Introduction

The Achilles tendon is the thickest and strongest tendon in the human body. Even though the tendon is so strong, it is one of the most frequently injured tendons. Treatment of patients after rupture is planned conservatively and surgically. Conservative treatment is generally applied to elderly patients with sedentary lives. If the treatment is surgical, it can be planned as open surgery or percutaneous surgery. In our study with rabbits, we wrapped a membrane made of plga (polylactic-co-glycolic acid) nanotubes impregnated with type 1 collagen around the tendon in rabbits that underwent open Achilles tendon repair surgery. After surgery, biomechanical and histological tests were performed on the tendons.

Nanoscale topography increases the bioactivity of a material and stimulates specific responses (third generation biomaterial properties) at the molecular level upon first generation (bioinert) or second generation (bioresorbable or bioactive) biomaterials.

We developed a technique (based upon the effects of nanoscale topography) that facilitated the in vitro expansion of bone graft for subsequent implantation and investigated the optimal conditions for growing new mineralised bone in vitro.

Two topographies (nanopits and nanoislands) were embossed into the bioresorbable polymer Polycaprolactone (PCL). Three dimensional cell culture was performed using double-sided embossing of substrates, seeding of both sides, and vertical positioning of substrates. The effect of Hydroxyapatite, and chemical stimulation were also examined.

Human bone marrow was harvested from hip arthroplasty patients, the mesenchymal stem cells culture expanded and used for cellular analysis of substrate bioactivity.

The cell line specificity and osteogenic behaviour was demonstrated through immunohistochemistry, confirmed by real-time PCR and quantitative PCR. Mineralisation was demonstrated using alizarin red staining.

Results showed that the osteoinduction was optimally conferred by the presence of nanotopography, and also by the incorporation of hydroxyapatite (HA) into the PCL. The nanopit topography and HA were both superior to the use of BMP2 in the production of mineralised bone tissue.

The protocol from shim production to bone marrow harvesting and vertical cell culture on nanoembossed HaPCL has been shown to be reproducible and potentially applicable to economical larger scale production.

Primary bone tumors are rare, complex and highly heterogeneous. Its diagnostic and treatment are a challenge for the multidisciplinary team. Developments on tumor biomarkers, immunohistochemistry, histology, molecular, bioinformatics, and genetics are fundamental for an early diagnosis and identification of prognostic factors. The personalized medicine allows an effective patient tailored treatment. The bone biopsy is essential for diagnosis. Treatment may include systemic therapy and local therapy. Frequently, a limb salvage surgery includes wide resection and reconstruction with endoprosthesis, biological or composites. The risk for local recurrence and distant metastases depends on the primary tumor and treatment response. Cancer patients are living longer and bone metastases are increasing. Bone is the third most frequently location for distant lesions. Bone metastases are associated to pain, pathological fractures, functional impairment, and neurological deficits. It impacts survival and patient quality of life. The treatment of metastatic disease is a challenge due to its complexity and heterogeneity, vascularization, reduced size and limited access. It requires a multidisciplinary treatment and depending on different factors it is palliative or curative-like treatment. For multiple bone metastases it is important to relief pain and increases function in order to provide the best quality of life and expect to prolong survival. Advances in nanotechnology, bioinformatics, and genomics, will increase biomarkers for early detection, prognosis, and targeted treatment effectiveness. We are taking the leap forward in precision medicine and personalized care

Bioactive glasses were first discovered in the late 1960s by Larry Hench. In the 1980s and 1990s bioactive glasses experienced a surge of research interest, an interest which has since declined. This talk will examine the current status of bioactive glasses and discuss future roles and applications for bioactive glasses in regenerative medicine, specifically those related to orthopaedic tissue engineering. Bioactive materials are often considered as those that have the ability to bond to mineralised bone tissue in the physiological environment, however, this talk, as well as examining this aspect, will consider the broader sense of bioactive as ‘having or eliciting a biological effect’. It will examine the role of bioactive glasses as active drug carriers and the influence which enhanced nanotechnology will have on the application of bioactive glasses in vivo

