Innovative Drug Delivery Systems for Regenerative Medicine.

In the past two decades, research on drug delivery systems has achieved significant advances [...].

Fit and forget: The future of dental implant therapy via nanotechnology.

Unlike orthopedic implants, dental implants require the orchestration of both osseointegration at the bone-implant interface and soft-tissue integration at the transmucosal region in a complex oral micro-environment with ubiquitous pathogenic bacteria. This represents a very challenging environment for early acceptance and long-term survival of dental implants, especially in compromised patient conditions, including aged, smoking and diabetic patients. Enabling advanced local therapy from the surface of titanium-based dental implants via novel nano-engineering strategies is emerging. This includes anodized nano-engineered implants eluting growth factors, antibiotics, therapeutic nanoparticles and biopolymers to achieve maximum localized therapeutic action. An important criterion is balancing bioactivity enhancement and therapy (like bactericidal efficacy) without causing cytotoxicity. Critical research gaps still need to be addressed to enable the clinical translation of these therapeutic dental implants. This review informs the latest developments, challenges and future directions in this domain to enable the successful fabrication of clinically-translatable therapeutic dental implants that would allow for long-term success, even in compromised patient conditions.

Calcium Phosphate Cements Combined with Blood as a Promising Tool for the Treatment of Bone Marrow Lesions.

The solid phase of a commercial calcium phosphate (Graftys® HBS) was combined with ovine or human blood stabilized either with sodium citrate or sodium heparin. The presence of blood delayed the setting reaction of the cement by ca. 7-15 h, depending on the nature of the blood and blood stabilizer. This phenomenon was found to be directly related to the particle size of the HBS solid phase, since prolonged grinding of the latter resulted in a shortened setting time (10-30 min). Even though ca. 10 h were necessary for the HBS blood composite to harden, its cohesion right after injection was improved when compared to the HBS reference as well as its injectability. A fibrin-based material was gradually formed in the HBS blood composite to end-up, after ca. 100 h, with a dense 3D organic network present in the intergranular space, thus affecting the microstructure of the composite. Indeed, SEM analyses of polished cross-sections showed areas of low mineral density (over 10-20 µm) spread in the whole volume of the HBS blood composite. Most importantly, when the two cement formulations were injected in the tibial subchondral cancellous bone in a bone marrow lesion ovine model, quantitative SEM analyses showed a highly significant difference between the HBS reference versus its analogue combined with blood. After a 4-month implantation, histological analyses clearly showed that the HBS blood composite underwent high resorption (remaining cement: ca. 13.1 ± 7.3%) and new bone formation (newly formed bone: 41.8 ± 14.7%). This was in sharp contrast with the case of the HBS reference for which a low resorption rate was observed (remaining cement: 79.0 ± 6.9%; newly formed bone: 8.6 ± 4.8%). This study suggested that the particular microstructure, induced by the use of blood as the HBS liquid phase, favored quicker colonization of the implant and acceleration of its replacement by newly formed bone. For this reason, the HBS blood composite might be worth considering as a potentially suitable material for subchondroplasty.

Enhanced Corrosion Resistance and Local Therapy from Nano-Engineered Titanium Dental Implants.

Titanium is the ideal material for fabricating dental implants with favorable biocompatibility and biomechanics. However, the chemical corrosions arising from interaction with the surrounding tissues and fluids in oral cavity can challenge the integrity of Ti implants and leach Ti ions/nanoparticles, thereby causing cytotoxicity. Various nanoscale surface modifications have been performed to augment the chemical and electrochemical stability of Ti-based dental implants, and this review discusses and details these advances. For instance, depositing nanowires/nanoparticles via alkali-heat treatment and plasma spraying results in the fabrication of a nanostructured layer to reduce chemical corrosion. Further, refining the grain size to nanoscale could enhance Ti implants' mechanical and chemical stability by alleviating the internal strain and establishing a uniform TiO2 layer. More recently, electrochemical anodization (EA) has emerged as a promising method to fabricate controlled TiO2 nanostructures on Ti dental implants. These anodized implants enhance Ti implants' corrosion resistance and bioactivity. A particular focus of this review is to highlight critical advances in anodized Ti implants with nanotubes/nanopores for local drug delivery of potent therapeutics to augment osseo- and soft-tissue integration. This review aims to improve the understanding of novel nano-engineered Ti dental implant modifications, focusing on anodized nanostructures to fabricate the next generation of therapeutic and corrosion-resistant dental implants. The review explores the latest developments, clinical translation challenges, and future directions to assist in developing the next generation of dental implants that will survive long-term in the complex corrosive oral microenvironment.

