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Attaching hydrogels to soft internal tissues is crucial for the development of various biomedical devices. Tough sticky hydrogel patches present high adhesion, yet with lack of injectability and the need for treatment of contacting surface. On the contrary, injectable and photo-curable hydrogels are highly attractive owing to their ease of use, flexibility of filling any shape, and their minimally invasive character, compared to their conventional preformed counterparts. Despite recent advances in material developments, a hydrogel that exhibits both proper injectability and sufficient intrinsic adhesion is yet to be demonstrated. Herein, a paradigm shift is proposed toward the design of intrinsically adhesive networks for injectable and photo-curable hydrogels. The bioinspired design strategy not only provides strong adhesive contact, but also results in a wide window of physicochemical properties. The adhesive networks are based on a family of polymeric backbones where chains are modified to be intrinsically adhesive to host tissue and simultaneously form a hydrogel network via a hybrid cross-linking mechanism. With this strategy, adhesion is achieved through a controlled synergy between the interfacial chemistry and bulk mechanical properties. The functionalities of the bioadhesives are demonstrated for various applications, such as tissue adhesives, surgical sealants, or injectable scaffolds.

Bone reconstruction techniques are mainly based on the use of tissue grafts and artificial scaffolds. The former presents well-known limitations, such as restricted graft availability and donor site morbidity, while the latter commonly results in poor graft integration and fixation in the bone, which leads to the unbalanced distribution of loads, impaired bone formation, increased pain perception, and risk of fracture, ultimately leading to recurrent surgeries. In the past decade, research efforts have been focused on the development of innovative bone substitutes that not only provide immediate mechanical support, but also ensure appropriate graft anchoring by, for example, promotingde novobone tissue formation. From the countless studies that aimed in this direction, only few have made the big jump from the benchtop to the bedside, whilst most have perished along the challenging path of clinical translation. Herein, we describe some clinically successful cases of bone device development, including biological glues, stem cell-seeded scaffolds, and gene-functionalized bone substitutes. We also discuss the ventures that these technologies went through, the hindrances they faced and the common grounds among them, which might have been key for their success. The ultimate objective of this perspective article is to highlight the important aspects of the clinical translation of an innovative idea in the field of bone grafting, with the aim of commercially and clinically informing new research approaches in the sector.

In this paper we report the synthesis of a library of phospho-amino acid analogues, via a novel single-step allyl-phosphoester protection/Pd-mediated deprotection strategy. These phosphoserine and phosphotyrosine analogues were then applied as additives to create adhesive calcium phosphate cements, allowing us to probe the chemical origins of the increased surface binding strength. We demonstrate the importance of multiple calcium binding motifs in mediating adhesion, as well as highlighting the crucial role played by substrate hydrophobicity and orientation in controlling binding strength.

A new class of materials, bone adhesives, could revolutionise the treatment of highly fragmented fractures. We present the first biological safety investigation of a bio-inspired bone adhesive. The formulation was based upon a modified calcium phosphate cement that included the amino acid phosphoserine. This material has recently been described as substantially stronger than other bioresorbable calcium phosphate cements. Four adhesive groups with the active substance (phosphoserine) and two control groups without phosphoserine were selected for in vitro and in vivo biocompatibility testing. The test groups were subject for cell viability assay and subcutaneous implantation in rats that was followed by gene expression analysis and histology assessment after 6 and 12 weeks. All adhesive groups supported the same rate of cell proliferation compared to the alpha-TCP control and had viability between 45-64% when compared to cell control. There was no evidence of an increased immune response or ectopic bone formation in vivo. To conclude, this bio-inspired bone adhesive has been proven to be safe, in the present study, without any harmful effects on the surrounding soft tissue., De två första författarna delar förstaförfattarskapet.

