During aerospace thin-walled component processing, the prediction and control of machining deformation have gained increasing attention. The initial residual stress in the blank is a major factor leading to the occurrence of machining deformation. This paper proposes the concept of uneven milling during the workpiece machining process, which is caused by the variation in local cutting depth resulting in uneven material removal thickness. Based on the elasticity theory, an analytical model is established to predict the evolution of overall residual stress and machining deformation in beam-like aluminum alloy components under uneven milling conditions. The effectiveness of the model is verified through finite element simulations and experiments. The results are as follows: (1) Under uneven milling conditions, the analytical model can accurately predict the distribution of residual stress and the machining deformation within the ZX section of the workpiece. (2) The uneven distribution of bending stress arises from the different curvature radii of various positions after workpiece deformation, leading to a 1 MPa to 3 MPa difference in stress between the middle and both ends of the workpiece. (3) During the layer-by-layer milling process, the magnitude of workpiece deformation is related to the stress state of the material removed, and there is a deformation superposition effect on the lower surface of the workpiece, further exacerbating the overall machining deformation. Widespread application of aluminum alloys has emerged in the design and fabrication of integrated thin-walled aerospace components, owing to their notable attributes of high strength, lightweight properties, and cost effectiveness . HoweverScholars have extensively discussed the mechanisms of inducing deformation through IRS and proposed analytical models and deformation control methods for predicting such deformation. Virkar et al. , based oIn recent years, research focused on the coupled influence of MIRS and IRS on machining deformation has increased. By combining numerical calculations of equivalent stiffness with plate shell theory, Li et al.  proposedMuch research has revealed the influence of initial residual and MIRS on machining deformation through simulation and experimental methods. Huang et al.  identifiTheoretical research provides the foundation and guidance for controlling machining deformation. Fan and Yang ,18 propoMoreover, the overall residual stress inference within the blank during processing is of significant importance for deformation control. Wang et al.  obtainedIn previous studies, the exploration of shape deviations caused by local cutting depth variations during workpiece machining is limited. Lin et al.  establisTherefore, this study introduces the concept of uneven milling, which refers to the uneven removal of material thickness caused by variations in local cutting depths. Based on the principles of elasticity, this study deduces the evolution of overall residual stress in beam-like components and a model for predicting machining deformations under the conditions of uneven milling is proposed. Finally, the model is validated using finite element simulations and machining experiments and the overall residual stress evolution patterns in workpieces under uneven milling are summarized.The billet is isotropic and homogeneous in nature.The influence of MIRS on machining deformation is ignored.IRS distribution at the same depth is uniform.Shear stresses influence is disregarded for the aluminum alloy beam undergoing pure bending deformation.This study presents an analytical model for machining deformation prediction, and puts forward the following four hypotheses:During the aluminum alloy billet forming process, residual stress primarily originates from forging, heat treatment, and cold working processes. These manufacturing processes induce billet stress and strain, which subsequently results in residual stress during cooling and as a result of uneven temperature distribution. Previous research has demonstrated that the deformation of beam-shaped aluminum alloy components primarily manifests as bending deformation along the longitudinal X-direction ,29,30. THere, After removing a layer of thickness e from the raw material, the original state of equilibrium is disrupted. To ensure internal force balance is maintained, a uniform stress The stress distribution σs(z)  for the As shown in The moment While I denotes the remaining unprocessed sections moment of inertia.As shown in By substituting Equations (3), (4), and (6)–(8) into Equation (9) and solving it, it is possible to obtain the distribution function for the overall stress in the workpiece under the uniform thickness milling condition. Based on the assumption of pure bending deformation according to beam bending theory, the effect of shear stress on the buckling deformation is neglected. Therefore, the bending deformation caused by the workpiece internal stress imbalance can be equivalent to the deformation induced by a uniform torque applied at both ends of the workpiece, denoted as Mx(e) . The def1 and C2 can be solved.In Equation (10), EI represents the beam flexural rigidity, where E is the elastic modulus. By substituting the boundary conditions i in i, the initial deflection is denoted as During the machining process, the cutting depth, denoted as ‘e’, is typically maintained at a constant value. However, after removal of the first workpiece layer, the distortion caused by redistribution of residual stress can result in localized variations in the cutting depth during the second layer removal. Such variations further result in an uneven removal of material thickness, known as the uneven milling phenomenon. i after material removal. This resultant force generates a uniform stress i, as shown in Equation (12).According to i:According to the superposition principle, the modified stress distribution i can be expressed as follows:Owing to the variation in material removal thickness, the size of the remaining blank portion also changes with the x-coordinate. Hence, the moment of inertia i that varies linearly with thickness Z, as expressed in Equation (18).The torque i, the newly remaining stress distribution that satisfies the force and moment equilibrium conditions can be represented as follows.At this point, in section i. Owing to the material removal thickness variation, the stress distribution function in each section differs. Therefore, by separately calculating the stress distribution function in each section, an n-dimensional stress function vector By substituting Equations (12), (13), (15)–(18) into Equation (19), the solution yields a new stress distribution function equation within section In addition, it is possible to discretize the thickness coordinate z into m discrete values in each section and substitute these into the Equation (20). This allows us to obtain the final blank overall stress matrix m and n values are sufficiently small, the stress matrix i, where E represents the material elastic modulus. By individually calculating the curvature equation in each section, an n-dimensional curvature vector In conclusion, when the l] to obtain the curvature fitting function In the curvature vector Note that in Equation (23), In recent years, researchers have increasingly focused on the shape-deviation issue that occurs during the milling process for large aluminum alloy thin-walled structural components. In this context, significant attention has been paid to the milling processes of thin-walled side walls and large frame lattice structures. The causes of such shape deviations include the workpiece thin-walled characteristics and improper clamping positions, which hinder effective machining deformation suppression caused by mechanical thermal and cutting force loads during the manufacturing process. These shape deviations are primarily attributed to the surface residual stress and thermoelastic effects of thin-walled components ,28. TherThis study proposes a model for predicting the evolution of overall residual stress and machining deformation in beam-type components under uneven thickness milling conditions. To validate the accuracy of the proposed model, 7050-T7451 aluminum alloy rolled plates were selected as experimental specimens. This material possesses the following mechanical properties: an elastic modulus of 71.7 GPa and a Poisson’s ratio of 0.33. As shown in In this research, the contour method was employed to measure the IRS longitudinal distribution along the specimen thickness (part 1). Compared to the layer removal and the crack compliance methods, the contour method can be used to determine residual stress throughout the cross-section of complex geometries ,31. The Current research indicates that the residual stress induced by machining is predominantly present near the material surface (within a few hundred μm) , and conTo characterize the local stress state before and after milling, a drilling depth of 2 mm was selected, divided into 25 incremental steps, with a drilling depth of 0.08 mm for each step. Strain data were collected using the HBM universal data acquisition system. The residual stress distribution was calculated following the ASTM-E837-20 standard  procedurThe calculation program was written using MATLAB 2012b software to obtain the stress distribution data and the prediction results of machining deformation. Add the IRS curve (as shown in (1)First, based on the element birth and death method, submodel one is established to satisfy the even thickness removal condition. Subsequently, utilizing the SIGINI subroutine, the IRS function shown in (2)Second, using the restart request techniques and manual remeshing techniques, the deformed entity resulting from the submodel one calculation is imported into submodel 2. Subsequently, by employing the element birth and death method, the mesh is partitioned and the model attributes are imposed. Moreover, using the Map Solution keyword, the submodel one stress result data are mapped onto the nodal points of each element in submodel two. This completes the simulation calculation for the second layer uneven removal.(3)Finally, following the Step 2 procedure, the deformed entity and stress result data from the submodel two calculation are mapped into submodel three. As a result, the simulation calculation for the third layer uneven removal was accomplished. In the aforementioned finite element model, C3D8R hexahedral elements with dimensions of 5 × 5 × 0.5 mm were utilized. Meanwhile, the following boundary conditions were defined: the displacement constraint on the left end of the model’s plane (Ux = Uy = Uz = 0), and the vertical (Z-direction) and horizontal (Y-direction) displacement on the right end (Uy = Uz = 0).To verify the theoretical analysis model’s accuracy, this study employed the ABAQUS general finite element analysis software package to construct a finite element model under the uneven milling conditions. As shown in This study also validates the effectiveness of the analytical model using milling experiments. Previous research has indicated that increasing the tool diameter , reducinAs depicted in Prior to the start of machining, the workpiece did not undergo any initial deformation. Therefore, when removing the first layer of part 2, the cutting depth during the milling process remains constant (uniform milling). However, when removing the second and third layers, the specimen will experience warping deformation due to the coupled effects of redistributed internal residual stress and thermal-elastic effects during machining ,28. ThisDuring the aircraft beam-like component machining process, the significant dimensions and thin-wall characteristics of parts hinder the effective suppression of deformation through process connections. As a result, variations in cutting depth are quite common throughout machining. Upon the first layer removal, the redistribution of overall residual stress and the introduction of additional residual stress in the machining process disrupt the internal stress equilibrium of the parts, leading to warping deformations and subsequent fluctuations in local cutting depths during the milling process. The analytical