Calcium phosphate ceramics and bioactive glasses are frequently used in orthopedic surgery to stimulate the regeneration of bone tissue due to their superior compatibility to bone tissue. Nevertheless, the brittleness and lack of self-healing behavior of bioceramics are still considered as serious drawbacks. Therefore, these bioceramics have been combined with organic biomaterials for several decades. Since the 1990s, the emergence of nanotechnology has accelerated the progress with respect to the development of organic-inorganic nanocomposites of improved functionality compared to conventional composite biomaterials. This presentation focuses on the development of injectable (nano)composites with self-healing and/or load-bearing capacity. To this end, the affinity between polymeric and inorganic components was tuned by modifying non-covalent interactions between both composite components. Specifically, we exploited reversible interactions between hydrogel matrices and inorganic nanoparticles (traditional nanocomposites), hydrogel nanoparticles and inorganic nanoparticles (colloidal nanocomposites), as well as fibers and bioceramic matrices (fiber-reinforced cement composites). The resulting composite biomaterials were mechanically strong and self-healing, which may open up new avenues of research on the applicability of self-healing and load-bearing composite biomaterials for regenerative medicine

Over the last 50 years, biomaterials, prostheses and implants saved and prolonged the life of millions of humans around the globe. The main clinical complications for current biomaterials and artificial organs still reside in an interfacial mismatch between the synthetic surface and the natural living tissue surrounding it. Today, nanotechnology, nanomaterials and surface modifications provides a new insight to the current problem of biomaterial complications, and even allows us to envisage strategies for the organ shortage. Advanced tools and new paths towards the development of functional solutions for cardiovascular clinical applications are now available. In this talk, the potential of nanostructured metallic degradable metals to provide innovative solutions at medium term for the cardiovascular field will be depicted. Focus will be on Fe-based biodegradable metals with exceptional resistance, ductility and elasticity, for pushing innovative vascular applications. The intrinsic goal of this talk is to present an extremely personal look at how biodegradable metals can impact materials, surfaces and interfaces, and how the resulting unique properties allowed biomedical functional applications to progress, from their introduction, to the promising future that biodegradable metals may or may not hold for improving the quality of the life of millions worldwide

One of the core tenets of our philosophy for tissue regeneration include the use of “raw materials,” where biomaterials themselves serve as both building blocks and bioactive signals. In recent years, a few groups around the world have gravitated toward cartilage matrix as a potentially chondroinductive material for cartilage regeneration. The major challenge to date in cartilage injury has been creating a biomaterial-only strategy that is capable of regenerating true hyaline-like cartilage without the addition of growth factors or exogenous cells. In the past few years, we have focused our efforts on establishing chondroinductivity in vitro, and in developing new materials synthesis strategies to provide ease of application for orthopedic surgeons in the operating room. By leveraging nanotechnology, we have developed a paste-like material constructed from cartilage matrix with encouraging mechanical performance post-crosslinking, and which avoids contraction after extended time. Looking to the future, we are working on next-generation approaches to chondroinductive materials. We have encouraging preliminary data which suggest the possibility of a chondroinductive response to a novel peptide sequence in vitro, which may be enhanced by simultaneous inclusion of adhesion peptides. Initial in vivo data in regeneration of rabbit femoral condyle cartilage defects may suggest promising regenerative capabilities with hydrogels based on these peptides. If indeed chondroinductive materials exist, and if they can be delivered easily, are safe, and can be provided at reasonable cost and with a reasonable regulatory strategy, chondroinductive materials may hold the potential to revolutionize cartilage regeneration