Drug Delivery Systems in Regenerative Medicine: An Updated Review.

Modern drug discovery methods led to evolving new agents with significant therapeutic potential. However, their properties, such as solubility and administration-related challenges, may hinder their benefits. Moreover, advances in biotechnology resulted in the development of a new generation of molecules with a short half-life that necessitates frequent administration. In this context, controlled release systems are required to enhance treatment efficacy and improve patient compliance. Innovative drug delivery systems are promising tools that protect therapeutic proteins and peptides against proteolytic degradation where controlled delivery is achievable. The present review provides an overview of different approaches used for drug delivery.

Antibacterial nanophotosensitizers in photodynamic therapy: An update.

Bacterial infections constitute a major challenge of clinical medicine, particularly in specialties such as dermatology and dental medicine. Antiseptics and antibiotics are the main adjunctive therapies to anti-infective procedures in these specialties. However, antibacterial photodynamic therapy (PDT) has been introduced as a novel and promising alternative to conventional antibacterial approaches. PDT relies on the formation of reactive oxygen species (ROS) by a photosensitizer (PS) after activation by a specific light source. Nanotechnology was later introduced to enhance the antibacterial efficacy of PS during PDT. In this review, we describe the different nanoparticles (NPs) used in PDT and their properties. Recent in vivo data of NPs in antibacterial PDT in dermatology and dental medicine and their safety concerns are also reviewed.

Photodynamic Therapy for Peri-Implant Diseases.

Peri-implant diseases are frequently presented in patients with dental implants. This category of inflammatory infections includes peri-implant mucositis and peri-implantitis that are primarily caused by the oral bacteria that colonize the implant and the supporting soft and hard tissues. Other factors also contribute to the pathogenesis of peri-implant diseases. Based on established microbial etiology, mechanical debridement has been the standard management approach for peri-implant diseases. To enhance the improvement of therapeutic outcomes, adjunctive treatment in the form of antibiotics, probiotics, lasers, etc. have been reported in the literature. Recently, the use of photodynamic therapy (PDT)/antimicrobial photodynamic therapy (aPDT) centered on the premise that a photoactive substance offers benefits in the resolution of peri-implant diseases has gained attention. Herein, the reported role of PDT in peri-implant diseases, as well as existing observations and opinions regarding PDT, are discussed.

Double-edged sword: Therapeutic efficacy versus toxicity evaluations of doped titanium implants.

Titanium-based orthopaedic/dental implants modified with various metal-doping strategies can enhance local therapy and bioactivity. Intentional or unintentional (because of loading and wear) release of metal ions/nanoparticles (NPs) from metal-doped implants can be therapeutic or cause adverse local tissue reactions, compromising long-term survival. Strategies to incorporate metals into implants, such as superficial or deep loading inside nano-engineered surfaces, including nanotubes, and the physiochemical characteristics of the released species significantly influence both their therapeutic and cytotoxic potential. In this review, we compare and contrast this 'double-edged sword' to arrive at an improved understanding of metal-doped implants to enable controlled therapy while minimising cytotoxicity concerns.

Perception of pharmacy students toward opioid-related disorders and roles of community pharmacists: A French nationwide cross-sectional study.

Background: Community pharmacists are among the frontline health professionals who manage patients with an opioid-related disorder (ORD). Pharmacists frequently have a negative attitude toward these patients, which could have a negative impact on their management. However, education on ORD may improve the attitude of future healthcare professionals. This cross-sectional study aimed to assess French pharmacy students' perceptions of ORD. Methods: This online survey was performed by emails sent to French pharmacy schools (between January 14, 2019 and May 31, 2019). The primary outcome was the perception (visual analogic scale) of ORD as a disease, the roles of community pharmacies (delivery of opioid agonist therapy-OAT and harm reduction kits), and the efficacy of OAT. The secondary outcomes assessed professional experience, university experience of and education on ORD, and the individual characteristics of students. Results: Among the 1,994 students included, 76.3% perceived ORD as a disease and felt that it was normal for pharmacists to deliver OAT (78.9%) and harm reduction kits (74.6%). However, only 46.9% perceived OAT as being effective. Multivariable analyses showed that females had a more positive perception in recognizing ORD as a disease. The progression through university years increased the positive perception of ORD as a disease and the delivery of OAT and harm reduction kits by pharmacists. Education on substance-related disorders had no impact on any scores. Students who had already delivered OAT had a negative perception of their efficacy. The students who had already performed pharmacy jobs or traineeships had a negative perception of harm reduction kit delivery. Conclusion: Education on substance-related disorders had no impact on students' perceptions. It seemed that the maturity acquired through university years had a stronger impact on the students' perceptions of ORD. Efforts must be made to improve our teaching methods and reinforce the confidence of students in the roles of community pharmacists.

