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During a sinus lift procedure the main requirement in order to position an implant is to have a maxillary sinus floor cortical bone thick enough to guarantee a primary stability in the implant inserted. In this way, the healing process is facilitated and osseointegration of the titanium surface may occur simultaneously, thus reducing the waiting time for the engraftment of the implant into the body. Unfortunately, these conditions are not always present. Hence, the need of developing an alternative approach that could simultaneously allow to perform sinus floor elevation along with an implant placement. Here we present the case of a 62-year-old patient that requires implant-prosthetic rehabilitation from 1.2 to 1.6 at diagnosis. In this study, we reported a novel application derived from the use of a heterologous bone scaffold (SmartBone@) in a sinus lift procedure. We showed the successful implant along with sinus lift with SmartBone@, both at the time of the surgery and after follow-up of the patient at 10 months from the implant. The possibility to perform simultaneously the contextual implant along with sinus lift dramatically reduced the waiting time for the patient of minimum 5-6 months required for osseointegration of the grafted biomaterials, before performing the implant procedure. This surgery represents an advance both in terms of medical technique and as life-benefit for the patient. [ABSTRACT FROM AUTHOR]

Xenografts are commonly used for bone regeneration in dental and orthopaedic domains to repair bone voids and other defects. The first-generation xenografts were made through sintering, which deproteinizes them and alters their crystallinity, while later xenografts are produced using cold-temperature chemical treatments to maintain the structural collagen phase. However, the impact of collagen and the crystalline phase on physicochemical properties have not been elucidated. We hypothesized that understanding these factors could explain why the latter provides improved bone regeneration clinically. In this study, we compared two types of xenografts, one prepared through a low-temperature chemical process (Treated) and another subsequently sintered at 1100°C (Sintered) using advanced microscopy, spectroscopy, X-ray analysis and compressive testing. Our investigation showed that the Treated bone graft was free of residual blood, lipids or cell debris, mitigating the risk of pathogen transmission. Meanwhile, the sintering process removed collagen and the carbonate phase of the Sintered graft, leaving only calcium phosphate and increased mineral crystallinity. Microcomputed tomography revealed that the Treated graft exhibited an increased high porosity (81%) and pore size compared to untreated bone, whereas the Sintered graft exhibited shrinkage, which reduced the porosity (72%), pore size and strut size. Additionally, scanning electron microscopy displayed crack formation around the pores of the Sintered graft. The Treated graft displayed median mechanical properties comparable to native cancellous bone and clinically available solutions, with an apparent modulus of 166 MPa, yield stress of 5.5 MPa and yield strain of 4.9%. In contrast, the Sintered graft exhibited a lower median apparent modulus of 57 MPa. It failed in a brittle manner at a median stress of 1.7 MPa and strain level of 2.9%, demonstrating the structural importance of the collagen phase. This indicates why bone grafts prepared through cold-temperature processes are clinically favourable., (© The Author(s) 2024. Published by Oxford University Press.)

