Tissue-implant Interface Research Articles

The response of soft tissue cells to Ti implants is modulated by blood-implant interactions.

Titanium-based dental implants have been highly optimized to enhance osseointegration, but little attention has been given to the soft tissue-implant interface, despite being a major contributor to long term implant stability. This is strongly linked to a lack of model systems that enable the reliable evaluation of soft tissue-implant interactions. Current in vitro platforms to assess these interactions are very simplistic, thus suffering from limited biological relevance and sensitivity to varying implant surface properties. The aim of this study was to investigate how blood-implant interactions affect downstream responses of different soft tissue cells to implants in vitro, thus taking into account not only the early events of blood coagulation upon implantation, but also the multicellular nature of soft tissue. For this, three surfaces (smooth and hydrophobic; rough and hydrophobic; rough and hydrophilic with nanostructures), which reflect a wide range of implant surface properties, were used to study blood-material interactions as well as cell-material interactions in the presence and absence of blood. Rough surfaces stimulated denser fibrin network formation compared to smooth surfaces and hydrophilicity accelerated the rate of blood coagulation compared to hydrophobic surfaces. In the absence of blood, smooth surfaces supported enhanced attachment of human gingival fibroblasts and keratinocytes, but limited changes in gene expression and cytokine production were observed between surfaces. In the presence of blood, rough surfaces supported enhanced fibroblast attachment and stimulated a stronger anti-inflammatory response from macrophage-like cells than smooth surfaces, but only smooth surfaces were capable of supporting long-term keratinocyte attachment and formation of a layer of epithelial cells. These findings indicate that surface properties not only govern blood-implant interactions, but that this can in turn also significantly modulate subsequent soft tissue cell-implant interactions.

IMPLANT DESIGN FACTORS THAT AFFECT PRIMARY STABILITY AND OSSEOINTEGRATION

Osseointegration can be defined as a direct structural and functional link between bone and implant surface. Asymptomatic and rigid fixation of alloplastic material in bone is crucial for implant stability and longterm success of dental implant treatment. The connection between implant and surrounding tissue is extremely dynamic. This interaction is the basis for the formation of a new structure - implant-tissue interface. The process of osseointegration is a combination of biological mechanisms as a result of which bone is formed on the walls of the osteotomous lodge growing to the implant surface (remote osteogenesis) and direct osteogenesis of bone on the surface of the implant (contact osteogenesis). The process is complex and there are a number of factors that affect the formation and maintenance of bone in the peri-implant space. The aim of the present study is to review the literature data on the macroscopic implant factors that affect primary stability and osseointegration

3D engineered human gingiva fabricated with electrospun collagen scaffolds provides a platform for in vitro analysis of gingival seal to abutment materials.

In order to advance models of human oral mucosa towards routine use, these models must faithfully mimic the native tissue structure while also being scalable and cost efficient. The goal of this study was to develop a low-cost, keratinized human gingival model with high fidelity to human attached gingiva and demonstrate its utility for studying the implant-tissue interface. Primary human gingival fibroblasts (HGF) and keratinocytes (HGK) were isolated from clinically healthy gingival biopsies. Four matrices, electrospun collagen (ES), decellularized dermis (DD), type I collagen gels (Gel) and released type I collagen gels (Gel-R)) were tested to engineer lamina propria and gingiva. HGF viability was similar in all matrices except for Gel-R, which was significantly decreased. Cell penetration was largely limited to the top layers of all matrices. Histomorphometrically, engineered human gingiva was found to have similar appearance to the native normal human gingiva except absence of rete pegs. Immunohistochemical staining for cell phenotype, differentiation and extracellular matrix composition and organization within 3D engineered gingiva made with electrospun collagen was mostly in agreement with normal gingival tissue staining. Additionally, five types of dental material posts (5-mm diameter x 3-mm height) with different surface characteristics were used [machined titanium, SLA (sandblasted-acid etched) titanium, TiN-coated (titanium nitride-coated) titanium, ceramic, and PEEK (Polyetheretherketone) to investigate peri-implant soft tissue attachment studied by histology and SEM. Engineered epithelial and stromal tissue migration to the implant-gingival tissue interface was observed in machined, SLA, ceramic, and PEEK groups, while TiN was lacking attachment. Taken together, the results suggest that electrospun collagen scaffolds provide a scalable, reproducible and cost-effective lamina propria and 3D engineered gingiva that can be used to explore biomaterial-soft tissue interface.

