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Bone substitutes are being increasingly used in surgery as over two millions bone grafting procedures are performed worldwide per year. Autografts still represent the gold standard for bone substitution, though the morbidity and the inherent limited availability are the main limitations. Allografts, i.e. banked bone, are osteoconductive and weakly osteoinductive, though there are still concerns about the residual infective risks, costs and donor availability issues. As an alternative, xenograft substitutes are cheap, but their use provided contrasting results, so far. Ceramic-based synthetic bone substitutes are alternatively based on hydroxyapatite (HA) and tricalcium phosphates, and are widely used in the clinical practice. Indeed, despite being completely resorbable and weaker than cortical bone, they have exhaustively proved to be effective. Biomimetic HAs are the evolution of traditional HA and contains ions (carbonates, Si, Sr, Fl, Mg) that mimic natural HA (biomimetic HA). Injectable cements represent another evolution, enabling mininvasive techniques. Bone morphogenetic proteins (namely BMP2 and 7) are the only bone inducing growth factors approved for human use in spine surgery and for the treatment of tibial nonunion. Demineralized bone matrix and platelet rich plasma did not prove to be effective and their use as bone substitutes remains controversial. Experimental cell-based approaches are considered the best suitable emerging strategies in several regenerative medicine application, including bone regeneration. In some cases, cells have been used as bioactive vehicles delivering osteoinductive genes locally to achieve bone regeneration. In particular, mesenchymal stem cells have been widely exploited for this purpose, being multipotent cells capable of efficient osteogenic potential. Here we intend to review and update the alternative available techniques used for bone fusion, along with some hints on the advancements achieved through the experimental research in this field.

This review provides an overview of various materials used in dentistry and oral and maxillofacial surgeries to replace or repair bone defects. The choice of material depends on factors such as tissue viability, size, shape, and defect volume. While small bone defects can regenerate naturally, extensive defects or loss or pathological fractures require surgical intervention and the use of substitute bones. Autologous bone, taken from the patient’s own body, is the gold standard for bone grafting but has drawbacks such as uncertain prognosis, surgery at the donor site, and limited availability. Other alternatives for medium and small-sized defects include allografts (from human donors), xenografts (from animals), and synthetic materials with osteoconductive properties. Allografts are carefully selected and processed human bone materials, while xenografts are derived from animals and possess similar chemical composition to human bone. Synthetic materials such as ceramics and bioactive glasses are used for small defects but may lack osteoinductivity and moldability. Calcium-phosphate-based ceramics, particularly hydroxyapatite, are extensively studied and commonly used due to their compositional similarity to natural bone. Additional components, such as growth factors, autogenous bone, and therapeutic elements, can be incorporated into synthetic or xenogeneic scaffolds to enhance their osteogenic properties. This review aims to provide a comprehensive analysis of grafting materials in dentistry, discussing their properties, advantages, and disadvantages. It also highlights the challenges of analyzing in vivo and clinical studies to select the most suitable option for specific situations.

Synthetic bone substitute materials (BSMs) are becoming the general trend, replacing autologous grafting for bone tissue engineering (BTE) in orthopedic research and clinical practice. As the main component of bone matrix, collagen type I has played a critical role in the construction of ideal synthetic BSMs for decades. Significant strides have been made in the field of collagen research, including the exploration of various collagen types, structures, and sources, the optimization of preparation techniques, modification technologies, and the manufacture of various collagen-based materials. However, the poor mechanical properties, fast degradation, and lack of osteoconductive activity of collagen-based materials caused inefficient bone replacement and limited their translation into clinical reality. In the area of BTE, so far, attempts have focused on the preparation of collagen-based biomimetic BSMs, along with other inorganic materials and bioactive substances. By reviewing the approved products on the market, this manuscript updates the latest applications of collagen-based materials in bone regeneration and highlights the potential for further development in the field of BTE over the next ten years.