Background. Medical applications of nanotechnology are promising because it allows the surface of biomaterial to be tailored to optimise the interfacial interaction between the biomaterial and its biological environment. Such interfaces are of interest in the domain of orthopaedic surgery as they could have anti-bacterial functions or could be used as drug delivery systems. The development of orthopaedics is moving towards better integration of biology in implants and surgical techniques, but the mechanical properties of implanted materials are still important for orthopaedic applications. During clinical implantation, implants are subjected to large mechanical stresses. In order to obtain the best performance during clinical use, mechanical properties of implants need to be investigated and understood. Method. We modified the topography of commercial titanium orthopaedic screws using electrochemical anodization in a 0.4 wt% hydrofluoric acid solution to produce titanium dioxide nanotube layers. The morphology of the nanotube layers were characterised using scanning electron microscopy. The mechanical properties of the nanotube layers were investigated by screwing and unscrewing an anodized screw into several different types of human bone while the torsional force applied to the screwdriver was measured using a torque screwdriver. The range of torsional force applied to the screwdriver was between 5 and 80 cN·m. Independent assessment of the mechanical properties of the same surfaces was performed on simple anodized titanium foils using a triboindenter. Results. The fabricated nanotube layers can resist mechanical stresses close to those found in clinical situations. Conclusion. The mechanical characteristics of this surface treatment appear to be sufficiently robust to withstand realistic clinical operating conditions that our in vitro experiments were designed to simulate. These results show that the nanotube layers remain intact after the implantation process. This may allow for the exciting possibility of nanotubes being loaded with molecules. Level of Evidence. II

Purpose. Gustilo type III open fractures are associated with high infection rates in spite of instituting a standard of care (SOC) consisting of intravenous antibiotics, irrigation and debridement (I&D), and delayed wound closure. Locally-delivered antibiotic has been proven to assist in reducing infection in open fractures. The aims of this study are to determine the effectiveness and safety of a new implantable and biodegradable antibacterial product. 1. in preventing bacterial infections and initiating bone growth in open fractures. Methods. The osteoconductive antibacterial BonyPid. TM. used is a synthetic bone void filler (comprised of ≤1 mm β-tricalcium phosphate granules) coated by a thin layer (≤20 µm) of PolyPid nanotechnology formulation. −. Upon implantation, the coating releases doxycycline at a constant rate for a predetermined period of 30 days. One BonyPid. TM. vial of 10 grams contains 65 mg of formulated doxycycline. After approval, sixteen subjects with Gustilo type III open tibia fractures, were implanted with the BonyPid. TM. immediately on the first surgical intervention (I&D), followed by external fixation. Patients had periodic laboratory, bacteriology and radiology follow-up. Results. Six months results showed that no infection developed and only one BonyPid. TM. implantation was needed with no subsequent I&D, in the target tibia fracture. Immediate soft wound closure was done in 6/16 subjects following implantation. Out of 10 remaining subjects, 3 needed soleus muscle transfer-skin grafting and 7 required delayed primary closure; by skin grafting (5) or suturing (2). Early callus formation was seen at 8–12 weeks post-surgery, followed by bone healing seen from 16 weeks onwards. Safety of implantation was remarkable, with only one deep infection at a fibular open fracture without BonyPid. TM. implantation. One BonyPid. TM. -related adverse event caused delay in skin healing due to excessive granules in the superficial soft tissues. Conclusion. BonyPid. TM. is effective in reducing bone infection and promoting early callus formation, resulting in early bone healing. BonyPid. TM. is safe for immediate implantation into contaminated/infected severe open-bone fractures. Results support that one month release of doxycycline in a controlled manner provides an effective way for treating open fractures. This new local antibiotic delivery system is applicable in unmet medical situations associated with localised infections