Bacterial-Specific Induction of Inflammatory Cytokines Significantly Decreases upon Dual Species Infections of Implant Materials with Periodontal Pathogens in a Mouse Model.

Cytokine profiles are often perturbed after infections of medical implants. With a non-invasive in vivo imaging system, we report in a mouse model that interferon expression after infection of subcutaneous implants with Streptococcus oralis, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Treponema denticola (alone or as a combination) was species-specific, persisted longer in the presence of implants, and notably decreased upon dual species infections. This type I interferon expression disappeared within two weeks; however, histology of implant–tissue interface indicated high recruitment of immune cells even after three weeks. This was suggestive that biomaterial-associated infections could have prolonged effects, including the systemic stimulation of inflammatory cytokines. The present study investigated the systemic impact of this chronic peri-implant inflammation on the systemic expression of inflammatory cytokines (23) using a multiplex assay. Initially, the cytokine measurement in murine fibroblasts exposed to periodontal pathogens remained limited to the expression of five cytokines, namely, IL-6, G-CSF, CXCL-1/KC, MCP-1 (MCAF), and IL-12 (p40). The systemic determination of cytokines in mice increased to 19 cytokines (IL-1α, IL-2, IL-3, IL-5, IL-6, IL-9, IL-12 (p40), IL-12 (p70), IL-13, IL-17A, CCL-11/Eotaxin, G-CSF, IFN-γ, CXCL1/KC, MCP-1 (MCAF), MIP-1α/CCL3, MIP-1β/CCL4, CCL5/RANTES, and TNF-α). Systemic induction of cytokines was species-specific in the mouse model. The cytokine induction from infected implants differed significantly from sole tissue infections and sterile implants. Notably, systemic cytokine induction decreased after infections with dual species compared to single species infections. These findings describe the systemic effect of chronic peri-implant inflammation on the systemic induction of inflammatory cytokines, and this effect was strongly correlated to the type and composition of initial infection. Systemic modulations in cytokine expression upon dual species infections exhibit an exciting pattern that might explain the complications associated with biomaterial-related infection in patients. Moreover, these findings validate the requirement of multispecies infections for pre-clinical studies involving animal models.

Laser Processing of Polymers for Surface Energy Control of Biomedical Implants

Poly (etheretherketone) (PEEK) is a high-performance rigid polymer that combines excellent chemical resistance, mechanical strength, and dimensional stability. PEEK is mostly used in the biomedical field for the manufacture of implants. However, the inherently bioinert PEEK surface poses a challenge in terms of adhesion at the implant-tissue interface. Effective enhancement of the adhesive properties of PEEK can be achieved by modifications of surface wettability and free energy. Although many studies investigate the influence of laser parameters on wettability and topography of PEEK, there is scarce information in literature on surface treatment with CO2 laser of neat PEEK. Furthermore, there is no detailed literature report on impact of various laser parameters on the biomechanical properties of PEEK relevant for implants. Therefore, this work focuses on enhancing surface functionality of PEEK through surface energy control. Samples treated at various laser power, fluence, beam pitch and number of passes were characterized with 3D profilometry, Rockwell hardness test, compression tests and contact-angle measurements. Generally, CO2 laser treatment of PEEK did not result in unfavorable changes in its bulk mechanical properties, namely, yield strength and elastic modulus only above the ablation threshold. At a fluence of 14 J/cm2, a significant reduction in hardness (98.03 HRM) was recorded with a single-pass processing. A positive correlation was observed between roughness parameters, groove geometries and laser fluence. More intense surface changes were achieved via ablative mechanism with single-pass processes at a lower total fluence in comparison to double-pass ones. Overall, all increases in roughness resulting from non-ablative processes led to improved wettability.