Bone defects and fractures present significant clinical challenges, particularly in orthopedic and maxillofacial applications. While minor bone defects may be capable of healing naturally, those of a critical size necessitate intervention through the use of implants or grafts. The utilization of traditional methodologies, encompassing autografts and allografts, is constrained by several factors. These include the potential for donor site morbidity, the restricted availability of suitable donors, and the possibility of immune rejection. This has prompted extensive research in the field of bone tissue engineering to develop advanced synthetic and bio-derived materials that can support bone regeneration. The optimal bone substitute must achieve a balance between biocompatibility, bioresorbability, osteoconductivity, and osteoinductivity while simultaneously providing mechanical support during the healing process. Recent innovations include the utilization of three-dimensional printing, nanotechnology, and bioactive coatings to create scaffolds that mimic the structure of natural bone and enhance cell proliferation and differentiation. Notwithstanding the advancements above, challenges remain in optimizing the controlled release of growth factors and adapting materials to various clinical contexts. This review provides a comprehensive overview of the current advancements in bone substitute materials, focusing on their biological mechanisms, design considerations, and clinical applications. It explores the role of emerging technologies, such as additive manufacturing and stem cell-based therapies, in advancing the field. Future research highlights the need for multidisciplinary collaboration and rigorous testing to develop advanced bone graft substitutes, improving outcomes and quality of life for patients with complex defects.

Zinc is a micronutrient of key importance for human health. An increasing number of studies indicate that zinc plays a significant role in bone tissue’s normal development and maintaining homeostasis. Zinc is not only a component of bone tissue but is also involved in the synthesis of the collagen matrix, mineralization, and bone turnover. It has been demonstrated that zinc can stimulate runt-related transcription factor 2 (Runx2) and promote the differentiation of osteoblasts. On the other hand, zinc has been found to inhibit osteoclast-like cell formation and to decrease bone resorption by stimulating osteoclasts’ apoptosis. Moreover, zinc regulates the RANKL/RANK/OPG pathway, thereby facilitating bone remodeling. To date, not all mechanisms of Zn activity on bone tissue are well understood and documented. The review aimed to present the current state of research on the role of zinc in bone tissue, its beneficial properties, and its effects on bone regeneration. Since calcium phosphates as bone substitute materials are increasingly enriched in zinc ions, the paper included an overview of research on the potential role of such materials in bone filling and regeneration.

Bone defects remain a significant health issue and a major cause of morbidity in elderly patients. Composites based on collagen/calcium phosphate have been widely used for bone repair in clinical applications, owing to their comparability to bone extracellular matrix. This study aimed to evaluate the effects of a scaffold of collagen/calcium phosphate (COL/β-TCP) on bone formation to assess its potential use as a bone substitute to repair bone defects. Bilateral full-thickness critically sized calvarial defects (8 mm in diameter) were created in New Zealand white rabbits and treated with COL/β-TCP or COL scaffolds. One defect was also left unfilled as a control. Bone regeneration was assessed through histological evaluation using hematoxylin and eosin and Masson’s trichrome staining after 4 and 8 weeks. Alizarin Red staining was also utilized to observe the mineralization process. Our findings indicated that COL/β-TCP implantation could better enhance bone regeneration than COL and exhibited both new bone growth and scaffold material degradation.

Bioactive glasses (BGs) have been a focus of research for over five decades for several biomedical applications. Although their use in bone substitution and bone tissue regeneration has gained important attention, recent developments have also seen the expansion of BG applications to the field of soft tissue engineering. Hard and soft tissue repair therapies can benefit from the biological activity of metallic ions released from BGs. These metallic ions are incorporated in the BG network not only for their biological therapeutic effects but also in many cases for influencing the structure and processability of the glass and to impart extra functional properties. The “classical” elements in silicate BG compositions are silicon (Si), phosphorous (P), calcium (Ca), sodium (Na), and potassium (K). In addition, other well-recognized biologically active ions have been incorporated in BGs to provide osteogenic, angiogenic, anti-inflammatory, and antibacterial effects such as zinc (Zn), magnesium (Mg), silver (Ag), strontium (Sr), gallium (Ga), fluorine (F), iron (Fe), cobalt (Co), boron (B), lithium (Li), titanium (Ti), and copper (Cu). More recently, rare earth and other elements considered less common or, some of them, even “exotic” for biomedical applications, have found room as doping elements in BGs to enhance their biological and physical properties. For example, barium (Ba), bismuth (Bi), chlorine (Cl), chromium (Cr), dysprosium (Dy), europium (Eu), gadolinium (Gd), ytterbium (Yb), thulium (Tm), germanium (Ge), gold (Au), holmium (Ho), iodine (I), lanthanum (La), manganese (Mn), molybdenum (Mo), nickel (Ni), niobium (Nb), nitrogen (N), palladium (Pd), rubidium (Rb), samarium (Sm), selenium (Se), tantalum (Ta), tellurium (Te), terbium (Tb), erbium (Er), tin (Sn), tungsten (W), vanadium (V), yttrium (Y) as well as zirconium (Zr) have been included in BGs. These ions have been found to be particularly interesting for enhancing the biological performance of doped BGs in novel compositions for tissue repair (both hard and soft tissue) and for providing, in some cases, extra functionalities to the BG, for example fluorescence, luminescence, radiation shielding, anti-inflammatory, and antibacterial properties. This review summarizes the influence of incorporating such less-common elements in BGs with focus on tissue engineering applications, usually exploiting the bioactivity of the BG in combination with other functional properties imparted by the presence of the added elements.