Phosphoserine-modified cements (PMCs) are a family of wet-field tissue adhesives that bond strongly to bone and biomaterials. The present study evaluated variations in the adhesive strength using a scatter plot, failure mode, and a regression analysis of eleven factors. All single-factor, continuous-variable correlations were poor (R2 < 0.25). The linear regression model explained 31.6% of variation in adhesive strength (R2 = 0.316 p < 0.001), with bond thickness predicting an 8.5% reduction in strength per 100 μm increase. Interestingly, PMC adhesive strength was insensitive to surface roughness (Sa 1.27–2.17 μm) and the unevenness (skew) of the adhesive bond (p > 0.167, 0.171, ANOVA). Bone glued in conditions mimicking the operating theatre (e.g., the rapid fixation and minimal fixation force in fluids) produced comparable adhesive strength in laboratory conditions (2.44 vs. 1.96 MPa, p > 0.986). The failure mode correlated strongly with the adhesive strength; low strength PMCs (<1 MPa) failed cohesively, while high strength (>2 MPa) PMCs failed adhesively. Failure occurred at the interface between the amorphous surface layer and the PMC bulk. PMC bonding is sufficient for clinical application, allowing for a wide tolerance in performance conditions while maintaining a minimal bond strength of 1.5–2 MPa to cortical bone and metal surfaces.

An approximately 1-µm thick hydroxyapatite coating was biomimetically deposited on an alkali-treated, commercially available orthopedic screw surface (type II anodized titanium). Tobramycin loaded into the coating via a simple soaking method was shown to provide a sustained release above the minimal inhibitory concentration 0.2 µg/µl for up to two days. Agar diffusion tests showed that the tobramycin-loaded coating was able to produce a zone of inhibition against Staphylococcus aureus for up to five days. Biocompatibility testing using outgrowth endothelial cells and primary osteoblasts suggested that good cell compatibility of the coating can be expected in vivo. A rabbit distal femur condyle model was used for in vivo evaluation of the antibacterial efficacy of the tobramycin-loaded coating, and this pilot study showed that the release of tobramycin was sufficient to locally eliminate very large amounts of bacteria in vivo (inoculation dose 104–105 CFU S. aureus/test site).

Background: Fracture fixation in weak bone is still a clinical challenge. Screw augmentation was shown to successfully increase their primary stability. The currently used calcium phosphate or polymeric bone cements, however, present important drawbacks such as induced toxicity and/or impaired bone neo-formation. A new approach to enhance bone screw primary stability without affecting bone formation is the use of non-setting, calcitim phosphate loaded soft materials as the augmentation material. Methods: Two types of biomaterials (non-crosslinked hyaluronic acid as viscous fluid and agar as hydrogel) were loaded with 40 wt/vol% of hydroxyapatite particles and characterized. The screw augmentation effect of all materials was evaluated through pull-out tests in bovine cancellous bone and compared to the non-augmented situation (control). The bone mineral density of each test sample was measured with CT scans and was used to normalize the pull-out strength. Findings: Both materials loaded with hydroxyapatite increased the normalized pull-out strength of the screws compared to control samples and particle-free materials. This counter-intuitive augmentation effect increased with decreasing bone mineral density and was independent from the type of the soft materials used. Interpretation: We were able to demonstrate that non-setting, injectable biomaterials loaded with ceramic particles can significantly enhance the primary stability of bone screws. This material combination opens the unique possibility to achieve a screw augmentation effect without impairing or even potentially favoring the bone formation in proximity to the screw. This effect would be particularly advantageous for the treatment of osteoporotic bone fractures requiring a stabilization with bone screws.