Measuring human mesenchymal stem cell remodeling in hydrogels with a step-change in elastic modulus.

Human mesenchymal stem cells (hMSCs) are instrumental in the wound healing process. They migrate to wounds from their native niche in response to chemical signals released during the inflammatory phase of healing. At the wound, hMSCs downregulate inflammation and regulate tissue regeneration. Delivering additional hMSCs to wounds using cell-laden implantable hydrogels has the potential to improve healing outcomes and restart healing in chronic wounds. For these materials to be effective, cells must migrate from the scaffold into the native tissue. This requires cells to traverse a step-change in material properties at the implant-tissue interface. Migration of cells in material with highly varying properties is not well characterized. We measure 3D encapsulated hMSC migration and remodeling in a well-characterized hydrogel with a step-change in stiffness. This cell-degradable hydrogel is composed of 4-arm poly(ethylene glycol)-norbornene cross-linked with an enzymatically-degradable peptide. The scaffold is made with two halves of different stiffnesses separated by an interface where stiffness changes rapidly. We characterize changes in structure and rheology of the pericellular region using multiple particle tracking microrheology (MPT). MPT measures Brownian motion of embedded particles and relates it to material rheology. We measure more remodeling in the soft region of the hydrogel than the stiff region on day 1 post-encapsulation and similar remodeling everywhere on day 6. In the interface region, we measure hMSC-mediated remodeling along the interface and migration towards the stiff side of the scaffold. These results can improve materials designed for cell delivery from implants to a wound to enhance healing.

Electrophoretic deposition of bioactive glass/zirconia core-shell nanoparticles on Ti6Al4V substrate

One approach to the improvement of implant-tissue interface is the creation of a bioactive surface. Here, bioactive glass-zirconia core-shell spherical nanoparticles were synthesized using a combination of sol-gel and sonochemical methods. The results revealed that the nanoparticles possess a ∼ 16 ± 4 nm rough tetragonal zirconia shell that surrounded the bioactive glass core. The optimized structure was coated on Ti6Al4V substrate through electrophoretic deposition technique. In order to obtain a stable suspension of nanoparticles in ethanol, dopamine was used as a surface treatment agent and cathodic electrophoretic deposition was successfully achieved on Ti6Al4V substrate. Also, the utilization of polyethyleneimine improved the adhesion between the coating and substrate. Due to the differences in surface charge of zirconia and bioactive glass nanoparticles, a high voltage and surfactant concentration are necessary for the simultaneous deposition of the particles. However, in the presence of core-shell nanoparticles, this issue was overcome. Microscopic examination of the coatings confirmed the elimination of cracks in core-shell constituted coatings. The adhesion between the coating and substrate increased significantly due to the rough surface of the core-shell nanoparticles. The Ca–P deposit formation on the surface of the bioactive glass and core-shell coatings were confirmed by scanning electron microscopy and energy-dispersive X-ray spectroscopy.

Developing Mg-Zn-Fish Bone Derived Hydroxyapatite Composites for Biomedical Applications: In vitro Degradation Studies

The study of magnesium (Mg) based biomaterials has emerged as a potential research area in recent times. Controlling the rapid corrosion and improving the implant-tissue interface kinetics for better tissue regeneration are the prime interests behind developing novel Mg-based composites. In the current work, the metal matrix composites of Mg-Zn, dispersed with nano-hydroxyapatite derived from fish bones (fHA), were produced by powder metallurgy route. The powders were mixed with the help of ball milling in the presence of ethanol and then sintered at 440 °C. From the microstructural studies, micro-lamellar morphology was noticed for the sintered compacts due to the flake-like morphology of the milled powders. The sintered compacts were then subjected to in vitro biodegradation studies in simulated conditions for one week. From the results, the presence of fHA was found to be highly influential in increasing the rate of mineral deposition on the surface of the composites. These higher mineral depositions protected the surface of the composites from further degradation. The results demonstrate that adding fHA to Mg accelerates biomineralization and controls degradation, leading to better implant-tissue interactions.