model predicts a slight discrepancy in the overall residual stress distribution on the ZX section of the workpiece compared to the stress results of the finite element model after uneven milling. To verify the stress distribution accuracy predicted by the analytical model, After each layer of milling is completed, the deformation deflections of three different points on both the upper and lower surfaces of the workpiece are measured using a coordinate measuring machine (CMM). The average value of these measurements is taken as the experimental result. According to Furthermore, noticeable differences in the deformity are also observed on the workpiece upper and lower surfaces under both the uniform and uneven milling scenarios. The comparison presented in the It should be noted that the workpiece deformity is closely correlated with the stress state of the material being removed. When the first material layer is removed , according to the results shown in In recent years, in-depth investigations have been conducted into the correlation between workpiece layout and deformation in raw materials. The research contends that the deformation caused by processing at the raw material center is generally smaller compared to the edges ,20. MoreIn conclusion, the comparative results have validated the accuracy of the analytical model. This model precisely predicts the final deformation outcomes of the workpiece, aligning well with finite element simulation and experimental measurement results. Moreover, the analytical model quantitatively characterizes the residual stress distribution map within the cross-sections of the workpiece during the layer-by-layer removal process and exhibits a remarkable consistency with the finite element simulation and experimental measurement results. It accurately predicts the evolution of residual stresses and machining deformation in beam-like aluminum alloy components caused by variations in cutting depth during processing.It should be noted that the proposed model in this study has certain limitations. It is based on the assumptions mentioned in The analytical model proposed in this study demonstrates accurate prediction of machining deflection and residual stress distribution on the ZX cross-section of beam-like aluminum alloy components under uneven milling conditions. When compared to finite element simulation results, the analytical model exhibits an average prediction error of 3.40% for residual stress distribution within the ZX cross-section and an average prediction error of 0.71% for machining deflection. Comparison with experimental measurements further confirms the good consistency between the predictive results of the analytical model and the experimental observations.Under the conditions of uneven milling, there exists a difference of 1 MPa to 3 MPa in residual stress between the middle and end positions of the aluminum alloy component. This difference is attributed to the varying curvature radii along the component during the uneven material removal process. The middle position of the component has the smallest curvature radius (higher degree of bending), while the curvature radii gradually increase towards the ends (lower degree of bending). As a result, the distribution of bending stress is uneven across the component. However, the existing literature on layer milling theory has not provided a sufficient description of this difference.During the layer-by-layer milling process, the magnitude of the workpiece deformation is influenced by the stress state of the material being removed. The greater the stress amplitude, the more significant the workpiece deformation. Under uneven milling conditions, there is a difference in deformation deflection between the upper and lower surfaces of the workpiece. The deformation on the upper surface is removed in the subsequent milling steps, while the lower surface undergoes successive layers of milling without the removal of previously deformed material. This accumulation of deformation deflection on the lower surface leads to further exacerbation of the overall machining deformation of the workpiece.In this study, A concept of uneven milling during the machining process of aluminum alloy components has been innovatively introduced. This concept refers to the unevenness in material removal thickness caused by variations in local cutting depth of the workpiece. Furthermore, an analytical model has been developed to predict the overall evolution of residual stresses and machining deformations in beam-like aluminum alloy components under uneven milling conditions. Finite element simulations and practical machining experiments were conducted to validate the accuracy of the proposed analytical model. By comparing the calculated results from the analytical model with experimental data, the following conclusions can be summarized:It should be noted that the proposed model in this study has certain limitations. It is based on the assumptions mentioned in


Asthma is a common pathology worldwide that occurs due to chronic inflammation of the respiratory airways. Persistent pulmonary inflammation leads to low-grade systemic inflammation, influencing blood vessels and triggering coronary artery disease (CAD) events. This review's objectives include discussing the susceptible population for CAD, the mechanism underlying CAD creation in asthma patients, the characteristics of asthma, and the influence of anti-asthmatic medications on CAD development. Adult-onset asthma is strongly linked to CAD and stroke. Future research may shed light on these disparities. Atherosclerosis and asthma are linked through both intrinsic and extrinsic pathways, with inflammation being the intrinsic pathway and hypoxia and tachyarrhythmia being the extrinsic pathways. The most probable mechanisms for increased coronary vasospastic angina (CVsA) incidence in asthmatic patients are vascular smooth muscle cell hypercontraction and endothelial dysfunction. Studies have shown a dose-response relationship between asthma control and myocardial infarction (MI) risk, with uncontrolled asthma at the highest risk. Impairment of ventilatory function is a distinct risk factor for lethal MI and cardiovascular death (CVD). The use of beta-2-agonists and chronic oral glucocorticoid therapy in severe asthmatics has been linked to increasing the risk for CAD. However, some studies have shown that the risk of MI among patients with active asthma is not related to the use of asthma medications. Further research is needed to determine the involvement of adult asthma features and their treatments in the development of CAD. Asthma is now more widespread than ever among young adults in Western society -5, whereCoronary artery disease (CAD) is a leading cause of death worldwide, and despite lowering age-specific mortality rates in affluent countries, an aging population keeps the absolute numbers rising . It has MethodologyIn conjunction with all authors, PubMed Central, Medline, and PubMed databases were searched using combinations of asthma and coronary artery diseases. A total of 598 studies were identified, and a free full-text filter was applied to yield 275 papers. Also, the following search strategy was selected based on the Medical Subject Headings (MeSH) vocabulary: ) AND ("Heart Diseases"[Majr]). No time parameters were set. Age criteria of 19-64 years were selected. We selected all types of study literature that was published in English with full text. Articles were excluded where the free full text could not be retrieved. Duplicate publications and gray literature were also excluded. All articles were reviewed, and any differences of opinion were discussed until a decision was reached. After discussion among all the authors, a total of 25 studies were unanimously included in the review.Understanding asthma and its subtypesAsthma is a chronic inflammatory disorder of the lung airway system that clinically presents as shortness of breath (SOB), wheezing, coughing, and chest tightness due to the interplay of inflammatory cells . The T-hUnderstanding CADCAD presents as an occlusion of the coronary arteries, the major vessels supplying the heart. This, in turn, may lead to myocardial infarction (MI), ischemia, and death. The pathophysiology behind this condition involves the formation of atheromatous plaques within the intima of the vessel wall, along with severe inflammation of the same. This causes a reduced supply of oxygen and nutrients to the cardiomyocytes . It has Epidemiology of CAD in asthmaticsThe age of onset and current age of presentation of asthma play a huge role in the development of CAD. According to a prospective study that examined the etiology of atherosclerosis, cardiovascular disease, and cerebrovascular disease in four US communities, adult-onset asthma, rather than child-onset asthma, was found to be strongly linked with the incidence of CAD and stroke. This study classified asthma as "adult-onset asthma" if the age of onset was 21 years or older or "child-onset asthma" if the onset was before age 21 . AnotherPathophysiologyResearchers and scholars have put forward many hypotheses to explain the association of CAD with adult asthma. Asthma may predispose to atherosclerosis through certain pathophysiologic routes that may be linked to the long-term inflammatory process of this disorder. Alternatively, the link between atherosclerosis and asthma may be caused by a common inflammatory pathway that predisposes people to both conditions . The immThe risk of MI may also be increased by platelet-activating factor (PAF) or particular eicosanoid mediators (such as cysteinyl LTs) released in asthma . PAF hasWhile much literature is present explaining the pathophysiology of traditional atherogenic CAD, not much study has been found to explain the cause of increased CVsA incidence in asthmatic patients . AccordiFactors affecting CAD development in adult asthmaticsNot all adult asthmatics are at higher risk of developing CAD. Studies have shown that between asthma control and MI risk, there is a significant dose-response relationship, with the risk being highest in individuals with uncontrolled asthma compared to adults with controlled asthma . This imLimitationsThe study is subject to some limitations, such as a lack of high-level evidence such as systematic reviews, randomized controlled trials, and meta-analyses. A small number of available clinical trials served as the basis for all of the research. All the research revealed that sample sizes and measurements varied. The variables and secondary outcomes used in all the research under consideration varied. The fundamental causes of these disparities between studies regarding the role of gender in asthmatics with CAD are unclear, and future research from nations with diverse ethnicities may serve to shed light on this discovery. We may be able to pinpoint treatment targets if we can clarify the clinical importance and mechanism of the pathophysiology of CAD in adult asthma patients. To decrease the cardiovascular mortality of asthmatics, additional research should be done to define the involvement of adult asthma features and their treatments in the development of CAD. Information from papers written in languages other than English was not included in this evaluation because it only contained English-language articles. Studies using animals were also omitted. Only studies done on human subjects were included in the review.We found strong evidence to support the role of adult asthma in the development of CAD, attributing the chronic inflammatory nature of both chronic diseases as the primary cause of the pathogenesis. Due to the hormonal effect of estrogen on the inflammatory cells, CAD is more commonly found in the female asthmatic population. More studies should be undertaken to unmask the key regulators of asthma influencing coronary vessel damage so that specific target therapy can prevent catastrophic outcomes in asthmatics. The risk rises in uncontrolled asthmatics or in those with rapid declines in ventilatory function, thus proving the importance of asthma control in avoiding CAD incidences. The role of beta-2-agonists in the progression of CAD is unclear and requires further research.