Spinal cord injury (SCI) is a devastating condition that can cause significant motor and sensory impairment. Microglia, the central nervous system's immune sentinels, are known to be promising therapeutic targets in both SCI and neurodegenerative diseases. The most effective way to deliver medications and control microglial inflammation is through nanovectors; however, because of the variability in microglial morphology and the lack of standardized techniques, it is still difficult to precisely measure their activation in preclinical models. This problem is especially important in SCI, where the intricacy of the glia response following traumatic events necessitates the use of a sophisticated method to automatically discern between various microglial cell activation states that vary over time and space as the secondary injury progresses. We address this issue by proposing a deep learning-based technique for quantifying microglial activation following drug-loaded nanovector treatment in a preclinical SCI model. Our method uses a convolutional neural network to segment and classify microglia based on morphological characteristics. Our approach's accuracy and efficiency are demonstrated through evaluation on a collection of histology pictures from injured and intact spinal cords. This robust computational technique has potential for analyzing microglial activation across various neuropathologies and demonstrating the usefulness of nanovectors in modifying microglia in SCI and other neurological disorders. It has the ability to speed development in this crucial sector by providing a standardized and objective way to compare therapeutic options., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Obtaining rapid mineralisation is a challenge in current bone graft materials, which has been attributed to the difficulty of guiding the biological processes towards osteogenesis. Amelogenin, a key protein in enamel formation, inspired the design of two intrinsically disordered peptides (P2 and P6) that enhance in vivo bone formation, but the process is not fully understood. In this study, we have elucidated the mechanism by which these peptides induce improved mineralisation. Our molecular dynamics analysis demonstrated that in an aqueous environment, P2 and P6 fold to interact with the surrounding Ca 2+ , PO 4 3- and OH - ions, which can lead to apatite nucleation. Although P2 has a less stable backbone, it folds to a stable structure that allows for the nucleation of larger calcium phosphate aggregates than P6. These results were validated experimentally in a concentrated simulated body fluid solution, where the peptide solutions accelerated the mineralisation process compared to the control and yielded mineral structures mimicking the amorphous calcium phosphate crystals that can be found in lamella bone. A pH drop for the peptide groups suggests depletion of calcium and phosphate, a prerequisite for intrinsic osteoinduction, while S/TEM and SEM suggested that the peptide regulated the mineral nucleation into lamella flakes. Evidently, the peptides accelerate and guide mineral formation, elucidating the mechanism for how these peptides can improve the efficacy of P2 or P6 containing devices for bone regeneration. The work also demonstrates how experimental mineralisation study coupled with molecular dynamics is a valid method for understanding and predicting in vivo performance prior to animal trials., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare no financial and personal relationships with other people or organisations that could inappropriately influence bias to this work. IPR rights of the consensus peptides (US Patent US8367602B2 and connected titles) belong to Industrie Biomediche Insubri SA (Switzerland), where Giuseppe Perale is a founding shareholder and the executive vice president. The patent related to the consensus peptides was invented by Ståle Petter Lyngstadaas but has since been sold to Industrie Biomediche Insubri SA. NuPep AS, owned solely by Øystein Øvrebø, has a licencing right to the consensus peptides IPR above., (Published by Elsevier B.V.)

Current pharmacological and surgical therapies for the central nervous system (CNS) show a limited capacity to reduce the damage progression; that together with the intrinsic limited capability of the CNS to regenerate greatly reduces the hopes of recovery. Among all the therapies proposed, the tissue engineering strategies supplemented with therapeutic stem cells remain the most promising. Neural tissue engineering strategies are based on the development of devices presenting optimal physical, chemical, and mechanical properties which, once inserted in the injured site, can support therapeutic cells, limiting the effect of a hostile environment and supporting regenerative processes. Thus, this review focuses on the employment of hydrogel and nanofibrous scaffolds supplemented with stem cells as promising therapeutic tools for the central and peripheral nervous systems in preclinical and clinical applications.