Mechanosensing by TRPV4 mediates stiffness-induced foreign body response and giant cell formation.

Implantation of biomaterials or devices into soft tissue often leads to the development of the foreign body response (FBR), an inflammatory condition that can cause implant failure, tissue injury, and death of the patient. Macrophages accumulate and fuse to generate destructive foreign body giant cells (FBGCs) at the tissue-implant interface, leading to the development of fibrous scar tissue around the implant that is generated by myofibroblasts. We previously showed that the FBR in vivo and FBGC formation in vitro require transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel. Here, we report that TRPV4 was required specifically for the FBR induced by implant stiffness independently of biochemical cues and for intracellular stiffening that promotes FBGC formation in vitro. TRPV4 deficiency reduced collagen deposition and the accumulation of macrophages, FBGCs, and myofibroblasts at stiff, but not soft, implants in vivo and inhibited macrophage-induced differentiation of wild-type fibroblasts into myofibroblasts in vitro. Atomic force microscopy demonstrated that TRPV4 was required for implant-adjacent tissue stiffening in vivo and for cytoskeletal remodeling and intracellular stiffening induced by fusogenic cytokines in vitro. Together, these data suggest a mechanism whereby a reciprocal functional interaction between TRPV4 and substrate stiffness leads to cytoskeletal remodeling and cellular force generation to promote FBGC formation during the FBR.

Organotypic in vitro block culture model to investigate tissue-implant interface. An experimental study on pig mandible

In vitro studies of implant-tissue attachment are primarily based on two-dimensional cell culture models, which fail to replicate the three-dimensional native human oral mucosal tissue completely. Thus, the present study aimed to describe a novel tissue culture model using pig mandibular block including alveolar bone and gingival soft tissues to evaluate the tissue attachment to titanium implant provided with hydrothermally induced TiO2 coating. Tissue attachment on TiO2 coated and non-coated implants were compared. Ti-6Al-4V alloy posts were used to function as implants that were inserted in five pig mandibles. Implants were delivered with two different surface treatments, non-coated (NC) titanium and hydrothermal induced TiO2 coated surfaces (HT). The tissue-implant specimens were cultured at an air/liquid interface for 7 and 14 days. The tissue-implant interface was analyzed by histological and immunohistochemical stainings. The microscopic evaluation suggests that pig tissue explants established soft and hard tissue attachment to both implant surfaces. The epithelial cells appeared to attach to the coated implant. The epithelium adjacent to the implant abutment starts to change its phenotype during the early days of the healing process. New bone formation was seen within small pieces of bone in close contact with the coated implant. In conclusion, this in vitro model maintains the viability of pig tissue and allows histologically and immunohistochemically evaluate the tissue-implant interface. HT-induced TiO2 coating seems to have a favorable tissue response. Moreover, this organotypic tissue culture model is applicable for further studies with quantitative parameters to evaluate adhesion molecules present at the implant-tissue interface.

Electrophoretic Deposition of Biocompatible and Bioactive Hydroxyapatite-Based Coatings on Titanium

Current trends in biomaterials science address the issue of integrating artificial materials as orthopedic or dental implants with biological materials, e.g., patients’ bone tissue. Problems arise due to the simple fact that any surface that promotes biointegration and facilitates osteointegration may also provide a good platform for the rapid growth of bacterial colonies. Infected implant surfaces easily lead to biofilm formation that poses a major healthcare concern since it could have destructive effects and ultimately endanger the patients’ life. As of late, research has centered on designing coatings that would eliminate possible infection but neglected to aid bone mineralization. Other strategies yielded surfaces that could promote osseointegration but failed to prevent microbial susceptibility. Needless to say, in order to assure prolonged implant functionality, both coating functions are indispensable and should be addressed simultaneously. This review summarizes progress in designing multifunctional implant coatings that serve as carriers of antibacterial agents with the primary intention of inhibiting bacterial growth on the implant-tissue interface, while still promoting osseointegration.