This is a showcase for technical description of a full digital workflow aimed to reconstruct and prosthetically rehabilitate the mandible after surgical resection. The surgery was performed following a computer-aided design and computer-aided manufacturing (CAD-CAM) guided workflow, using 3D reconstruction of the mandible and the fibula. After 2 years, when the ossification of the flap was reached and verified by a computed tomography (CT) scan, surgery was performed using a two-step implant rehabilitation, with successful outcomes. Maxilla and mandible are critical components of the facial skeleton, with several functional and aesthetic attributes. Total or subtotal resection can lead to severe impairment of the patient’s quality of life. The goal of reconstructive surgery is to restore patient symmetry and functionality as close as possible to their premorbid state. This is particularly important because the jaws represent the only toothed portion of the skeleton, with multiple functions such as mastication, breathing, swallowing, speech and lip competency, located in a cosmetically demanding region of the head and neck district.Ameloblastoma is a rare aggressive odontogenic epithelial tumor: it is a slow-growing but locally invasive benign neoplasm involving the mandible (80%) and maxilla . The mosSurgery is the gold standard treatment for ameloblastomas, but the type of resection depends on tumor size and location. According to Dell’Aversana Orabona et al. , gross tSeveral donor sites of vascularized bone free flaps for head and neck reconstruction have been described in the literature. The fibula free flap is considered one of the main surgical option for mandibular reconstruction after tumor resection .Dental prosthetic rehabilitation of large maxillofacial defects using free tissue transfer and endosseous implants is considered the standard of care and the fibula flap provides favorable bone quality and quantity to receive and integrate dental implants to facilitate prosthetic rehabilitation ,5,6. UsuUntil recently, the results of the surgical restoration relied on surgical skills and it was an operator-dependent procedure with unpredictable results. Today, the application of computer-aided design (CAD) and computer-aided manufacturing (CAM) in the medical field allows surgeons to plan cases virtually and create personalized surgical devices, reducing surgical time and minimizing the chance of failure during the reconstruction. The free fibula flap has some limitations due to the height and contour of the fibula, but the rise in VSP  and the progression in the prototypization techniques of surgical guides and implants helps overcome the challenges of the procedure to maximize functional and aesthetic results.This is a showcase for the technical description of a full digital workflow aimed to reconstruct and prosthetically rehabilitate the mandible after surgical resection.A 41-year-old woman was admitted in our unit for an ameloblastoma of the left mandible. Clinical examination revealed a swelling of the alveolar region from 3.2 to 3.8 with irregular edges and firm consistency. The orthopantomography (OPT) and the head and neck computer tomography (CT) scan with thin slices of 1 mm showed an osteolytic lesion, with multilocular radiolucency extending from 3.2 to the ascending ramus of the left side .Incisional biopsy of the lesion was performed and showed a solid ameloblastoma. A CT angiography of the lower extremities was performed to evaluate the vessels and bone for the FFF.The patient underwent a partial mandibulectomy : a full digital workflow for the microsurgical reconstruction with free fibula flap and prosthetic implant rehabilitation is described below.https://horosproject.org/). On the basis of the digital imaging (DICOM) data acquired from the CT scan, the mandible was reconstructed in 3D using InVesalius software   to produce a standard triangulation language (STL) file of the patient’s mandibular and fibular bones  3D printer  with surgical guide resin (Formlabs) at a 0.1 mm printing resolution. After printing, the models were removed from the build platform and washed for 20 min in a Form Wash (Formlabs) filled with 99% isopropyl alcohol to clean the parts and remove the liquid resin. Then they were post-cured at 60 °C for 30 min in a Form Cure (Formlabs) to achieve biocompatibility and optimal mechanical properties.Prior to the surgery, the physic models were used to model the titanium reconstruction plates; then, the osteotomy surgical guides and the titanium plates underwent a sterilization using a low temperature hydrogen peroxide plasma technology  .The surgery was performed under general anesthesia. A mucosal incision from 3.8 to 4.3 was performed and after the jaw exposure, the surgical osteotomy guides were fixed to the bones with titanium screws . Mandibular and fibula osteotomies were performed using a surgical saw and a piezoelectric device . The bony segments were connected using the titanium plates designed and modeled on the digitally planned model. Microvascular anastomoses were performed inside the neck, the peroneal artery was anastomosed end-to-end to the facial artery, while meanwhile one of the peroneal vein was anastomosed end-to-end to a major tributary of the internal jugular vein. A skin paddle was used to cover the mucosal gap.At 2 years of follow-up, a CT scan was performed to time the optimal placement of the implant rehabilitation.Implant rehabilitation was carried out using a guided CAD-CAM technique to avoid interference with the reconstruction plate. The procedure was performed under local anesthesia: an intraoral incision in the buccal vestibule was performed and the alveolar ridge was exposed. Four endosseous implants (Tekka In-Kone) were positioned, as programmed in the virtual plan, through a dental- and crestal-supported surgical guide.One month later, after a radiographic confirmation of osseointegration, the final implant-retained prosthesis was placed to complete the oral rehabilitation. There was no need for a flap thinning prior to the implant placement. .After obtaining the radical resection, the histological diagnosis confirmed the initial ameloblastoma suspect. A significant bone defect of 33 cm in length was identified and subsequently removed, followed by successful reconstruction. The surgery and immediate postsurgical care were uneventful, and no complications such as allergies or infections were observed.The removal of plates and screws was not performed. The patient did not report any discomfort related to the plates and screws; moreover, the CAD/CAM workflow allowed the implants to be positioned without interfering with the reconstruction plate and its screws.The mandibular reconstruction procedure achieved a positive outcome, with the digitally planned 3D models demonstrating excellent alignment with the final surgical results. To produce the model and guide, the total cost incurred was about EUR 4.6; meanwhile, the complete service for the start-up process of a CAD/CAM system costs between EUR 4000 and EUR 6000. Overall, the surgical intervention and reconstruction proved successful, providing an effective solution for the ameloblastoma-related bone defect and the expenses associated with manufacturing the 3D models and guides were reasonable.The reconstruction of mandibular defects is a complex procedure due to the anatomic and functional features of the bone.The fibula free flap (FFF) has become the gold standard for surgical reconstruction of mandibular bony defects since Hidalgo first used it in 1989 [The FFF is the most used vascularized bone graft (VBG) used in orofacial reconstructions because it provides adequate bone length, long vascular pedicle and bicortical architecture, increasing primary implant fixation. Implant failure rates in fibula free flaps are higher compared to the native mandibular bone; in any case, a success rate exceeding 91% has been reported [The main difficulty of a FFF in a mandibular reconstruction is represented by the modeling and reshaping of the fibula to achieve proper volume and height for the future dental implant rehabilitation. Another critical step is the intra-surgical correct modeling of the titanium plate, in order to avoid a plate breakage after improper adjustments and reshaping. Since Hirsch et al.  first deThe advantages of surgical CAD/CAM reconstructive procedures include ideal presurgical planning for tumor resection and surgical reproducibility for site and orientation osteotomies. The main disadvantages are the cost and the product delivery time.As showed by this case, CAD/CAM prototypization allowed modeling of the titanium plate prior to surgery, minimizing the stress and the bending fatigue of the plate and reducing the risk of fracture. Moreover, the digital creation of osteotomy guides offered a good bone-to-bone contact between the distal fibula segment and the residual mandible, maximizing the post-reconstruction facial symmetry. The digital surgical planning offers a noticeable reduction in operation time, reducing both the blood loss and the risks of ischemia of the fibula flap .In order to reduce the ischemic time of the fibular flap, the donor pedicle should not be dissected from the lower leg until the harvested fibula has already been shaped and the recipient vessel prepared .Dental implants are one of the important factors involved in the multidisciplinary rehabilitation of patients who have undergone a surgical resection of the maxillofacial district. Improving the optimal aesthetic and functional outcomes for patients with mandible ameloblastoma can be achieved using dental implants. A successful dental restoration can be more challenging on these particular types of patients because of the surgical resection of bone and the damage of the soft tissue, mostly the oral mucosa.A functional and stable prosthetic rehabilitation after tumor resection can only be achieved using osseointegrated implants; due to the retention of bone height, they provide a reliable long-term stability, whereas removable partial dentures retained by clasps to the remaining teeth are associated with gradual bone loss.A possible drawback of the fibular flap is a relative lack of bone height, but this limitation can be overcome by double-barreling the fibular flap for the mandibular reconstruction.The CAD/CAM workflow allows for a highly accurate implant placement, allowing the insertion of implants to ensure maximum resistance to masticatory forces based on the thickness of FFF and minimizing the angular deviation between the central axes of the planned and final position of the implant.As reported by Ch’ng et al., it is difficult to define an appropriate protocol for the placement of implants in patients with head and neck cancer  and mostSeveral factors must be considered for the timing of a postsurgical dental implant rehabilitation in a VBG; among these, the donor site morbidity is paramount.Placing the osseointegrated implants with a 6–24 months delay after the reconstructive surgery allows for optimum control of the fibula flap vitality, reducing the possibility of a flap failure after the implant rehabilitation.A proper healing time before the implant’s placement ensures a good bone regeneration, which should be evaluated by an OPT and should include an appropriate remodeling and adaptation of the intraoral soft tissue surrounding the reconstructed segment . Hence, The fibula free flap is considered to be one of the main surgical options for mandibular reconstruction after large bone resections, especially in cases of a benign lesion, such as ameloblastomas. The CAD-CAM presurgical planning can provide optimal bone healing, ensuring the vitality of the free flap and allowing for the anatomical and functional rehabilitation of the mandible, using dental implants, and improving the patient’s quality of life. Appropriate timing of the placement of dental implants is critical to guarantee the successful outcome in patients who need this type of reconstruction.