Unusual Oxidative Dealkylation Strategy toward Functionalized Phenalenones as Singlet Oxygen Photosensitizers and Photophysical Studies.

A series of functionalized 6-alkoxy phenalenones was prepared through an unprecedented oxidative dealkylation of readily available phenalene precursors. The starting phenalenes were efficiently synthesized via an aminocatalyzed annulation/O-alkylation strategy starting from simple substrates. The spectroscopic properties of some phenalenones were investigated in different solvents. Introducing an alkoxy substituent at the 6-position onto the phenalenone framework results in a red shift of the absorption. The synthesized phenalenones exhibit low fluorescence quantum yields, and the fluorescence decay was studied in different solvents, highlighting the presence of several lifetimes. The singlet oxygen (1O2) photosensitizing propensity of some phenalenones was investigated, and the results showed the striking importance of the phenalenone molecular structure in generating singlet oxygen with high yields. The ability of phenalenones to generate singlet oxygen was then harnessed in three photooxygenation reactions: anthracene oxidation, oxy-functionalization of citronellol through the Schenck-ene reaction, and photooxidation of a diene.

Fibrin as a Multipurpose Physiological Platform for Bone Tissue Engineering and Targeted Delivery of Bioactive Compounds.

Although bone graft is still considered as the gold standard method, bone tissue engineering offers promising alternatives designed to mimic the extracellular matrix (ECM) and to guide bone regeneration process. In this attempt, due to their similarity to the ECM and their low toxicity/immunogenicity properties, growing attention is paid to natural polymers. In particular, considering the early critical role of fracture hematoma for bone healing, fibrin, which constitutes blood clot, is a candidate of choice. Indeed, in addition to its physiological roles in bone healing cascade, fibrin biochemical characteristics make it suitable to be used as a multipurpose platform for bioactive agents' delivery. Thus, taking advantage of these key assets, researchers and clinicians have the opportunity to develop composite systems that might further improve bone tissue reconstruction, and more generally prevent/treat skeletal disorders.

Delivery systems of local anesthetics in bone surgery: are they efficient and safe?

Management of postoperative pain following bone surgery includes administration of local anesthetics (LAs). Smart delivery systems, including triggered systems, have been designed to provide a continuous release of LA in situ. However, these systems can provide a high level of LA locally. This review will examine the state-of-the-art regarding the LA delivery systems optimized for management of postoperative pain in bone surgery and will discuss the potential adverse effects of LAs on the overall pathways of bone healing, including the inflammation response phase, hemostasis phase, tissue repair phase and remodeling phase. There is a clinical need to document these effects and the potential impacts on the clinical outcome of the patient.

Pain Management After Bone Reconstruction Surgery Using an Analgesic Bone Cement: A Functional Noninvasive In Vivo Study Using Gait Analysis.

Postoperative pain after bone reconstruction is a serious complication that could jeopardize the global success of a surgery. This pain must be controlled and minimized during the first 3 to 4 postoperative days to prevent it from becoming chronic. In this study, a critical-size bone defect was created at the femoral distal end of rats and filled by an injectable calcium phosphate cement (CPC) loaded or not with local anesthetics (bupivacaine or ropivacaine). A functional evaluation of the gait was performed using the CatWalk system to compare the postoperative pain relief enhanced by the different CPCs after such a bone filling surgery. The results demonstrated significant pain relief during the short-term postoperative period, as shown by the print area and intensity parameters of the operated paw. At 24hours, the print area decreased by 65%, 42%, and 24%, and the intensity decreased by 25%, 9%, and 1% for unloaded, ropivacaine-loaded, and bupivacaine-loaded CPCs, respectively, compared with the preoperative values. Bupivacaine-loaded CPC provided an earlier return to full functional recovery than ropivacaine-loaded CPC. Moreover, the CPCs retained their biologic and mechanical properties. For all these reasons, anesthetic-loaded CPCs could be part of the global pain management protocol after bone reconstruction surgery such as iliac crest bone grafting procedures. PERSPECTIVE: Bupivacaine-loaded CPC provided an earlier return to full gait function than ropivacaine-loaded CPC, with preserved bone filling properties. Such analgesic CPCs deserve further in vivo investigation and may be part of the global pain management protocol after bone reconstruction or bone augmentation surgery such as iliac crest bone grafting.