Light-guided sectioning for precise in situ localization and tissue interface analysis for brain-implanted optical fibers and GRIN lenses.

SUMMARYOptical implants to control and monitor neuronal activity in vivo have become foundational tools of neuroscience. Standard two-dimensional histology of the implant location, however, often suffers from distortion and loss during tissue processing. To address that, we developed a three-dimensional post hoc histology method called “light-guided sectioning” (LiGS), which preserves the tissue with its optical implant in place and allows staining and clearing of a volume up to 500 μm in depth. We demonstrate the use of LiGS to determine the precise location of an optical fiber relative to a deep brain target and to investigate the implant-tissue interface. We show accurate cell registration of ex vivo histology with single-cell, two-photon calcium imaging, obtained through gradient refractive index (GRIN) lenses, and identify subpopulations based on immunohistochemistry. LiGS provides spatial information in experimental paradigms that use optical fibers and GRIN lenses and could help increase reproducibility through identification of fiber-to-target localization and molecular profiling.

PVA/gelatin-based hydrogel coating of nickel-titanium alloy for improved tissue-implant interface

Nickel-titanium shape memory alloys have attracted notable interest for biomedical applications due to their unique properties. However, there are still some concerns on the potential release of nickel ions causing adverse reactions in-vivo at high concentrations. In this work, samples were coated with a polyvinyl alcohol/gelatin hydrogel. Coating stability, corrosion resistance and biocompatibility were investigated. Coated samples exhibited similar shape memory response to that of the uncoated substrates in wire form. Additionally, the hydrogel coating led to a decrease in the surface temperature and significantly improved the corrosion resistance of the shape memory substrate. The presence of the hydrogel layer does not affect the biocompatibility of the alloy while providing a semi-degradable, hydrophilic surface that forms a cushion at the tissue-implant interfaces.

New insights into spatio-temporal dynamics of mesenchymal progenitor cell ingress during peri-implant wound healing: Provided by intravital imaging

Surface topography drives the success of orthopedic and dental implants placed in bone, by directing the biology occurring at the tissue-implant interface. Over the last few decades, striking advancements have been made in the development of novel implant surfaces that enhance bone anchorage to their surfaces through contact osteogenesis: the combination of the two phenomena of recruitment and migration of mesenchymal progenitor cells to the implant surface, and their differentiation into bone-forming cells. While the latter is generally understood, the mechanisms and dynamics underlying the migration and recruitment of such progenitor cells into the wound site have garnered little attention. To address this deficit, we surgically inserted metallic implants with two different surface topographies into the skulls of mice, and then employed real-time spatiotemporal microscopic monitoring of the peri-implant tissue healing to track the ingress of cells. Our results show that nano-topographically complex, in comparison to relatively smooth, implant surfaces profoundly affect recruitment of both endothelial cells, which are essential for angiogenesis, and the mesenchymal progenitor cells that give rise to the reparative tissue stroma. The latter appear concomitantly in the wound site with endothelial cells, from the vascularized areas of the periosteum, and demonstrate a proliferative “bloom” that diminishes with time, although some of these cells differentiate into important stromal cells, pericytes and osteocytes, of the reparative wound. In separate experiments we show, using trajectory plots, that the directionality of migration for both endothelial and perivascular cells can be explained by implant surface dependent release of local cytokine gradients from platelets that would become activated on the implant surfaces during initial blood contact. These findings provide new biological insights into the earliest stages of wound healing, and have broad implications in the application of putative nano-topographically complex biomaterials in many tissue types.

Combination of Nitric Oxide Release and Surface Texture for Mitigating the Foreign Body Response.