Over the past few years, pharmaceutical and biomedical areas have made the most astounding accomplishments in the field of medicine, diagnostics and drug delivery. Nanotechnology-based tools have played a major role in this. The implementation of this multifaceted nanotechnology concept encourages the advancement of innovative strategies and materials for improving patient compliance. The plausible usage of nanotechnology in drug delivery prompts an extension of lipid-based nanocarriers with a special reference to barriers such as the skin and blood–brain barrier (BBB) that have been discussed in the given manuscript. The limited permeability of these two intriguing biological barriers restricts the penetration of active moieties through the skin and brain, resulting in futile outcomes in several related ailments. Lipid-based nanocarriers provide a possible solution to this problem by facilitating the penetration of drugs across these obstacles, which leads to improvements in their effectiveness. A special emphasis in this review is placed on the composition, mechanism of penetration and recent applications of these carriers. It also includes recent research and the latest findings in the form of patents and clinical trials in this field. The presented data demonstrate the capability of these carriers as potential drug delivery systems across the skin  as well as to the brain, which can be exploited further for the development of safe and efficacious products. In the human body, biological barriers such as the skin, blood–brain barrier (BBB), mucosal membranes and membranes around cells and nuclei etc, limit the delivery of drugs to the desired sites to achieve the necessary therapeutic actions. On the one hand, these barriers protect the human body from invading pathogens and on the other hand, they limit drug transport. Therefore, much research has been explored to overcome this obstacle which in general involves two main approaches, including the formulation-based and device-based approaches. In the device-based approach, novel devices have been designed, often operated by expensive power sources, to overcome the barriers and impediments. They disrupt the structure of the organ temporarily and allow for the delivery of macromolecules through it ,2,3. AltSkin (the largest organ of the body) is comprised of three distinct layers including the epidermis (outermost layer); dermis (middle layer); and hypodermis (innermost layer). The epidermis is further divided into different layers and is primarily composed of keratin, which acts as a substantial barrier to drug permeation and has a thickness of 53 μm . The supThe delivery of drugs to the central nervous system (CNS) has been a challenging as well an active area of drug development, attributed to the presence of the BBB . This isThe burgeoning application of lipid-based nanocarriers in pharmaceutical formulations for the delivery of diversified therapeutic agents is gaining momentum over the last decades . They haThis review includes a discussion of several lipid-based nanocarriers, their composition and applications. It also includes recent research and development findings  regarding the use of lipid-based drug delivery systems across the skin and BBB for disease treatment. This work also summarizes recent findings from different known databases, which are Google Scholar, Google patents, Science Direct, MEDLINE (PubMed), Scopus and SciFinder. This article compiles the latest progress in the performances and advantages of the said carrier systems in dealing with these interesting yet challenging biological barriers. This not only generates evidence to support the applications of these delivery systems against the major biological barriers of the human body, but also encourages future research in this arena for more successful therapeutic outcomes by overcoming these challenges.Rampant applications of multifunctional nanoparticles in the pharmaceutical arena have gained attention in the last few decades, which have led to the accelerated development of therapeutic and imaging agents . For theSolid lipids are the main components of lipid-based nanocarriers. Depending on the chemical composition of the lipids they can be classified as homolipids, heterolipids and complex lipids. Homolipids are known as simple lipids containing esters of fatty acids and alcohol. They contain only carbon (C), hydrogen (H) and oxygen (O), and are the primary materials of interest for oral delivery vehicles. The long-chain fatty acids (ranging from C14 to C24) appear usually in common fat while the medium-chain fatty acids (ranging from C6 to C12) are typical elements of coconut oil or palm kernel oil. Beeswax, carnauba wax, glycerides and sterides are examples of homolipids. Heterolipids, also known as compound lipids, are lipids containing nitrogen (N) and phosphorus (P) atoms in addition to the C, H and O. Phospholipids that are widely used in pharmaceuticals are an example of this type of lipid. Two main classes of phospholipids that occur naturally in qualities sufficient for pharmaceutical applications are phosphoglycerides and phosphosphingolipids. Some phosphosphingolipids such as ceramide are used mainly in topical dosage forms. Phospholipids can be obtained from all types of biomasses as they are essential structural components in all kinds of membranes in living organisms. Glycolipids and sulfolipids are other two examples of heterolipids. The complex lipids occur closely associated with proteins present in cell membranes and subcellular particles. Active tissues generally have a higher complex lipid content and may also contain phospholipids, lipoproteins, chylomicrons, etc. Lipoproteins are spherical lipid–protein complexes that are responsible for the transport of cholesterol and other lipids within the body .Lipids are hydrophobic molecules which are insoluble in water and have been used for making different pharmaceutical formulations. They improve the solubility, absorption, permeation and hence the bioavailability of poorly soluble drugs with relatively less-toxic effects. The biocompatibility, biodegradability and nontoxic nature of these molecules make them more popular for the designing of nanocarriers for biomedical uses . DiffereAlthough the exact mechanism of action for the penetration of these systems is not known, some of the mechanisms of such vesicles in altering the skin permeability have been suggested, such as (i) penetration of the whole drug-loaded vesicle into the layers of the skin; (ii) they might act as penetration enhancers by fluidizing skin lipids; (iii) direct carrier–skin drug exchange by “collision complex transfer”; and (iv) lipid vesicle-interceded drug delivery through skin appendages such as hair follicles and sweat ducts. Besides all these functions, they enhanced the adhesiveness, hydration, occlusion and lubrication of the skin ,33,34,35Further, the smaller size of these nanocarriers (10–200 nm) allows them to cross the BBB and penetrate through the brain by the endocytosis mechanism . AdditioLipid-based nanocarrier systems are highly biocompatible and biodegradable systems, successfully used as carriers for poorly water-soluble drugs and oligonucleotides (DNA/RNA) in gene therapy. Further, they can be used for encapsulating active ingredients for targeted drug delivery in the body. The following section describes different lipid nanocarriers used in the pharmaceutical arena.Liposomes are small, spherical vesicles that contain natural or synthetic non-toxic phospholipids as their key ingredients. They have an aqueous core surrounded by a hydrophobic lipid bilayer membrane in such a way that the hydrophilic solutes dissolved in the core cannot readily pass through the bilayer. Both hydrophilic and hydrophobic molecules can be loaded in liposomal vesicles and hence can be used for drug delivery. The liposomes can be classified as unilamellar vesicles (having one bilayer membrane), oligo lamellar vesicles (having 2–5 bilayer membranes) and multilamellar vesicles (having 5 or more bilayer membranes). Unilamellar vesicles are further subdivided into three categories that include small unilamellar vesicles, large unilamellar vesicles and giant lamellar vesicles. Among these, unilamellar vesicles are mostly used in drug delivery because of their small size , uniform drug capsulation and they release kinetics together with long circulation times . The disThe majority of the conventional liposomes are restricted to the first layer of the epidermis and are unable to reach systemic circulation. Hence, they are restricted to use in local dermal drug delivery and demand new classes of nano lipid vesicles for enhancing flexibility and skin permeation. However, in the case of the brain, the interstitium is dense and highly charged, thus restricting the movement of many classes of nanocarriers within the CNS. This issue can be circumvented by liposomes with surface modifications that mask the particle charge, thus allowing for more uniform brain penetration. Secondly, the modification of nanocarriers with targeting moiety can enhance retention in a diseased site. Therefore, the disrupted BBB can be targeted with liposomes that are specifically formulated for penetration and retention at the diseased location .Liposomal formulations can be further categorized into (1) rigid vesicles (liposomes and niosomes) and (2) elastic or ultra-deformable vesicles (transferosomes and ethosomes). Their composition, structure and preparation methods are more or less similar; however, their differences relate to their deformability and mechanism of penetration through the skin .These are non-ionic surfactant vesicles composed of single-chain surfactant molecules in combination with cholesterol. These surfactants form an enclosed bilayer in a water medium. The presence of surfactant alters the permeation through biological barriers and makes it more penetrable with enhanced systemic absorption. These systems are capable of carrying both lipophilic and hydrophilic drugs and comparatively more stable than traditional liposomes . They ofNiosomes can penetrate into the skin by adsorption onto the cell surface with little or no internalization of either aqueous or lipid components. It may take place either as a result of attracting physical forces or as a result of binding by specific receptors to ligands on the vesicle membrane, thus transferring the drug directly from vesicles to the skin. Further, niosomes may fuse with the cell membrane, resulting in the complete mixing of the niosomal contents with the cytoplasm. Lastly, niosomes may undergo endocytosis, with lysozymes present in the cytoplasm degrading the membranous structure of the niosome, thereby releasing the entrapped material into the