrobial properties Coatings are generally used as antimicrobials in these trials Non-invasive monitoring In vivo monitoring Implant tracking Telemetric systems 18 External immobilization compared with limited immobilization using a novel real-time localization system of the prostate Limited relation to regeneration of tissues around implants Osseointegration 22 Denosumab in enhancement of bone bonding of hip prosthesis in postmenopausal women (ProliaHip) Trial to evaluate the efficacy of denosumab on the biologic incorporation of cementless hip prosthesis Regenerative medicine 65 An efficacy and safety study of srm003 in the treatment of subjects undergoing placement of an arteriovenous graft to facilitate hemodialysis access In this study it is hypothesized that when placed outside the blood vessel, the seeded gelatin matrix containing endothelial cells can provide a continuous supply of multiple growth regulatory compounds to the underlying cells within the blood vessel Surface modification or microtexture or porous 54 Performance of microtextured dental implants Bisphosphonate-coated dental implants Voice prosthesis made in porous titanium after total laryngectomy or pharyngolaryngectomy Surface modification is normally made by mechanical texturing of the surface Tissue engineering 37 Cranial reconstruction using mesenchymal stromal cells and resorbable biomaterials Bioactive glass (sol-gel) for alveolar bone regeneration after surgical extraction The studies address tissue repair without the presence or involvement of surgical implants Technique, keywords . Studies found . Example(s) . Comments or results . Biosensor 22 Second generation drug-eluting stents with everolimus-eluting stent Several trials are related to drug-eluting stents, which have shown benefits compared with bare metals Biochips or biosensing or whole-cell biochips 2 A biochip for rapid diagnosis of complicated urinary tract infection Not strictly related to tissue engineering and surgical implants Bioelectronics or organic electronics or conductive polymers 7 Neuromuscular electrical stimulation versus intermittent pneumatic compression for blood flow Unrelated to tissue engineering and surgical implants Cell delivery 6 Stem cell therapy in patients with severe heart failure and undergoing left ventricular assist device placement This study is designed to determine whether the delivery of cells just after implantation of left ventricular assist device will help to improve the pumping function of your heart Guided regeneration 20 Evaluation of the safety and efficacy of a guided bone regeneration membrane for the treatment of femoral fractures Some studies relate tissue regeneration with surgical implant, particularly for bones in dental procedures using membranes Implant coating or surface coating 6 Clinical assessment of a new catheter surface coating with antimicrobial properties Coatings are generally used as antimicrobials in these trials Non-invasive monitoring In vivo monitoring Implant tracking Telemetric systems 18 External immobilization compared with limited immobilization using a novel real-time localization system of the prostate Limited relation to regeneration of tissues around implants Osseointegration 22 Denosumab in enhancement of bone bonding of hip prosthesis in postmenopausal women (ProliaHip) Trial to evaluate the efficacy of denosumab on the biologic incorporation of cementless hip prosthesis Regenerative medicine 65 An efficacy and safety study of srm003 in the treatment of subjects undergoing placement of an arteriovenous graft to facilitate hemodialysis access In this study it is hypothesized that when placed outside the blood vessel, the seeded gelatin matrix containing endothelial cells can provide a continuous supply of multiple growth regulatory compounds to the underlying cells within the blood vessel Surface modification or microtexture or porous 54 Performance of microtextured dental implants Bisphosphonate-coated dental implants Voice prosthesis made in porous titanium after total laryngectomy or pharyngolaryngectomy Surface modification is normally made by mechanical texturing of the surface Tissue engineering 37 Cranial reconstruction using mesenchymal stromal cells and resorbable biomaterials Bioactive glass (sol-gel) for alveolar bone regeneration after surgical extraction The studies address tissue repair without the presence or involvement of surgical implants We used keywords from the text and Table 3 to search for trials at www.clinicaltrials.gov. We have highlighted two studies (in bold) that are representative of the idea of implementing tissue engineering and regenerative techniques around implants, and briefly discussed them in the section ‘Clinical trials’. Open in new tab Table 4 List of ongoing human clinical trials where some of the techniques described in this review are currently being investigated Technique, keywords . Studies found . Example(s) . Comments or results . Biosensor 22 Second generation drug-eluting stents with everolimus-eluting stent Several trials are related to drug-eluting stents, which have shown benefits compared with bare metals Biochips or biosensing or whole-cell biochips 2 A biochip for rapid diagnosis of complicated urinary tract infection Not strictly related to tissue engineering and surgical implants Bioelectronics or organic electronics or conductive polymers 7 Neuromuscular electrical stimulation versus intermittent pneumatic compression for blood flow Unrelated to tissue engineering and surgical implants Cell delivery 6 Stem cell therapy in patients with severe heart failure and undergoing left ventricular assist device placement This study is designed to determine whether the delivery of cells just after implantation of left ventricular assist device will help to improve the pumping function of your heart Guided regeneration 20 Evaluation of the safety and efficacy of a guided bone regeneration membrane for the treatment of femoral fractures Some studies relate tissue regeneration with surgical implant, particularly for bones in dental procedures using membranes Implant coating or surface coating 6 Clinical assessment of a new catheter surface coating with antimicrobial properties Coatings are generally used as antimicrobials in these trials Non-invasive monitoring In vivo monitoring Implant tracking Telemetric systems 18 External immobilization compared with limited immobilization using a novel real-time localization system of the prostate Limited relation to regeneration of tissues around implants Osseointegration 22 Denosumab in enhancement of bone bonding of hip prosthesis in postmenopausal women (ProliaHip) Trial to evaluate the efficacy of denosumab on the biologic incorporation of cementless hip prosthesis Regenerative medicine 65 An efficacy and safety study of srm003 in the treatment of subjects undergoing placement