Understanding the Progression of Bone Metastases to Identify Novel Therapeutic Targets.

Bone is one of the most preferential target site for cancer metastases, particularly for prostate, breast, kidney, lung and thyroid primary tumours. Indeed, numerous chemical signals and growth factors produced by the bone microenvironment constitute factors promoting cancer cell invasion and aggression. After reviewing the different theories proposed to provide mechanism for metastatic progression, we report on the gene expression profile of bone-seeking cancer cells. We also discuss the cross-talk between the bone microenvironment and invading cells, which impacts on the tumour actions on surrounding bone tissue. Lastly, we detail therapies for bone metastases. Due to poor prognosis for patients, the strategies mainly aim at reducing the impact of skeletal-related events on patients' quality of life. However, recent advances have led to a better understanding of molecular mechanisms underlying bone metastases progression, and therefore of novel therapeutic targets.

Gallium enhances reconstructive properties of a calcium phosphate bone biomaterial.

Calcium phosphate (CaP)-based biomaterials are commonly used in bone reconstructive surgery to replace the damaged tissue, and can also serve as vectors for local drug delivery. Due to its inhibitory action on osteoclasts, the semi-metallic element gallium (Ga) is used for the systemic treatment of disorders associated with accelerated bone resorption. As it was demonstrated that Ga could be incorporated in the structure of CaP biomaterials, we investigated the biological properties of Ga-loaded CaP biomaterials. Culturing bone cells on Ga-CaP, we observed a decrease in osteoclast number and a downregulation of late osteoclastic markers expression, while Ga-CaP upregulated the expression of osteoblastic marker genes involved in the maturation of bone matrix. We next investigated in vivo bone reconstructive properties of different Ga-loaded biomaterials using a murine bone defect healing model. All implanted biomaterials showed a good osseointegration into the surrounding host tissue, accompanied by a successful bone ingrowth and bone marrow reconstruction, as evidenced by histological analysis. Moreover, quantitative micro-computed tomography analysis of implants revealed that Ga enhanced total defect filling. Lastly, we took advantage for the first time of a particular mode of non-linear microscopy (second harmonic generation) to quantify in vivo bone tissue reconstruction within a CaP bone substitute. By doing so, we showed that Ga exerted a positive impact on mature organized collagen synthesis. As a whole, our data support the hypothesis that Ga represents an attractive additive to CaP biomaterials for bone reconstructive surgery. Copyright © 2017 John Wiley & Sons, Ltd.

The multiple therapeutic applications of miRNAs for bone regenerative medicine.

With the aging of the general population, there is an increasing need for bone defect repair, prompting the development of reliable alternatives to autologous bone grafting, without the usually associated major drawbacks (i.e., limited volume and severe postoperative pain). Given the crucial role that miRNAs appear to have in bone tissue physiopathology, exploring their potential has recently garnered increased interest. In this review, we first describe the involvement of miRNAs in bone metabolism, and then focus on their potential therapeutic applications (as bone biomarkers and molecular targets). We also highlight the as yet unsolved biological (i.e., off-target effects) and technological (i.e., specific delivering) challenges associated with their use.

Molecular Mechanisms of Anti-metastatic Activity of Curcumin.