medium vehicle, which can be achieved by forming a niosomal gel . NiosomeThese are non-invasive, phospholipid-containing nano lipid carriers that are more efficient at delivering drug molecules into the skin in terms of both the quantity and depth as compared to the other vesicles. They are mainly composed of lipids, ethanol and water. The percentage of ethanol in this vesicular system has been reported to be in the range of 10–50% . It has These can be prepared by four principal methods including the cold method; hot method; classic method; and mechanical dispersion method ,74. ThesThe enhanced delivery of drugs through ethosomes may be ascribed to an interaction between ethosomes and skin lipids. The presence of ethanol interacts with the polar heads of the lipid molecules, resulting in a reduction in the transition temperature of the lipids present in the stratum corneum, thus improving their fluidity and reducing the density of the lipid layers ,76,77. TTransethosomes are a combination of transferosomes and ethosomes. Transferosomes are composed of phospholipids and an edge activator (single-chain surfactant) that weakens the lipid bilayers and increases their deformability by reducing the interfacial tension. These have a deformable quality as well as a skin permeation capability and can be taken up by systemic as well as topical routes. Ethanol is a central character of transethosomal systems, giving a unique identity to them as a vesicular system. It is believed that the first part of the mechanism is due to the “ethanol effect”, whereby the intercalation of the ethanol into intercellular lipids increases lipid fluidity and decreases the density of the lipid bilayer. The lipid layer of the stratum corneum is fluidized by the impact of ethanol and its high concentration in transethosomes promotes the malleability and flexibility of these systems, enhancing their penetration through tiny openings formed in the stratum corneum due to fluidization. The presence of the alcohol amount in the vesicular system also controls its diameter, as it provides a net negative charge to the vesicle surface by reducing its size . TransetSLNs are one of the novel carriers in the pharmaceutical industry for the delivery of multiple drugs ,82. SLNsNLCs emerged as the second generation nano lipid carriers to surmount the limitations of first generation nanocarriers. NLCs are nanocarrier systems derived from oil-in-water-type nanoemulsions. They are composed of lipids , water and emulsifying agents/surfactants/co-surfactants. These are formulated by mixing solid lipids with small amounts of liquid lipids, which results in the rearrangement of the matrix structure. The components used in formulating the NLCs include oils , solid lipids , counter-ions  and emulsifying agents  . NLCs anThe advantages of NLCs can be listed as: a decreased polymorphic transition, little crystalline index, enhanced encapsulation efficiency, drug loading, physical stability, chemical stability and bioavailability, with the controlled release of the encapsulated components. Moreover, they can be altered with various targeting ligands such as peptides, antibodies or even small targeting moieties. Comparatively, the disadvantages include the irritation and sensitizing action of the surfactants; cytotoxic effects related to the nature of the lipid matrix and concentration; and the efficiency in the case of proteins, peptide drugs and gene delivery systems that need to be exploited . Both SLBoth SLNs or NLCs having a particle size of less than 200 nm show good adhesiveness over the skin by forming a monolayer. This hydrophobic monolayer film exhibits occlusive action on the skin and hinders the loss of moisture owing to evaporation. This results in a reduction in the corneocyte packing and the opening of inter-corneocyte gaps, hence facilitating drug penetration into the deeper layers of the skin. The loss of water content from the SLN induces crystal modification of the SLN matrix and this can induce drug expulsion and penetration . MoreoveThis has an oil-like lipid matrix and is usually prepared by incorporating drugs in the internal oil phase or at the interface of oil–water . Thus, dThese are also good vehicles for drug administration through the skin. LNEs are used to augment physicochemical properties that are desirable for transdermal drug delivery systems. They can enhance adhesiveness and hydration when they are applied over the skin. Nanosized fragments are able to form a thin film on the skin surface, thus enhancing the pore obstruction and hence reducing the water evaporation from the skin by maintaining skin hydration. LNEs are used for improving drug absorption through the skin, providing protection from degradation through the oral route, reducing irritation and offering a sustained release action ,97. ThesOn the other hand, these have many factors that limit their uses, such as the use of ultrasounds or high-pressure homogenizers, the use of high concentrations of emulsifier, expensive production, the lack of knowledge about the mechanisms that affect and cause problems during their production , etc. .Microemulsions are transparent, thermodynamically stable, colloidal drug carrier systems consisting of isotropic mixtures of oil, water and surfactant, often in combination with a cosurfactant. Usually, they have a droplet size of less than 100 nm and hence cannot be seen by the naked eye. Although microemulsions and nanoemulsions are completely different systems from the thermodynamic point of view, the size of the microemulsion may create confusion with a nanoemulsion. Microemulsions have a simple fabrication method, good stability, increased solubilization and bioavailability with a reduced cost which makes them suitable for practical applications ,102,103.Microemulsions act as potential drug delivery systems through biological membranes. The efficacy of a microemulsion can be related to the improved solubilization as compared to conventional dosage forms. Further, the specific composition of microemulsions and the presence of surfactants and co-surfactants (may act as co-solvents for poor water-soluble drugs) can interact with the stratum corneum (as permeation enhancers) and enable the penetration of active ingredients through the skin ,105,106.The delivery of drugs across the skin can be used for achieving local  as well as systemic  actions. The local dermal delivery effect can be superficial, but for systemic delivery the release rate and penetration of the drug are significant factors for showing the therapeutic action. Transdermal drug delivery is an advanced route of drug conveyance for therapeutics activity, where the formulations containing the active ingredients are applied against the skin from where these molecules are absorbed slowly into deeper tissues. Subsequently, they either target receptors or enter into the systemic circulation and show the desired action. Transdermal delivery has several benefits, such as lower fluctuations of plasma drug levels, sustained or controlled drug release, circumventing first-pass metabolism, improving patient compliance compared to other delivery systems, etc. ,109. TheLipid-based nanocarrier systems have been developed to deliver the active moieties via several application routes, such as parenteral, skin, oral, ocular, nasal and pulmonary inhalation. Among them, skin delivery is one of the most investigated pathways for drug conveyance. It is well known that the human skin is a multifunctional organ. Besides other functions, it also acts as a delivery route for drugs by circumventing many of the limitations of oral and parenteral administration. The application of therapeutic products over the skin surface is one of the methods used for administering drugs. It is suggested that cutaneous administration of lipid-based nanocarrier systems is relatively safe by evading direct contact and also lessens the risk of acute and chronic toxicity. However, the barrier property of the skin restricts the effective permeation of the carriers which demands a safe and efficient system that provides an anticipated therapeutic action with minimal toxicity. Drug delivery through the skin is a relatively safe method with reduced side effects as compared to other routes for treating diseases. The skin helps to mitigate the illness either by localized applications  or by systemic absorption , depending upon the intended use. Skin administration avoids the hepatic first-pass effect and an enhanced localization of bioactive through skin organelles such as hair follicles. Lipid-based nanocarriers have been found to have the capability to treat diseases safely mainly due to the biocompatibility and the versatility of the lipids. Other advantages of this system may be listed as an improved drug stability, occlusion, skin hydration, penetration, retention and efficacy of the drug as compared to other drug nanocarriers. This type of delivery approach increases the concentration gradient in the upper skin layers and facilitates the gradual release from the system without causing cytotoxicity or morphological alterations in the skin layers. The various mechanisms by which a drug can pass through the skin can be listed as inter-cellular, trans-cellular and trans-appendages. The penetration mechanism through the skin depends on the physicochemical characteristics of free drugs  and the drug delivery system   for a transdermal application. The objective of the study was to examine the potential of ethosomes as lipid nanocarrier vesicles for the transdermal enhancement of the model of a poor-soluble drug. The optimized ethosomal suspension showed a vesicular size of 165.71 ± 2.73 nm and zeta potential of −36.63 ± 2.78 mV. This release study demonstrated a superior sustained release over 24 h as compared to a plain gel incorporating Ranolazine. An MTT assay demonstrated increased cytotoxic potential of the drug on the H9C2-mouse cardiomyoblast cell line. In conclusion, the prospective ethosomal vesicles proved to have better safety, efficacy and patient compliance with minimum skin irritation through the transdermal route .Another study demonstrated the formulation and evaluation of an NLC loaded with Olmesartan medoxomil an antihypertensive agent to overcome its poor bioavailability. The formulation was prepared by high-speed hot homogenization and the melt emulsification low-temperature solidification method and then was used as transdermal patches. The optimized NLC was found to possess a particle size, zeta potential and entrapment efficiency of 284 nm, −24.16 mV and 80.17%, respectively. The study concluded that the bioavailability of the drug was improved appreciably as compared to the pure drug and drug-loaded NLC for the oral route .Centella