The tissue response to polyurethane (PU)-coated implants employing active and/or passive FBR mitigation techniques was evaluated over a 28 day study in a diabetic swine model. Active FBR mitigation was achieved through the sustained release of nitric oxide (NO) from a mesoporous silica nanoparticle-doped PU coating. Passive FBR mitigation was achieved through the application of a foam- or fiber-based topcoat. These topcoats were designed to possess topographical features known to promote tissue integration with foam-coated implants having pore sizes of approximately 50 μm and fiber-coated implants consisting of fiber diameters of less than 1 μm. Nitric oxide-release profiles were minimally impacted by the presence of either topcoat. Inflammatory cell density and collagen density at the implant-tissue interface were assessed at 7, 14, 21, and 28 days following implantation. Nitric oxide-releasing implants had significantly lower inflammatory cell density and collagen density than non-NO-releasing controls. The presence of a topcoat did not significantly impact inflammatory cell density, though top-coated textured implants resulted in significantly lower collagen density, irrespective of NO release. Overall, coatings that combine NO release with surface texture demonstrated the greatest potential for tissue-based biomedical device applications.

Diabetes as a Risk Factor for Orthopedic Implant Surface Performance: A Retrieval and In Vitro Study

Orthopedic devices are often associated with increased risk for diabetic patients due to impaired wound healing capabilities. Adverse biological responses for immunocompromised patients at the implant-tissue interface can lead to significant bone resorption that may increase failure rates. The goal of this study was to characterize the surface of implants removed from diabetic patients to determine underlying mechanisms of diabetes-induced impaired osseointegration. Thirty-nine retrieved titanium and stainless-steel orthopedic devices were obtained from diabetic and non-diabetic patients, and compared to non-implanted controls. Optical Microscopy, Scanning Electron Microscopy, Energy Dispersive X-ray Spectroscopy, and X-ray Photoelectron Spectroscopy revealed changes in morphology, chemical composition, oxidation state, and oxide thickness of the retrieval specimens, respectively. Additionally, titanium disks were immersed for 28 days in simulated in vitro diabetic conditions followed by Inductively Coupled Plasma-Optical Emission Spectroscopy to quantify metal dissolution. Electrochemical testing was performed on specimens from retrievals and in vitro study. Aside from biological deposits, retrievals demonstrated surface discoloration, pit-like formations and oxide thinning when compared to non-implanted controls, suggesting exposure to unfavorable acidic conditions. Cyclic load bearing areas on fracture-fixation screws and plates depicted cracking and delamination. The corrosion behavior was not significantly different between diabetic and non-diabetic conditions of immersed disks or implant type. However, simulated diabetic conditions elevated aluminum release. This elucidates orthopedic implant failures that potentially arise from diabetic environments at the implant-tissue interface. Design of new implant surfaces should consider specific strategies to induce constructive healing responses in immunocompromised patients while also mitigating corrosion in acidic diabetic environments.

Osteoimmunology drives dental implant osseointegration: A new paradigm for implant dentistry.

There is a complex interaction between titanium dental implants, bone, and the immune system. Among them, specific immune cells, macrophages play a crucial role in the osseointegration dynamics. Infiltrating macrophages and resident macrophages (osteomacs) contribute to achieving an early pro-regenerative peri-implant environment. Also, multinucleated giant cells (MNGCs) in the bone-implant interface and their polarization ability, maintain a peri-implant immunological balance to preserve osseointegration integrity. However, dental implants can display cumulative levels of antigens (ions, nano and microparticles and bacterial antigens) at the implant–tissue interface activating an immune-inflammatory response. If the inflammation is not resolved or reactivated due to the stress signals and the immunogenicity of elements present, this could lead implants to aseptic loosening, infections, and subsequent bone loss. Therefore, to maintain osseointegration and prevent bone loss of implants, a better understanding of the osteoimmunology of the peri-implant environment would lead to the development of new therapeutic approaches. In this line, depicting osteoimmunological mechanisms, we discuss immunomodulatory strategies to improve and preserve a long-term functional integration between dental implants and the human body.Scientific field of dental science: implant dentistry.

Hierarchical Microstructure Tailoring of Pure Titanium for Enhancing Cellular Response at Tissue-Implant Interface.