In recent years, the management of bone defects in regenerative medicine and orthopedic surgery has been the subject of extensive research efforts. The complexity of fractures and bone loss arising from trauma, degenerative conditions, or congenital disorders necessitates innovative therapeutic strategies to promote effective healing. Although bone tissue exhibits an intrinsic regenerative capacity, extensive fractures and critical-sized defects can severely compromise this process, often requiring bone grafts or substitutes. Tissue engineering approaches within regenerative medicine have introduced novel possibilities for addressing nonunions and challenging bone defects refractory to conventional treatment methods. Key components in this field include stem cells, bioactive growth factors, and biocompatible scaffolds, with a strong focus on advancements in bone substitute materials. Both natural and synthetic substitutes present distinct characteristics and applications. Natural grafts—comprising autologous, allogeneic, and xenogeneic materials—offer biological advantages, while synthetic alternatives, including biodegradable and non-biodegradable biomaterials, provide structural versatility and reduced immunogenicity. This review provides a comprehensive analysis of the diverse bone grafting alternatives utilized in orthopedic surgery, emphasizing recent advancements and persistent challenges. By exploring both natural and synthetic bone substitutes, this work offers an in-depth examination of cutting-edge solutions, fostering further research and innovation in the treatment of complex bone defects.

Background: For decades, regenerative medicine and dentistry have been improved with new therapies and innovative clinical protocols. The aim of the present investigation was to evaluate through a critical review the recent innovations in the field of bone regeneration with a focus on the healing potentials and clinical protocols of bone substitutes combined with engineered constructs, growth factors and photobiomodulation applications. Methods: A Boolean systematic search was conducted by PubMed/Medline, PubMed/Central, Web of Science and Google scholar databases according to the PRISMA guidelines. Results: After the initial screening, a total of 304 papers were considered eligible for the qualitative synthesis. The articles included were categorized according to the main topics: alloplastic bone substitutes, autologous teeth derived substitutes, xenografts, platelet-derived concentrates, laser therapy, microbiota and bone metabolism and mesenchymal cells construct. Conclusions: The effectiveness of the present investigation showed that the use of biocompatible and bio-resorbable bone substitutes are related to the high-predictability of the bone regeneration protocols, while the oral microbiota and systemic health of the patient produce a clinical advantage for the long-term success of the regeneration procedures and implant-supported restorations. The use of growth factors is able to reduce the co-morbidity of the regenerative procedure ameliorating the post-operative healing phase. The LLLT is an adjuvant protocol to improve the soft and hard tissues response for bone regeneration treatment protocols.

This study compares the biocompatibility of a novel hybrid bone substitute material based on biphasic granules in a type I collagen scaffold using both subcutaneous and calvarial implantation models, in accordance with DIN EN ISO 10993-6. Given the distinct biological environments, materials may exhibit different behaviors in connective bone tissue. The aim was to evaluate irritation scores and cellular tissue responses to better understand the material's performance in both settings. This study evaluated the biocompatibility and host tissue response of test materials in male Wistar rats through subcutaneous and calvaria implantation models, following DIN EN ISO 10993-6, assessing cellular responses, material degradation, and bone regeneration at 10-, 30-, and 60-days post-implantation. Subcutaneous implants elicited a stronger inflammatory reaction with higher counts of polymorphonuclear cells, lymphocytes, multinucleated giant cells, and plasma cells at day 10, alongside consistently elevated irritancy scores. In contrast, calvaria implants showed increased neovascularization, reflecting bone-specific regenerative processes. Although capsule formation and cellular infiltration were similar between models, material degradation and phagocytosis were significantly greater subcutaneously at day 60. These results highlight the critical impact of implantation site on immune activation, vascularization, and biomaterial resorption, underlining the importance of model selection in preclinical biomaterial assessment.