asiatica transfersomes and rosemary essential oil nanoemulsion. Here, this combination was used to synergistically prevent UVB radiation effects on the skin with the help of lipid-based nanocarriers for their anti-aging actions. The result showed that the size (less than 200 nm) and the physicochemical properties of lipid-based formulation increased the delivery of the active ingredients by overcoming the skin barrier. Further, the in vivo experiments revealed that the topical application of the gel could act synergistically and have the potential to prevent oxidative stress and collagen degradation in the skin from UVB-induced photoaging [One recent study investigated the properties and function of a gel combining the otoaging .Another study developed and optimized potential NLCs embedded in transdermal patches for enhancing the transdermal delivery of capsaicin for skeleton–muscular and neuropathic pain. This research claimed that due to the exceptional properties and particle size (under 200 nm) of the lipid nanocarriers, capsaicin entrenched in the formulation penetrated faster in the epidermis and to a deeper extent than free capsaicin. These patches offered a sustained release and a superior accumulation in the deeper skin layers as compared to those containing free capsaicin in the form of conventional patches. Further, capsaicin NLCs-loaded patches exhibited comparatively lower skin side effects (in terms of skin irritation) than the conventional capsaicin patches, concluded from animal skin irritation experiments .One of the investigations depicted the formulation and evaluation of naproxen transethosomal gel for sustained transdermal delivery for the management of musculoskeletal pain utilization. Transethosomes were prepared via the ethanol injection method and incorporated in carbopol 940 hydrogel. They were spherical in shape having a particle size in the range of 56.94 nm to 291.7 nm. The in vitro skin permeation study displayed an enhanced skin deposition and the in vivo studies showed the efficiency of naproxen transethosomal gel in lessening the oedema rate. The authors concluded that the developed formulation could be considered a perfect alternative to the conventional gel for managing musculoskeletal pain .One more study was carried out on tocopherol succinate-loaded ethosomal gel for its delivery and evaluated its moisturizing, antioxidant and anti-aging effects. This formulation was prepared via the cold method and the particle size was found to be 179.1 nm with good entrapment. The in vitro release study showed an initial burst release pattern, the ex vivo permeation study showed increased drug accumulation into the layers of the skin and the in vivo study using a chronometer and cutometer demonstrated good moisturizing and mechanical properties, and good physical stability .Another study formulated topical Apremilast-loaded NLCs gel for the management of psoriasis by using Compritol 888ATO, oleic acid, Tween and Span, and Transcutol P and finally dispersed in Carbopol. In vitro drug diffusion and ex vivo skin permeation results confirmed the potential of the NLC form of poorly water-soluble drugs for topical applications and improved drug deposition in the skin .A different study investigated the simvastatin NLC-loaded transdermal patch prepared via the solvent evaporation method for its bioavailability enhancement, bypassing hepatic metabolism. Simvastatin is highly lipophilic but has been excreted very efficiently in an unchanged form after oral administration, making only 5% of drugs bioavailable for this therapeutic effect. This study proved that a transdermal patch showed an enhancement in the bioavailability of simvastatin as compared to the marketed oral dosage form, with an enhanced bioavailability and therapeutic effect .In another investigation, a topical NLC formulation of the corticosteroid anti-inflammatory drug betamethasone dipropionate containing oleic acid was prepared to facilitate its penetration into the deeper layers of skin by overcoming systemic side effects. The NLC was prepared by high shear homogenization followed by the sonication method and was shown to penetrate more efficiently into the skin layers as compared to a traditional cream. Further, NLC formulations that comprised a higher percentage of oleic acid showed higher penetration through the skin .One study described a novel topical SLN preparation of piroxicam for transdermal delivery with oleic acid as a penetration enhancer. The prepared SLNs have particle sizes is around 102 ± 5.2 nm with a zeta potential 30.21 ± 2.05 mV. It showed good compatibility between piroxicam and the vehicle components with a higher entrapment efficiency and sustained release pattern. The optimized SLN showed a quick anti-inflammatory action beginning in the 3rd hour after its application and proved to be a promising carrier for the encapsulation and sustained release of piroxicam, with great anti-inflammatory potential .® 888 ATO, Lanette® O and oleic acid for treating inflammatory conditions of the skin. All three formulations were compared in terms of their effectiveness against the said condition. They observed that all the formulations had a high drug payload, physical stability and drug-excipient compatibility. These formulations improved the skin penetration rate of the drug by three to four times as compared to a traditional gel incorporating LRX. Further, the nanoemulsion showed the highest rate of drug penetration through animal skin followed by NLC, SLN and a gel formulation. Thus, this study suggested all three formulations of LRX can be used topically for relieving painful and inflammatory conditions of the skin with decreased side effects compared to existing oral products [In one study, SLN, NLC and nanoemulsion of lornoxicam (LRX) were prepared by using Compritolproducts .Another study described the enhancement of the dermal retention and reduction in associated side effects of the poor water-soluble polyphenolic compound in azelaic acid for treating acne and rosacea by formulating NLCs. These were prepared via the solvent diffusion–solvent evaporation method for sustained release action. The mean particle size of azelaic acid-loaded NLCs was 81.57 ± 9.6 nm with a low PDI and high negative zeta potential. The authors concluded that the developed NLCs have enormous potential to improve the penetration of azelaic acid through the skin, which is the requirement for the topically applied formulations for the management of skin diseases by avoiding systemic adverse effects associated with its usage .From the above-cited research, we can conclude that lipid-based nanocarriers are widely used for both the local and systemic delivery of drugs across the skin. They display relatively greater effectiveness as compared to free drugs with sustained action, good stability, compatibility and fewer skin side effects. They also avoid systemic adverse effects associated with oral dosage forms with improved patient compliance. Additionally, these lipid-based systems also show good effectiveness for poorly water-soluble drugs as evident through various in vitro, ex vivo and in vivo studies.The BBB is the primary obstruction for CNS delivery by controlling the influx and efflux of biological substances. This is a highly specialized structure composed of microvascular endothelial cells covering the cerebral capillaries penetrating the brain and spinal cord of most organisms. Brain microvascular endothelial cells control exchanges between the blood and surrounding cells but provide limited diffusion. This is because these cells assembling the microvascular lining of the BBB have no or less gap in the outer membrane. Along with these cells, the BBB also consists of two other cellular components including pericytes and astrocyte end-feet that combine with neuronal terminations to form the BBB ,133. TheDespite advanced CNS drug discovery, the majority of the CNS disorders remain undertreated because of the lack of an effective drug delivery system. It is well accepted that the failure of therapy is attributed not only to the potency of the drugs, but also to the presence of barriers that hinder the efficient delivery of the molecule (such as BBB in the case of the brain). Additionally, large molecular mass hydrophilic molecules carrying charge further exaggerate the problems because of the very poor diffusional properties in the biological milieu. However, the poor aqueous solubility and low potency of therapeutic agents in the CNS lead to higher toxicity and major side effects, demanding potential delivery models for brain treatment. Generally, to enter the brain drugs should pass through the endothelial cells. Primarily there are two passages for this purpose that can be described as: (1) the paracellular pathway  which could be used for the transportation of ions and solutes crossing the BBB, and (2) the transcellular pathway/transcytosis  which could be used for the transportation of many substances across the BBB. Normally, the transcellular pathway allows for the passive diffusion of lipophilic molecules with a size of less than 500 Da. It further allows for the transportation of gas molecules depending on specific receptors, the transportation of hydrophilic polar molecules such as glucose and proteins depending on specific transporters . These mechanisms could be employed to design nanomaterials for crossing the BBB. Caveolae is another transportation pathway in the brain which depends on a formed vesicle around the molecules through cellular invagination. Currently, the transcellular pathway has been widely investigated and several approaches have been devised for the transportation of drugs into the brain. Nonetheless, the active efflux pumps lessen the BBB-crossing efficiency of most of the drugs . The sysNanocarriers deliver the drugs into the CNS either directly after peripheral administration or alternatively through the naturally occurring trans-synaptic retrograde passage to enter the CNS from the peripheral nerves as described above. The intranasal route is another route by which a drug has directly entered the brain after intravenous administration by bypassing the BBB ,140,141.Lipid-based nanocarrier systems that are primarily comprised of natural, biocompatible materials and/or a combination of natural lipids may provide a solution for this problem. The size of these systems lies in the nano range which makes them flow in the systemic circulation, preventing macrophage uptake. The composition of these systems is generally similar to that of cell membranes hence, they have a minimum impact on both the intracellular and extracellular environments ,88. FurtRecent research describes the preparation and characterization of valproic acid NLC via the