We previously described an immortalized, genetically-engineered human Mesenchymal stromal cell line to generate BMP2-enriched Chondrogenic Matrices (MB-CM), which after devitalization and storage could efficiently induce ectopic bone tissue by endochondral ossification. In order to increase the efficiency of MB-CM utilization towards engineering scaled-up bone structures, here we hypothesized that MB-CM can retain osteoinductive properties when combined with an osteoconductive material. We first tested different volumetric ratios of MB-CM:SmartBone® (as clinically used, osteoconductive reference material) and assessed the bone formation capacity of the resulting composites following ectopic mouse implantation. After 8 weeks, as little as 25% of MB-CM was sufficient to induce bone formation and fusion across SmartBone® granules, generating large interconnected bony structures. The same composite percentage was then further assessed in a scaled-up model, namely within an axially-vascularized, confined, ectopically prefabricated flap (0.8 cm 3 ) in rats. The material efficiently induced the formation of new bone (31% of the cross-sectional area after 8 weeks), including bone marrow and vascular elements, throughout the flap volume. Our findings outline a strategy for efficient use of MB-CM as part of a composite material, thereby reducing the amount required to fill large spaces and enabling utilization in critically sized grafts, to address challenging clinical scenarios in bone reconstruction. STATEMENT OF SIGNIFICANCE: Most bone repair strategies rely either on osteconductive properties of ceramics and devitalized bone, or osteoinductive properties of growth factors and extracellular matrices (ECM). Here we designed a composite material made of a clinically accepted osteoconductive material and an off-the-shelf tissue engineered human cartilage ECM with strong osteoinductive properties. We showed that low amount of osteoinductive ECM potentiated host cells recruitment to form large vascularized bone structures in two different animal models, one being a challenging prefabricated bone-flap model targeting challenging clinical bone repair. Overall, this study highlights the use of a promising human off-the-shelf material for accelerated healing towards clinical applications., Competing Interests: Declaration of Competing Interest Giuseppe Perale is executive vicepresident, cofounder and shareholder of Industrie Biomediche Insubri SA., (Copyright © 2022. Published by Elsevier Ltd.)

Spinal cord injury (SCI) is an injurious process that begins with immediate physical damage to the spinal cord and associated tissues during an acute traumatic event. However, the tissue damage expands in both intensity and volume in the subsequent subacute phase. At this stage, numerous events exacerbate the pathological condition, and therein lies the main cause of post-traumatic neural degeneration, which then ends with the chronic phase. In recent years, therapeutic interventions addressing different neurodegenerative mechanisms have been proposed, but have met with limited success when translated into clinical settings. The underlying reasons for this are that the pathogenesis of SCI is a continued multifactorial disease, and the treatment of only one factor is not sufficient to curb neural degeneration and resulting paralysis. Recent advances have led to the development of biomaterials aiming to promote in situ combinatorial strategies using drugs/biomolecules to achieve a maximized multitarget approach. This review provides an overview of single and combinatorial regenerative-factor-based treatments as well as potential delivery options to treat SCIs.

Musculoskeletal defects are an enormous healthcare burden and source of pain and disability for individuals. With an aging population, the proportion of individuals living with these medical indications will increase. Simultaneously, there is pressure on healthcare providers to source efficient solutions, which are cheaper and less invasive than conventional technology. This has led to an increased research focus on hydrogels as highly biocompatible biomaterials that can be delivered through minimally invasive procedures. This review will discuss how hydrogels can be designed for clinical translation, particularly in the context of the new European Medical Device Regulation (MDR). We will then do a deep dive into the clinically used hydrogel solutions that have been commercially approved or have undergone clinical trials in Europe or the United States. We will discuss the therapeutic mechanism and limitations of these products. Due to the vast application areas of hydrogels, this work focuses only on treatments of cartilage, bone, and the nucleus pulposus. Lastly, the main steps toward clinical translation of hydrogels as medical devices are outlined. We suggest a framework for how academics can assist small and medium MedTech enterprises conducting the initial clinical investigation and post-market clinical follow-up required in the MDR. It is evident that the successful translation of hydrogels is governed by acquiring high-quality pre-clinical and clinical data confirming the device mechanism of action and safety., Competing Interests: M.M.S. is co‐inventor on patent application 1911235.8 submitted by Imperial College London, related to ultrasound‐triggered liposome payload release., (© 2022 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