There are clinical situations in fracture repair, e.g. osteochondral fragments, where current implant hardware is insufficient. The proposition of an adhesive enabling fixation and healing has been considered but no successful candidate has emerged thus far. The many preclinical and few clinical attempts include fibrin glue, mussel adhesive and even “Kryptonite” (US bone void filler). The most promising recent attempts are based on phosphorylating amino acids, part of a common cellular adhesion mechanism linking mussels, caddis fly larvae, and mammals. Rapid high bond strength development in the wetted fatty environment of fractured bone, that is sustained during biological healing, is challenging to prove both safety and efficacy. Additionally, there are no “predicate” preclinical animal and human models which led the authors to develop novel evaluations for an adhesive candidate “OsStictm” based on calcium salts and amino acids. Adhesive formulations were evaluated in both soft (6/12 weeks) and hard tissue (3,7,10,14 & 42 days) safety studies in murine models. The feasibility of a novel adhesiveness test, initially proven in murine cadaver femoral bone, is being assessed in-vivo (3,7,10,14 & 42 days) in bilateral implantations with a standard tissue glue as the control. In parallel an ex-vivo human bone model using freshly harvested human donor bone is under development to underwrite the eventual clinical application of such an adhesive. This is part of a risk mitigation project bridging between laboratory biomaterial characterisation and a commercial biomaterial development where safety and effectiveness have to meet today´s new medical device requirements.

Disease and injuries that affect the skeletal system may require surgical intervention and internal fixation, i.e. orthopedic plate and screw insertion, to stabilize the injury and facilitate tissue repair. If the surrounding bone quality is poor the screws may migrate, or the bone may fail, resulting in screw pull-out. Though numerous studies have shown that cement augmentation of the interface between bone and implant can increase screw holding strength in bone, the physical properties of cement that influence pull-out force have not been investigated. The present study sought to determine how the physical properties of calcium phosphate cements (CPCs), and the strength of the biological or synthetic material surrounding the augmented screw, affected the corresponding orthopedic screw pull-out force in urethane foam models of healthy and osteoporotic bone (Sawbones). In the simplest model, where only the bond strength between screw thread and cement (without Sawbone) was tested, the correlation between pull-out force and cement compressive strength (R2 = 0.79) was weaker than correlation with total cement porosity (R2 = 0.89). In open pore Sawbone that mimics “healthy” cancellous bone density the stronger cements produced higher pull-out force (50-60% increase). Higher strength, lower porosity, cements also produced higher pull-out forces (50-190% increase) in Sawbones with cortical fixation if the failure strength of the cortical material was similar to (bovine tibial bone), or greater than (metal shell), actual cortical bone. This result is of particular clinical relevance where fixation with a metal plate implant is indicated, as the nearby metal can simulate a thicker cortical shell and, thereby, increase the pull-out force of screws augmented with stronger cements. The improvement in pull-out force was apparent even at low augmentation volumes of 0.5 ml (50% increase), which suggest that in clinical situations where augmentation volume is limited the stronger

Locally applied bisphosphonates, such as zoledronate, have been shown in several studies to inhibit peri-implant bone resorption and recently to enhance peri-implant bone formation. Studies have also demonstrated positive effects of hydroxyapatite (HA) particles on peri-implant bone regeneration and an enhancement of the anti-resorptive effect of bisphosphonates in the presence of calcium. In the present study, both hydroxyapatite nanoparticles (nHA) and zoledronate were combined to achieve a strong reinforcing effect on peri-implant bone. The nHA-zoledronate combination was first investigated in vitro with a pre-osteoclastic cell assay (RAW 264.7) and then in vivo in a rat model of postmenopausal osteoporosis. The in vitro study confirmed that the inhibitory effect of zoledronate on murine osteoclast precursor cells was enhanced by loading the drug on nHA. For the in vivo investigation, either zoledronate-loaded or pure nHA were integrated in hyaluronic acid hydrogel. The gels were injected in screw holes that had been predrilled in rat femoral condyles before the insertion of miniature screws. Micro-CT-based dynamic histomorphometry and histology revealed an unexpected rapid mineralization of the hydrogel in vivo through formation of granules, which served as scaffold for new bone formation. The delivery of zoledronate-loaded nHA further inhibited a degradation of the mineralized hydrogel as well as a resorption of the peri-implant bone as effectively as unbound zoledronate. Hyaluronic acid with zoledronate-loaded nHA, thanks to its dual effect on inducing a rapid mineralization and preventing resorption, is a promising versatile material for bone repair and augmentation.