high-speed homogenization method through the nasal route of drug administration bypassing the BBB. The particle size of the NLC was found to be 142.5 nm which is in the optimal range for BBB permeation. The rate of release of Valproic acid from the optimized NLC was found to be 66.12% in 3 days and permeations of 26.55% in 6 h. The study results indicate that this NLC is efficient in being absorbed through the nasal route and delivering the drugs at a therapeutically sufficient concentration into the brain for treating epilepsy without causing damage to the BBB .Recent experiments designed and developed a transferrin-decorated NLC containing rapamycin. This drug has low water solubility, rapid in vivo degradation and an immunosuppressive effect. Further, the BBB-related challenges limit its clinical use for brain diseases. Here, NLCs were prepared to have particle sizes ranging from 120 to 150 nm and a good entrapment efficiency and showed ≥80% cell viability in the MTT assay. They displayed a significantly increased cellular uptake (97% vs. 60%) after 2 h of incubation and an appropriate brain accumulation with a lower uptake on U-87 MG glioblastoma cells. Moreover, rapamycin-loaded NLCs did not exhibit an immunosuppressive effect. In conclusion, Tf-decorated NLCs can be considered a safe and efficient carrier for the brain-targeting of rapamycin for treating neurological disorders [One latest study developed a targeted delivery system based on an NLC modified with two proteolytically stable D-peptides, D8 and RI-VAP called Dual-NLCs. D8 holds a high affinity towards nicotine acetylcholine receptors and can penetrate through the BBB efficiently. RI-VAP is a specific ligand of the cell surface GRP78 and a specific angiogenesis and cancer cell-surface marker, capable of circumventing the blood-brain tumor barrier (BBTB). The study showed that this formulation could penetrate through in vitro BBB and BBTB models with excellent efficiency and could internalize into brain capillary endothelial cells, tumor neovascular endothelial cells and glioma cells with high specificity as compared to non-targeted/mono-targeted NLCs. Maximum therapeutic efficiency was established by an in vitro cytotoxicity study. Further, the superior targeting capability and the efficient anti-glioma behavior were confirmed through an animal study. Conclusively, this formulation has the potential for advanced brain cancer treatment with promising results .Another current study explains the berberine-loaded NLCs coated with chitosan (BER-CTS-NLCs) via the intranasal route for treating Alzheimer’s disease. The size of the formulation was found to be 180.9 ± 4.3 nm having sustained-release properties, a surface charge of 36.8 mV and improved ex vivo permeation through nasal mucosa It has been found that the intranasal formulation of BER-CTS-NLCs is a more efficient system for maintaining greater drug levels in the brain with increased drug targeting efficiency as compared to a BER solution. Authors concluded that the optimized NLCs are speculated to be a successful approach for improving the action of BER in treating Alzheimer’s disease through the proposed route .In one more study, Riluzole-loaded NLCs were formulated and functionalized with lactoferrin (Lf), which improved conveyance within the BBB by interacting with Lf receptors in the endothelium of the brain to treat the neurodegenerative disease Amyotrophic lateral sclerosis. Nanoparticles exhibited a particle size in the range of 180 and 220 nm, a narrow size distribution and at least 3 months of stability. The encapsulation efficiency was found to be 94–98%. By formulating riluzole-loaded NLC, the brain targeting increased by overcoming the BBB. Further, the authors claimed the biocompatibility of the formulation through an MTT assay and the stability of the system for 3 months with the suitability of the delivery system for the brain .C. elegans, and the results demonstrated no toxicity for all tested formulations in varieties of concentrations [In a current investigation, omega-3 (ω-3) fatty acid nanoemulsions (NEs) loaded with curcumin (CUR) and quercetin (QU) were prepared and claimed to have improved treatments efficiency, as they had the potential to increase the nose-to-brain permeation of CUR and QU. These compounds possess good anti-inflammatory and antioxidant properties but have low water solubility and poor bioavailability, hence the nanoemulsion was designed to increase these limitations. The study claimed the stability and sustained release behavior of the system as described above for the efficient treatment of neurodegenerative brain diseases. Furthermore, the toxicity of the formulations was tested in an animal model, trations .Another study described the thymoquinone-enriched naringenin (NGN)-loaded NLC through the nasal route for mitigating depression. Here, Thymoquinone (TQ) oil was used as the liquid lipid and showed synergistic actions. The droplet size was found in the range of 84.17 to 86.71 nm with narrow PDI and good entrapment efficiency. The study proved that the release profile, permeation, antioxidant and pharmacodynamic behavior of the TQ-loaded NGN-NLC was better as compared to the NGN suspension through the nasal mucosa. In conclusion, the TQ-enriched NGN-NLC was proved to be an efficient system for the brain delivery to abate depression .One of the studies claimed a delivery system with macrophage (MA) membrane-coated SLNs on the surface of the MA membrane, created by binding the rabies virus glycoprotein (RVG29) and triphenylphosphine cation molecules for efficient antioxidant delivery to neuronal mitochondria. According to the investigation, the MA membranes masked the SLNs and prevented elimination via RES-rich organs by inheriting the macrophage’s immunological characteristics and helping to cross the BBB and selectively targeting neurons. This was possible owing to the presence of RVG29 on the surface. This Genistein-encapsulated DDS demonstrated the most favorable outcomes in relieving Alzheimer’s disease symptoms in vitro and in vivo via the synergistic action of the combination of MA membranes RVG29 and TPP .Another finding describes the treatment of Alzheimer’s disease by repurposing imatinib mesylate-loaded liposomes which were originally used as an anti-cancer agents. Liposome was fabricated to overcome the side effects and poor brain bioavailability of the drug. The particle size was optimized up to 150 nm with a sustained-release action up to 96 h. The authors claimed that there was improved brain deposition and enhanced residence time via the nose-to-brain administration for the liposomal formulation in comparison with simple drug solutions through pharmacokinetics study .Current research compared the poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) and SLNs for the intranasal delivery of meloxicam. The authors observed that SLNs displayed an increased encapsulation efficacy (EE) and drug loading (DL), mucoadhesion, permeation and in vitro release than particulate NPs. They claimed that there was improved brain deposition of the SLNs through animal experiments. In conclusion, the MEL-encapsulated C-SLNs are a promising carrier in enhancing the brain bioavailability of meloxicam through the intranasal route as compared to PLGA NPs .Another investigation explained the SLN of Rose damascene prepared via the micro-emulsion method with covalently attached lactoferrin onto the surface of the nanoparticles for targeted delivery. Rose damascene may increase memory and acetylcholine esterase inhibition but simultaneously has a hydrophilic content, and hence cannot pass the BBB. For this reason, SLNs were fabricated with a lactoferrin coating. The results revealed that the size, entrapment efficiency and drug loading were found to be 52 nm, 98, 93.6 before conjugation and 161 nm, 11.2, 15.9 after conjugation, respectively The pharmacodynamics study result showed that the formulation can improve short-term memory and may also decrease anxiety and depression in scopolamine-induced animals In a new study, Dopamine-SLN adsorbing proanthocyanidins (GSE/DA-SLN) were formulated by combining Dopamine (DA) and proanthocyanidins (antioxidant derived from grape seeds) for treating the oxidative stress related to Parkinson’s disease. The objective of the study was to control the missing DA and to increase the levels of the neurotransmitter that is needed for a patient suffering from Parkinson’s. However, these were unable to cross the BBB, hence an SLN was fabricated. Proanthocyanidins were found on the SLN surface and had efficacy in preventing DA autoxidation. They showed high mucoadhesive strength, no cytotoxicity through the MTT test and were claimed as an effective nose-to-brain delivery system for Parkinson’s disease .Another experiment explained the formulation of SLNs encapsulating Rutin for the effective brain delivery to target tumors through the BBB. Rutin-loaded SLNs were fabricated via the oil-in-water microemulsion technique, producing spherical-shaped particles with an average particle diameter of 100 nm and having stability for 5 days in circulation. In vitro studies proved the biocompatibility and stability of the formulation. The study concluded that the Rutin-encapsulated SLN formulations can have the capacity to target tumors across the BBB .One of the researchers described the development of a stable NLC system for carrying curcumin for brain cancer therapy. The formulation had a particle size of 146.8 nm, zeta potential of −21.4 mV and entrapment efficiency of 90.86%. This curcumin-loaded NLC showed increased cytotoxicity to the astrocytoma–glioblastoma cell line than simple curcumin. Further, the biodistribution studies showed higher drug concentrations in the brain after the intranasal administration of NLCs than that of the plain drug and proved to be a promising drug delivery system for brain cancer therapy .This current study describes the design, development and performance of the ligustrazine phosphate transdermal ethosomal system to treat Alzheimer’s disease for its antioxidant effect. The study result showed that the penetration ability, as well as the drug deposition in the skin of the ethosomal formulation, were significantly higher than those for the aqueous one. Further, this transdermal ethosomal system improved the behavioral performance in the animal models and offers a potential alternative therapeutic drug in the fight against Alzheimer’s .The present research described the formulation of nanosized drug delivery systems using liposomes and niosomes incorporating pramipexole for Parkinson’s disease. Furthermore, it evaluated the penetration and antiparkinsonian action of the nanosized, PEGylated pramipexole-encapsulated liposomes and niosomes. The