Cancer is the leading cause of death worldwide. Although cancer occurs as a localized disease, its morbidity and mortality rates remain high due to the ability of cancer cells to break-off from the primary tumor and spread to distant organs. Currently, chemotherapy is the main treatment for cancer; however, the increase in proportion of drug-resistant cancer cells and unpleasant side-effects of chemotherapy are still the major challenges in cancer therapy. Curcumin is a natural polyphenol compound and the main bioactive constituent of Indian spice turmeric, widely used in Indian and Chinese medicines. Curcumin has well-known therapeutic actions, including anti-inflammatory, anti-microbial, anti-oxidant and anti-cancer properties. Curcumin induces cancer cell apoptosis through regulating various signaling pathways and arresting tumor cell cycle. Curcumin's therapeutic/ preventative actions on metastatic cancers have not been yet fully understood and studied. The present review explores the potential anti-metastatic mechanisms of curcumin, including inhibition of transcription factors and their signaling pathways (e.g., NF-κB, ApP-1 and STAT3), inflammatory cytokines (e.g., CXCL1, CXCL2, IL-6, IL-8), multiple proteases (e.g., uPA, MMPs), multiple protein kinases (e.g., MAPKs, FAK), regulation of miRNAs (e.g., miR21, miR181b) and heat shock proteins (HLJ1). In addition, possible synergistic actions of combination therapy of curcumin with current chemotherapies are discussed in this review.

Gallium, a promising candidate to disrupt the vicious cycle driving osteolytic metastases.

Bone metastases of breast cancer typically lead to a severe osteolysis due to an excessive osteoclastic activity. On the other hand, the semi-metallic element gallium (Ga) displays an inhibitory action on osteoclasts, and therefore on bone resorption, as well as antitumour properties. Thus, we explored in vitro Ga effects on osteoclastogenesis in an aggressive bone metastatic environment based on the culture of pre-osteoclast RAW 264.7 cells with conditioned medium from metastatic breast tumour cells, i.e. the breast tumour cell line model MDA-MB-231 and its bone-seeking clone MDA-231BO. We first observed that Ga dose-dependently inhibited the tumour cells-induced osteoclastic differentiation of RAW 264.7 cells. To mimic a more aggressive environment where pro-tumourigenic factors are released from bone matrix due to osteoclastic resorption, metastatic breast tumour cells were stimulated with TGF-ß, a mayor cytokine in bone metastasis vicious cycle. In these conditions, we observed that Ga still inhibited cancer cells-driven osteoclastogenesis. Lastly, we evidenced that Ga affected directly and strongly the proliferation/viability of both cancer cell lines, as well as the expression of major osteolytic factors in MDA-231BO cells. With the exception of two small scale clinical studies from 1980s, this is the first time that antitumour properties of Ga have been specifically studied in the context of bone metastases. Our data strongly suggest that, through its action against the vicious cycle involving bone cells and tumour cells, Ga represents a relevant and promising candidate for the local treatment of bone metastases in patients with breast cancer.

Therapeutic actions of curcumin in bone disorders.

Curcumin is the active component of turmeric extract derived from the Curcuma longa plant. In the last decade, curcumin has raised a considerable interest in medicine owing to its negligible toxicity and multiple therapeutic actions including anti-cancer, anti-inflammatory and anti-microbial activities. Among the various molecular targets of curcumin, some are involved in bone remodeling, which strongly suggests that curcumin can affect the skeletal system. The review sheds light on the current and potential applications of curcumin to treat bone disorders characterized by an excessive resorption activity. Within the scope of this review, the novel formulations of curcumin to overcome its physico-chemical and pharmacokinetic constraints are also discussed.

Design and properties of novel gallium-doped injectable apatitic cements.

Different possible options were investigated to combine an apatitic calcium phosphate cement with gallium ions, known as bone resorption inhibitors. Gallium can be either chemisorbed onto calcium-deficient apatite or inserted in the structure of ß-tricalcium phosphate, and addition of these gallium-doped components into the cement formulation did not significantly affect the main properties of the biomaterial, in terms of injectability and setting time. Under in vitro conditions, the amount of gallium released from the resulting cement pellets was found to be low, but increased in the presence of osteoclastic cells. When implanted in rabbit bone critical defects, a remodeling process of the gallium-doped implant started and an excellent bone interface was observed. STATEMENT OF SIGNIFICANCE: The integration of drugs and materials is a growing force in the medical industry. The incorporation of pharmaceutical products not only promises to expand the therapeutic scope of biomaterials technology but to design a new generation of true combination products whose therapeutic value stem equally from both the structural attributes of the material and the intrinsic therapy of the drug. In this context, for the first time an injectable calcium phosphate cement containing gallium was designed with properties suitable for practical application as a local delivery system, implantable by minimally invasive surgery. This important and original paper reports the design and in-depth chemical and physical characterization of this groundbreaking technology.