SmartBone ® (SB) is a biohybrid bone substitute advantageously proposed as a class III medical device for bone regeneration in reconstructive surgeries (oral, maxillofacial, orthopedic, and oncology). In the present study, a new strategy to improve SB osteoinductivity was developed. SB scaffolds were loaded with lyosecretome, a freeze-dried formulation of mesenchymal stem cell (MSC)-secretome, containing proteins and extracellular vesicles (EVs). Lyosecretome-loaded SB scaffolds (SBlyo) were prepared using an absorption method. A burst release of proteins and EVs (38% and 50% after 30 min, respectively) was observed, and then proteins were released more slowly with respect to EVs, most likely because they more strongly adsorbed onto the SB surface. In vitro tests were conducted using adipose tissue-derived stromal vascular fraction (SVF) plated on SB or SBlyo. After 14 days, significant cell proliferation improvement was observed on SBlyo with respect to SB, where cells filled the cavities between the native trabeculae. On SB, on the other hand, the process was still present, but tissue formation was less organized at 60 days. On both scaffolds, cells differentiated into osteoblasts and were able to mineralize after 60 days. Nonetheless, SBlyo showed a higher expression of osteoblast markers and a higher quantity of newly formed trabeculae than SB alone. The quantification analysis of the newly formed mineralized tissue and the immunohistochemical studies demonstrated that SBlyo induces bone formation more effectively. This osteoinductive effect is likely due to the osteogenic factors present in the lyosecretome, such as fibronectin, alpha-2-macroglobulin, apolipoprotein A, and TGF-β.

Bone defect is a noteworthy health problem and is the second most transplanted tissue after blood. Numerous bone grafts are designed and applied in clinics. Limitations, however, from different aspects still exist, including limited supply, mechanical strength, and bioactivity. In this study, two biomimetic peptides (P2 and P6) are incorporated into a composite bioactive xeno hybrid bone graft named SmartBonePep ® , with the aim to increase the bioactivity of the bone graft. The results, which include cytotoxicity, proliferation rate, confocal microscopy, gene expression, and protein qualification, successfully prove that the SmartBonePep ® has multi-modal biological effects on human mesenchymal stem cells from bone marrow. The effective physical entrapment of P6 into a composite xeno-hybrid bone graft, withstanding manufacturing processes including exposure to strong organic solvents and ethylene oxide sterilization, increases the osteogenic potential of the stem cells as well as cell attachment and proliferation. P2 and P6 both show a strong biological potential and may be future candidates for enhancing the clinical performance of bone grafts., Competing Interests: The rights for SmartBone® and SmartBonePep® patents and trademarks belong to Industrie Biomediche Insubri S.A. (Switzerland). GP is a founding shareholder and the executive vice president of Industrie Biomediche Insubri S.A. (Switzerland), the company that fully owns all IPRs (US Patent US8367602B2, PCT/IB2007/004068, EP Patent EP2358407B1, and related bundles) on SmartBone® and SmartBonePep® and their trademarks. FB works as employee for the same company. FB was employed by the company Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH). HH and SL was part time employed by the company Corticalis AS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Zhu, Blahnová, Perale, Xiao, Betge, Boniolo, Filová, Lyngstadaas and Haugen.)

The marine environment is a rich source of biologically active molecules for the treatment of human diseases, especially cancer. The adaptation to unique environmental conditions led marine organisms to evolve different pathways than their terrestrial counterparts, thus producing unique chemicals with a broad diversity and complexity. So far, more than 36,000 compounds have been isolated from marine micro- and macro-organisms including but not limited to fungi, bacteria, microalgae, macroalgae, sponges, corals, mollusks and tunicates, with hundreds of new marine natural products (MNPs) being discovered every year. Marine-based pharmaceuticals have started to impact modern pharmacology and different anti-cancer drugs derived from marine compounds have been approved for clinical use, such as: cytarabine, vidarabine, nelarabine (prodrug of ara-G), fludarabine phosphate (pro-drug of ara-A), trabectedin, eribulin mesylate, brentuximab vedotin, polatuzumab vedotin, enfortumab vedotin, belantamab mafodotin, plitidepsin, and lurbinectedin. This review focuses on the bioactive molecules derived from the marine environment with anticancer activity, discussing their families, origin, structural features and therapeutic use.