in vitro evaluation for penetration using the BBB cell co-culture model for all formulations was also done. The in vivo effectiveness was also tested. The results showed that all formulations were BBB-permeable and displayed better effects at a lesser concentration than that of conventional pramipexole tablets used for routine treatments. The study concluded that the nanosized pramipexole-encapsulated neutral niosomes showed good therapeutic effects in animal models .This study investigated the niosomes incorporating the oral alkylating agent temozolomide with chlorotoxin surface modification for targeting glioblastomas. Surface modification with the peptide made it a highly potent system to target the glioblastoma cells of brain tumors. Temozolomide-loaded niosomes were formulated using the conventional thin-film hydration method, characterized and evaluated. The particle size of the chlorotoxin-loaded formulation was found to be 220 ± 1.45 nm with an entrapment efficiency of 79.09 ± 1.56%. Quantitative tissue distribution studies revealed that improved penetration of the drug into the brain may have been owed to the surface modification, with fewer depositions in the highly perfused organs .The current research was an attempt to systemically deliver a schizophrenia drug, Quetiapine Fumarate (QF), through a non-invasive intranasal route using NLC to overcome the challenges of the BBB. The desired QF-loaded NLCs were developed and monitored to improve the QF bioavailability and brain targeting abilities. The result showed that there was no morphological damage after administration. Further, the ex vivo study displayed a two-fold increase in the ex vivo nasal diffusion as compared to QF. The QF blood–brain ratio showed a 10-fold increase for NLCs administered through the nasal route (in comparison to the intravenous route), supporting retention of the drug at the desired site. The study supports a potential nose-to-brain transport of QF-NLC for the effective management of schizophrenia by circumventing the BBB .The above-mentioned studies described the capabilities of lipid-based nanocarriers for ameliorating brain disorders through different routes either by crossing or by circumventing the BBB. They support the retention of the drug at the desired site with enhanced residence time and no morphological damage. Further, they proved to be better than their conventional counterpart in relation to their bioavailability and therapeutic efficacy. These investigations might encourage researchers to investigate their future applications in this arena.Currently, lipid-based nanocarriers provide an outstanding potential and use as highly competent and safe treatment options by conquering the barriers of skin and BBB. The application of lipid nanoparticulates in skin drug delivery systems is increasing recently as they are safe, biocompatible, biodegradable, and have satisfactory pharmacokinetics and pharmacodynamics properties with enhanced benefit–risk ratios. They are efficient at providing protection against the degradation on the skin’s surface, creating a concentration gradient in the upper layer of skin and facilitating steady release. Further, they do not cause cytotoxicity or morphological alteration in the skin layers. The same effect can also be achieved for brain disorders by utilizing lipid-based nanocarriers, as they hold a promising natural tendency to distribute the drugs directly to the brain on account of their lipidic nature. Although they have potent applications to target the brain by crossing the BBB, the optimization of the dose should be accomplished to achieve an optimal therapeutic index. Along with the screening and stability of the lipid in the bloodstream, surface functionalization should also be investigated to limit the accumulation in normal tissues and/or the BBB. Further, limited evidence discloses the ability of lipids for brain delivery after oral administration by achieving sufficient therapeutic windows to enhance the permeability of the BBB. However, there are gaps in the literature regarding the form and concentrations of lipids required to produce the anticipated outcome. The use of lipid carriers for brain targeting through the oral route has not been investigated fully to determine with certainty if similar permeability-enhancing effects would be observed for parenteral administration, hence demanding a proper investigation. The physiological lipids and excipients that are used for fabricating these types of formulations are generally recognized as safe  and the


Saccharomyces cerevisiae established that the cell wall integrity (CWI) pathway is the central MAPK cascade required both to monitor the structural and functional status of this essential cell envelope and to trigger an appropriate salvage response under conditions that perturb its integrity [Adaptation to external changes is necessary for all cell types to survive and thrive in diverse environments. Key to these responses are the MAPK-mediated signaling pathways, intracellular communication routes that sense external stimuli at the cell surface and are ubiquitous in the eukaryotic world . Unlike ntegrity . Subsequntegrity . Therefontegrity .Saccharomyces cerevisiae or the pathogens Candida and Cryptococcus. In addition, they also address the role of the CWI pathway as a target for developing antifungal drugs and for manipulating the surface properties of fungi to improve productivity in industrial processes.In this Special Issue, expert researchers in this relevant subject have contributed with seven reviews and eleven original articles to advance our understanding of the CWI pathway by covering different structural, regulatory, and functional aspects in distinct yeasts and filamentous fungi. Yoshimi et al. summarize the current knowledge of CWI signaling in several filamentous fungal species, from sensor proteins required for the recognition of environmental changes to MAPK cascades and their targets involved in the regulation of cell wall polysaccharide synthesis genes . To discCandida albicans and its interconnections with other stress-activated pathways for remodeling the cell envelope under different stresses is reviewed by Ibe & Munro [Cryptococcus neoformans, and its involvement in some of the virulence traits of this pathogen, such as thermotolerance, melanin synthesis, capsule growth, and Titan cell formation [C. neoformans to enlarge cell size by increasing its protective external structure and undergoing such a characteristic morphological change has been extensively studied, as it allows the fungus to evade and resist the host immune system. These authors also emphasize the role of the CWI pathway as a pharmacological target that can be exploited to improve the effectiveness of existing antifungals as well as to develop new therapies.The importance of this signaling pathway in  & Munro . They anormation . The abiS. cerevisiae [Schizosaccharomyces pombe life cycle both during growth and in response to stress [S pombe and S. cerevisiae, highlighting the differences between these two model yeasts with distinct modes of growth [The function of the CWI pathway beyond the regulation of cell wall homeostasis is discussed in the reviews on budding and fission yeast models provided by González-Rubio et al. and by Cansado et al., respectively. In the former, the authors summarize the currently available methodologies to identify phosphorylation targets of Slt2, the MAPK of the pathway, and compile all the genuine Slt2 substrates reported to date, whose variety of functions reflects the multiple processes regulated by the CWI pathway in revisiae . They alo stress . Among to stress . They def growth .mtl1 mutants, suggesting a CWI-independent function for this sensor. Unraveling the role of the different receptors of the CWI pathway in cellular physiology promises to be an interesting field of research in the coming years.The research papers in this Special Issue present very significant insights into different aspects of various key components of this signaling pathway, ranging from receptors to effectors. Starting with the former, Schöppner et al. address the relationship between the structure and functional properties of the ScWsc1 receptor . By solvGFA1 expression, coding the glutamine:fructose-6-phosphate amidotransferase, a key enzyme within the conserved hexosamine biosynthetic pathway (HBP) essential for different metabolic pathways. Taken together, these results suggest the importance of Slt2 in modulating the bioenergetics of the protective response under ER stress, as well as confirm the key role of the CWI pathway in the crosstalk between different signaling pathways.This issue also provides new data that refine our understanding of the complex regulation and functional roles of Pkc1, the top kinase of the CWI pathway. Liu et al. demonstrate that this kinase is hyperphosphorylated in response to DNA damage in a Hrr25-dependent manner. Hrr25 (HO and Radiation Repair) is an orthologue of casein kinase 1 (CK1) and is involved in the transcriptional response to DNA damage . MutatioS. cerevisiae using high-dimensional morphological phenotyping. Comprehensive analysis of their morphological phenotypes provides strong clues about the functions of the affected proteins belonging to the same cluster of mutants, in particular the mechanistic and functional roles of the distinct glycoproteins in cell morphogenesis.Novel components participating in the maintenance of cell wall integrity are also uncovered. By performing two high-throughput screenings using the yTHC collection of yeast conditional mutant strains, Sanz et al. provide insights into essential genes required to cope with cell wall damage conditions, as well as those affecting CWI-associated gene expression . This woParacoccidioides brasiliensis plays an important role in cell wall homeostasis, in contrast to the involvement of histidine kinases in the response to high osmolarity in S. cerevisiae [Schizosaccharomyces japonicus [S. pombe are conserved in S. japonicus, others have evolved differently in both fission yeast species.Finally, two contributions reflect how evolution, using conserved elements, has shaped signaling pathways in fungi. In this line, the work of Navarro et al. shows that the dimorphism-regulating histidine kinase (Drk1) of the pathogenic fungus revisiae . In turnaponicus . They prIn sum, this Special Issue covers many, although not all, aspects of the signaling mechanisms and functions of the CWI pathway. It is our sincere hope that the articles presented here serve general readers by providing the most up-to-date information on this important aspect of fungal biology, as well as inspiring new ideas and challenging questions for researchers in the coming years.