In this study, we developed a novel in vitro model to study how microstructured and hydrophilic titanium implants impact bone remodeling for dental and orthopaedic applications. Our approach intersects biomaterials and systems physiology, revealing for the first time that implant surface properties are capable of regulating the communication among the cells involved in remodeling of primary bone during osseointegration. We believe that the basic research presented in our manuscript will provide important knowledge in our understanding of factors that impact implant success. Furthermore, it provides a solid foundation for the development of materials that enable rapid osseointegration and earlier loading times for implants in bone that has been compromised by trauma or disease.

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Successful osseointegration of an endosseous implant involves migration and differentiation of mesenchymal stem cells (MSCs) on the implant surface. Micro-structured, hydrophilic titanium surfaces direct MSCs to undergo osteoblastic differentiation in vitro, in the absence of media additives commonly used in cultures grown on tissue culture polystyrene (TCPS). This process involves non-canonical Wnt5a, in contrast to canonical Wnt3a typically credited with osteoblastic differentiation on TCPS. Wnt proteins have been implicated in morphological development and tissue patterning, suggesting that additional Wnts may participate. Here, we demonstrate that Wnt11 is a mediator of osteoblast commitment of MSCs, and increases in a surface-roughness dependent manner. Experiments using cells silenced for Wnt11 indicate that cross-talk between Wnt5a and Wnt11 occurs. Wnt11 potentially acts upstream to Wnt5a, increasing Wnt5a expression and factors associated with osteogenesis. Thus, Wnt11 contributes to peri-implant bone formation distal to the implant surface through a heavily regulated signaling cascade of autocrine/paracrine proteins.

Establishment of a patent vasculature at the bone-implant interface plays a significant role in determining overall success of orthopaedic and dental implants. Osteoblasts produce vascular endothelial growth factor-A (VEGF-A), an important regulator of angiogenesis during bone formation and healing, and the amount secreted is sensitive to titanium (Ti) surface microtopography and surface energy. The purpose of this study was to determine if surface properties modulate cellular response to VEGF-A. MG63 osteoblast-like cells were transfected with shRNA targeting VEGF-A at >80% knockdown. Cells stably silenced for VEGF-A secreted reduced levels of osteocalcin, osteoprotegerin, FGF-2, and angiopoietin-1 when cultured on grit-blasted/acid-etched (SLA) and hydrophilic SLA (modSLA) Ti surfaces and conditioned media from these cultures caused reduced angiogenesis in an endothelial tubule formation assay. Treatment of MG63 cells with 20 ng/mL rhVEGF-A165 rescued production in silenced cells and increased production of osteocalcin, osteoprotegerin, FGF-2, and angiopoietin-1, with greatest effects on control cells cultured on modSLA. Addition of a neutralization antibody against VEGF receptor 2 (VEGFR2; Flk-1) resulted in a significant increase in VEGF-A production. Overall, this study indicates that VEGF-A has two roles in osseointegration: enhanced angiogenesis and an autocrine/paracrine role in maturation of osteoblast-like cells in response to Ti surface properties.

Additive manufacturing can be used to create personalized orthopedic and dental implants with varying geometries and porosities meant to mimic morphological properties of bone. These qualities can alleviate stress shielding and increase osseointegration through bone ingrowth, but at the expense of reduced fatigue properties compared to machined implants, and potential for loose build particle erosion. Hot isostatic pressure (HIP) treatment is used to increase fatigue resistance; implant surface treatments like grit‐blasting and acid‐etching create microroughness and reduce the presence of loose particles. However, it is not known how HIP treatment affects surface treatments and osseointegration of the implant to bone. We manufactured two titanium–aluminum–vanadium constructs, one with simple through‐and‐through porosity and one possessing complex trabecular bone‐like porosity. We observed HIP treatment varied in effect and was dependent on architecture. Micro/meso/nano surface properties generated by grit‐blasting and acid‐etching were altered on biomimetic HIP‐treated constructs. Human mesenchymal stem cells (MSCs) were cultured on constructs fabricated +/− HIP and subsequently surface‐treated. MSCs were sensitive to 3D‐architecture, exhibiting greater osteogenic differentiation on constructs with complex trabecular bone‐like porosity. HIP‐treatment did not alter the osteogenic response of MSCs to these constructs. Thus, HIP may provide mechanical and biological advantages during implant osseointegration and function.