of an arteriovenous graft to facilitate hemodialysis access In this study it is hypothesized that when placed outside the blood vessel, the seeded gelatin matrix containing endothelial cells can provide a continuous supply of multiple growth regulatory compounds to the underlying cells within the blood vessel Surface modification or microtexture or porous 54 Performance of microtextured dental implants Bisphosphonate-coated dental implants Voice prosthesis made in porous titanium after total laryngectomy or pharyngolaryngectomy Surface modification is normally made by mechanical texturing of the surface Tissue engineering 37 Cranial reconstruction using mesenchymal stromal cells and resorbable biomaterials Bioactive glass (sol-gel) for alveolar bone regeneration after surgical extraction The studies address tissue repair without the presence or involvement of surgical implants Technique, keywords . Studies found . Example(s) . Comments or results . Biosensor 22 Second generation drug-eluting stents with everolimus-eluting stent Several trials are related to drug-eluting stents, which have shown benefits compared with bare metals Biochips or biosensing or whole-cell biochips 2 A biochip for rapid diagnosis of complicated urinary tract infection Not strictly related to tissue engineering and surgical implants Bioelectronics or organic electronics or conductive polymers 7 Neuromuscular electrical stimulation versus intermittent pneumatic compression for blood flow Unrelated to tissue engineering and surgical implants Cell delivery 6 Stem cell therapy in patients with severe heart failure and undergoing left ventricular assist device placement This study is designed to determine whether the delivery of cells just after implantation of left ventricular assist device will help to improve the pumping function of your heart Guided regeneration 20 Evaluation of the safety and efficacy of a guided bone regeneration membrane for the treatment of femoral fractures Some studies relate tissue regeneration with surgical implant, particularly for bones in dental procedures using membranes Implant coating or surface coating 6 Clinical assessment of a new catheter surface coating with antimicrobial properties Coatings are generally used as antimicrobials in these trials Non-invasive monitoring In vivo monitoring Implant tracking Telemetric systems 18 External immobilization compared with limited immobilization using a novel real-time localization system of the prostate Limited relation to regeneration of tissues around implants Osseointegration 22 Denosumab in enhancement of bone bonding of hip prosthesis in postmenopausal women (ProliaHip) Trial to evaluate the efficacy of denosumab on the biologic incorporation of cementless hip prosthesis Regenerative medicine 65 An efficacy and safety study of srm003 in the treatment of subjects undergoing placement of an arteriovenous graft to facilitate hemodialysis access In this study it is hypothesized that when placed outside the blood vessel, the seeded gelatin matrix containing endothelial cells can provide a continuous supply of multiple growth regulatory compounds to the underlying cells within the blood vessel Surface modification or microtexture or porous 54 Performance of microtextured dental implants Bisphosphonate-coated dental implants Voice prosthesis made in porous titanium after total laryngectomy or pharyngolaryngectomy Surface modification is normally made by mechanical texturing of the surface Tissue engineering 37 Cranial reconstruction using mesenchymal stromal cells and resorbable biomaterials Bioactive glass (sol-gel) for alveolar bone regeneration after surgical extraction The studies address tissue repair without the presence or involvement of surgical implants We used keywords from the text and Table 3 to search for trials at www.clinicaltrials.gov. We have highlighted two studies (in bold) that are representative of the idea of implementing tissue engineering and regenerative techniques around implants, and briefly discussed them in the section ‘Clinical trials’. Open in new tab However, we have highlighted two studies (in bold) that are representative of the concepts described in our manuscript. In one of the studies, searching for ‘regenerative medicine’, investigators are currently studying the effect of placing a matrix loaded with endothelial cells outside an arteriovenous graft to facilitate hemodialysis access graft, under the hypothesis that when placed outside the blood vessel, the seeded gelatin matrix containing endothelial cells can provide a continuous supply of multiple growth regulatory compounds to the underlying cells within the blood vessel. An even clearer example of combination of regenerative medicine with implant surgery is the study conducted at the University of Minnesota titled ‘Stem Cell Therapy in Patients With Severe Heart Failure & Undergoing Left Ventricular Assist Device Placement’. This study, which has not yet reported results, involves delivering stem cells to determine whether the delivery of cells just after implantation of a left ventricular assist device will help to improve the pumping function of the heart, then combining regeneration with implantation. Conclusions If the fields of medical implants, tissue engineering and regenerative medicine converge into a combined research area applying translational solutions drawn from engineering and regenerative medicine, there will be significant opportunities to address implant failure. Regenerative medicine approaches in medical implants is somewhat a novel concept and is a topic that in itself represents a new area in regenerative medicine. The objective in this manuscript has been to equip the reader with talking points about how it could be possible to transfer some of the concepts currently in development in tissue engineering and regenerative medicine to medical implants, with the final objective of achieving total and permanent integration between the implant and the tissues surrounding them. It is possible that in the future, implants will be designed as a single unit with proactive delivery systems that simultaneously will provide long-term access to the tissues. Artificial implants will continue to increase in complexity and number, while their failure rates will remain basically unchanged unless existing and novel methods are developed to better integrate them with the human body. References 1 Busscher HJ , Van der Mei HC , Subbiahdoss G , et al. 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TI - Implementing tissue engineering and regenerative medicine solutions in medical implants
JF - British Medical Bulletin
DO - 10.1093/bmb/ldt036
DA - 2014-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/implementing-tissue-engineering-and-regenerative-medicine-solutions-in-zgXETCIwIr
SP - 3
EP - 18
VL - 109
IS - 1
DP - DeepDyve
ER -