The main goal of this research is to scrutinize the effect of texture and grain size on the biological response of hierarchical structured pure titanium (Ti), examining the interrelation between grain refinement mechanisms with texture variation. The hierarchical structure was produced using two methods of severe plastic deformation (SPD). The Ti specimens were first processed up to six passes by equal channel angular pressing (ECAP) and subsequently treated at the top surface using surface mechanical attrition treatment (SMAT). Microstructure examination by Electron backscatter diffraction (EBSD) indicates that the SMAT-treated surface was categorized into three distinct microstructural regions based on the type of grain refinement process involved during SPD: twin induced dynamic recrystallization (TDRX) and geometric dynamic recrystallization (GDRX) in the topmost surface, and continuous (CDRX) and discontinuous dynamic recrystallization (DDRX) in the lower regions of the sample. The biological experiments showed meaningful improvement in the cellular response of SMATed and ECAPed samples. It was demonstrated that grain refinement could have the capability of improving the biological response of Ti surface. In this regard, SMATed + 2ECAPed sample showed the best result although it has not the smallest grain size and the highest texture intensity. It was observed that texture and grain orientation of planes have an important impact on the biological response of pure Ti and dominance of prismatic (1010) texture can improve the cell viability, adhesion and its differentiation. Therefore, microstructure and texture tailoring through combined SPD methods could be a promising strategy for the improvement of the next generation of medical implants.

Bone and Cartilage Interfaces With Orthopedic Implants: A Literature Review.

The interface between a surgical implant and tissue consists of a complex and dynamic environment characterized by mechanical and biological interactions between the implant and surrounding tissue. The implantation process leads to injury which needs to heal over time and the rapidity of this process as well as the property of restored tissue impact directly the strength of the interface. Bleeding is the first and most relevant step of the healing process because blood provides growth factors and cellular material necessary for tissue repair. Integration of the implants placed in poorly vascularized tissue such as articular cartilage is, therefore, more challenging than compared with the implants placed in well-vascularized tissues such as bone. Bleeding is followed by the establishment of a provisional matrix that is gradually transformed into the native tissue. The ultimate goal of implantation is to obtain a complete integration between the implant and tissue resulting in long-term stability. The stability of the implant has been defined as primary (mechanical) and secondary (biological integration) stability. Successful integration of an implant within the tissue depends on both stabilities and is vital for short- and long-term surgical outcomes. Advances in research aim to improve implant integration resulting in enhanced implant and tissue interface. Numerous methods have been employed to improve the process of modifying both stability types. This review provides a comprehensive discussion of current knowledge regarding implant-tissue interfaces within bone and cartilage as well as novel approaches to strengthen the implant-tissue interface. Furthermore, it gives an insight into the current state-of-art biomechanical testing of the stability of the implants. Current knowledge reveals that the design of the implants closely mimicking the native structure is more likely to become well integrated. The literature provides however several other techniques such as coating with a bioactive compound that will stimulate the integration and successful outcome for the patient.

A biomimetic engineered bone platform for advanced testing of prosthetic implants

Existing methods for testing prosthetic implants suffer from critical limitations, creating an urgent need for new strategies that facilitate research and development of implants with enhanced osseointegration potential. Herein, we describe a novel, biomimetic, human bone platform for advanced testing of implants in vitro, and demonstrate the scientific validity and predictive value of this approach using an assortment of complementary evaluation methods. We anchored titanium (Ti) and stainless steel (SS) implants into biomimetic scaffolds, seeded with human induced mesenchymal stem cells, to recapitulate the osseointegration process in vitro. We show distinct patterns of gene expression, matrix deposition, and mineralization in response to the two materials, with Ti implants ultimately resulting in stronger integration strength, as seen in other preclinical and clinical studies. Interestingly, RNAseq analysis reveals that the TGF-beta and the FGF2 pathways are overexpressed in response to Ti implants, while the Wnt, BMP, and IGF pathways are overexpressed in response to SS implants. High-resolution imaging shows significantly increased tissue mineralization and calcium deposition at the tissue-implant interface in response to Ti implants, contributing to a twofold increase in pullout strength compared to SS implants. Our technology creates unprecedented research opportunities towards the design of implants and biomaterials that can be personalized, and exhibit enhanced osseointegration potential, with reduced need for animal testing.