Summary. Aim of this study is to design, develop and preclinical test PET nanostructured scaffolds for the transplantation and differentiation of MSCs in the treatment of bone defects. The interaction of cells with nanotopographical features has proven to be an important signaling modality in controlling MSC differentiation. Introduction. The wide bone defects, caused by trauma, tumor, infectious, periprosthetic osteolysis, need to be surgically treated because their low potential of repair. Nowadays the bone allograft and autograft represent 80% of all transplantation done in the world. However this technique shows many disadvantages, such as the risk of infections, the immunological rejection, the low bone availability and the high costs. These reasons have motivated extensive research to find alternative strategies. As shown in literature, the future strategies are based on the synergic combination of different methodologies: use of biomimetic scaffold in order to support bone regeneration, use of mesenchymal stromal cells (MSCs) and growth factors. Successful regeneration necessitates the development of tissue-inducing scaffolds that mimic the hierarchical architecture of native tissue extracellular matrix (ECM). Cells in nature recognise and interact with the surface topography they are exposed to via ECM proteins. Here we are going to show the guidelines recently published for the design and development of nanostructured scaffolds for the bone regeneration, and the morphofunctional changing of MSCs interacting with nanogratings. Methods. Aim of this study is to design, develop and preclinical test PET nanostructured scaffolds for the transplantation and differentiation of MSCs in the treatment of bone defects. The first step of our study was the extraction of patient's bone marrow and the isolation of MSCs. After characterizing (demonstrating the typical cell surface markers) and isolating the MSCs were cultivated on the PET substrates. The PET nanosubstrates were obtained by a low temperature embossing lithography (HEL) achieving low-damage nanotopographic surface modifications. After MSC cultivation on PET substrates we made a cytotoxicity evaluation, an optic and confocal microscopic evaluation (cells adhesion, cells polarization…) and tests to optimise cell differentiation towards osteogenic fate. Results. PET is a highly suitable thermo-plastic material, able to sustain the necessary methods to obtain nanostructured substrates. MSCs cultivated on nanostructured PET rapidly align with the direction of the nanostructure itself without any cytotoxic effects. After the cultivation on the nanostructures, MSCs sustained cytoskeleton changes suggesting the activation of intracellular signaling (mechanotrasduction) promoting osteogenesis. Discussion. The mechanisms by which nanotopographic cues influence stem cell proliferation and differentiation appear to involve changes in cytoskeletal organization and structure, potentially in response to the geometry and size of the underlying features of the ECM by a process called mechanotrasduction. The interaction of cells with nanotopographical features such as pores, ridges, groves, fibers, nodes, and their combinations has proven to be an important signaling modality in controlling cellular processes. Integrating nanotopographical cues is especially important in engineering complex tissues that have multiple cell types and require precisely defined cell-cell and cell-matrix interactions at the nanoscale. Thus, in the next-generation regenerative engineering approaches, nanoscale materials/scaffolds are expected to play a parimary role in controlling MSC fate and the consequent regenerative capacity. We believe that the continuous development of nanotechnology and deeply comprehension of how mechanical inputs can affect cell biology is fundamental to design the future scaffold for orthopedic application

Despite its intrinsic ability to regenerate form and function after injury, bone tissue can be challenged by a multitude of pathological conditions. While innovative approaches have helped to unravel the cascades of bone healing, this knowledge has so far not improved the clinical outcomes of bone defect treatment. Recent findings have allowed us to gain in-depth knowledge about the physiological conditions and biological principles of bone regeneration. Now it is time to transfer the lessons learned from bone healing to the challenging scenarios in defects and employ innovative technologies to enable biomaterial-based strategies for bone defect healing. This review aims to provide an overview on endogenous cascades of bone material formation and how these are transferred to new perspectives in biomaterial-driven approaches in bone regeneration.

Cite this article: T. Winkler, F. A. Sass, G. N. Duda, K. Schmidt-Bleek. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: The unsolved challenge. Bone Joint Res 2018;7:232–243. DOI: 10.1302/2046-3758.73.BJR-2017-0270.R1.

The August 2015 Research Roundup360 looks at: Lightbulbs, bleeding and procedure durations; Infection and rheumatoid agents; Infection rates and ‘bundles of care’ revisited; ACI: new application for a proven technology?; Hydrogel coating given the thumbs up; Hydroxyapatite as a smart coating?

Objectives

The major problem with repair of an articular cartilage injury is the extensive difference in the structure and function of regenerated, compared with normal cartilage. Our work investigates the feasibility of repairing articular osteochondral defects in the canine knee joint using a composite lamellar scaffold of nano-ß-tricalcium phosphate (ß-TCP)/collagen (col) I and II with bone marrow stromal stem cells (BMSCs) and assesses its biological compatibility.

Objectives

There is increasing application of bone morphogenetic proteins (BMPs) owing to their role in promoting fracture healing and bone fusion. However, an optimal delivery system has yet to be identified. The aims of this study were to synthesise bioactive BMP-2, combine it with a novel α-tricalcium phosphate/poly(D,L-lactide-co-glycolide) (α-TCP/PLGA) nanocomposite and study its release from the composite.