The use of metallic and polymeric materials for implants has been increasing over the past decade. This trend can be attributed to a variety of factors including a significant increase in basic science research focused on implant material characteristics and how various surface modifications may stimulate osseointegration and, ultimately, fusion. There are many interbody fusion devices and dental implants commercially available; however, detailed information about their surface properties, and the effects that various materials and surface modifications may have on osteogenesis, is lacking in the literature. While the concept of bone-implant osseointegration is a relatively recent addition to the spine fusion literature, there is a comparatively large body of literature related to dental implants. The purpose of this article is to summarize the science of surface modified bone-facing implants, focusing on biomimetic material chemistry and topography of titanium implants, to promote a better understanding of how these characteristics may impact bone formation and osseointegration. This manuscript has the following aspects: highlights the role of titanium and its alloys as potent osteoconductive bioactive materials; explores the importance of biomimetic surface topography at the macro-, micro- and nano-scale; summarizes how material surface design can influence osteogenesis and immune responses in vitro; focuses on the kinds of surface modifications that play a role in the process. Biomimetic surface modifications can be varied across many clinically available biomaterials, and the literature supports the hypothesis that those biomaterial surfaces that exhibit physical properties of bone resorption pits, such as roughness and complex hierarchical structures at the submicron and nanoscale, are more effective in supporting osteoblast differentiation in vitro and osteogenesis in vivo.

BackgroundOsseointegration is dependent on the implant surface, surrounding bone quality, and the systemic host environment, which can differ in male and female patients. Titanium (Ti) implants with microstructured surfaces exhibit greater pullout strength when compared to smooth-surfaced implants and exhibit enhanced osteogenic cellular responses in vitro. Previous studies showed that 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] has a greater effect on rat osteoblast differentiation on microstructured Ti compared to smooth Ti surfaces and tissue culture polystyrene (TCPS). The stimulatory effect of 17β-estradiol (E2) on differentiation is observed in female osteoblasts on micro-rough Ti, but it is not known if male osteoblasts behave similarly in response to E2 and microtopography. This study assessed whether human male and female osteoblasts exhibit sex-specific differences in response to E2 and 1α,25(OH)2D3 when cultured on microstructured Ti surfaces.MethodsOsteoblasts from three male and three female human donors were cultured on Ti discs with varying surface profiles: a smooth pretreatment (PT), a coarse grit-blasted/acid-etched (SLA), and an SLA surface having undergone modification in a nitrogen environment and stored in saline to maintain hydrophilicity (modSLA). Cells cultured on these surfaces were treated with E2 or 1α,25(OH)2D3.ResultsMale and female human osteoblasts responded similarly to microstructure although there were donor-specific differences; cell number decreased, and osteocalcin (OCN), osteoprotegerin (OPG), and latent and active transforming growth factor 1 increased on SLA and modSLA compared to TCPS. Female osteoblasts had higher alkaline phosphatase activity and OCN production than male counterparts but produced less OPG. Both sexes responded similarly to 1α,25(OH)2D3. E2 treatment reduced cell number and increased osteoblast differentiation and factor production only in female cells.ConclusionsMale and female human osteoblasts respond similarly to microstructure and 1α,25(OH)2D3 but exhibit sexual dimorphism in substrate-dependent responses to E2. E2 affected female osteoblasts, suggesting that signaling is sex-specific and surface-dependent. Donor osteoblasts varied in response, demonstrating the need to test multiple donors when examining human samples. Understanding how male and female cells respond to orthopedic biomaterials will enable greater predictability post-implantation as well as therapies that are more patient-specific.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0190-x) contains supplementary material, which is available to authorized users.