The early fixation of bone screws after surgical implantation still remains a challenge in the field of traumatology. Whilst hydroxyapatite (HA) coatings are known to enhance the fixation of implants; their removal at a later time-point may be problematic. An HA coating has been developed to demonstrate that both implant fixation and safe removal are feasible in the same design. Accordingly the aim of this study was to compare the in-vivo performance of thin biomimetic HA coated titanium screws to uncoated counterparts used as control after bilateral implantation in the femoral condyle of 36 New Zealand White Rabbits. The screws were analysed macroscopically, by histology, micro-CT and biomechanically at both two and six weeks post-implantation. The HA coated screws demonstrated excellent biocompatibility. At two weeks the HA coated screws demonstrated a significant increase in removal torque values as well as a strong trend towards higher pull-out forces. In addition histology confirmed a higher degree of osseointegration and direct bone to implant contact. At six weeks no difference in pull-out force and removal torque could be detected. SEM images confirmed the absence of any residual HA coating indicating a fast coating degradation in-vivo. The low level of removal torque after full osseointegration at 6 weeks supports the feasibility of safe and easy removal of the implant. The HA coating under study appears to offer a unique characteristic of enhanced fixation with a minimal increase in removal torque after full osseointegration. This may be of value in clinical applications where it is necessary to assure both screw fixation and later removal.

The present study investigates the use of nanoporous, biomimetic hydroxyapatite (HA) coatings deposited on TiO2 coated fixation pins as functional implant surfaces for the local release of Tobramycin in order to prevent bacterial colonization. The impact of HA-coating thickness, coating morphology and biomechanical forces during insertion into synthetic bone on the drug loading and release properties are analyzed. The coatings are shown to exhibit bactericidal effects against Staphylococcus aureus in agar medium for a duration of 6 days after loading by adsorption with Tobramycin for only 5 min at elevated temperature and pressure. Furthermore, high performance liquid chromatography analysis shows a drug release in phosphate buffered saline for 8 days with antibiotic concentration remaining above the minimal inhibitory concentration for S. aureus during the entire release period. Biomechanical insertion tests into synthetic bone and conventional scratch testing demonstrate adhesive strength at the HA/TiO2 interface. Biocompatibility is verified by cell viability tests. Outgrowth endothelial cells, as well as primary osteoblasts, are viable and firmly attached to both HA and TiO2 surfaces. The results presented are encouraging and support the concept of functional HA coatings as local drug delivery vehicles for biomedical applications to treat as well as to prevent post-surgical infections.

Implant migration, loosening and cut-out as well as nosocomial infections are current problems during surgery. New innovative strategies to overcome these issues are emphasized in today's research. The currentwork presents a novel strategy involving co-precipitation ofTobramycin with biomimetic hydroxyapatite (HA) formation to produce implant coatings that may ensure controlled local drug delivery to prevent early bacterial colonization of the implant. A sub-micron thin HA layer served as seed layer for the co-precipitation process and allowed for incorporation of Tobramycin in the coating from a stock solution of antibiotic concentrations as high as 20 mg/ml. Concentrations from 0.5 to 20 mg/ml Tobramycin and process temperatures of 37 °C and 60 °C were tested to assess the optimal parameters resulting in a thin Tobramycin delivering HA coating on discs and orthopedic fixation pins. The coating morphology and thickness as well as drugrelease profile were evaluated via scanning electron microscopy and high performanceliquid chromatography. The coatings were found to deliver pharmaceutically relevant amounts of Tobramycinover a period as of12 days. To the best of our knowledge, this is the longest release period ever observed for a fast-loaded biomimetic implant coating. The presented approach may form thefoundation for development of combination device/antibiotic delivery vehicles tailored to meet well-defined clinical needs combatting infections and ensuring fast implant in-growth.