Titanium and its alloys have been widely used in bone tissue defect treatment owing to their excellent comprehensive properties. However, because of the biological inertness of the surface, it is difficult to achieve satisfactory osseointegration with the surrounding bone tissue when implanted into the body. Meanwhile, an inflammatory response is inevitable, which leads to implantation failure. Therefore, solving these two problems has become a new research hotspot. In current studies, various surface modification methods were proposed to meet the clinical needs. Yet, these methods have not been classified as a system to guide the follow-up research. These methods are demanded to be summarized, analyzed, and compared. In this manuscript, the effect of physical signal regulation (multi-scale composite structure) and chemical signal regulation (bioactive substance) generated by surface modification in promoting osteogenesis and reducing inflammatory responses was generalized and discussed. Finally, from the perspective of material preparation and biocompatibility experiments, the development trend of surface modification in promoting titanium implant surface osteogenesis and anti-inflammatory research was proposed.

Incorporating neuroimaging-revealed structural details into finite element (FE) head models opens vast new opportunities to better understand brain injury mechanisms. Recently, growing efforts have been made to integrate fiber orientation from diffusion tensor imaging (DTI) into FE models to predict white matter (WM) tract-related deformation that is biomechanically characterized by tract-related strains. Commonly used approaches often downsample the spatially enriched fiber orientation to match the FE resolution with one orientation per element (i.e., element-wise orientation implementation). However, the validity of such downsampling operation and corresponding influences on the computed tract-related strains remain elusive. To address this, the current study proposed a new approach to integrate voxel-wise fiber orientation from one DTI atlas (isotropic resolution of 1 mm(3)) into FE models by embedding orientations from multiple voxels within one element (i.e., voxel-wise orientation implementation). By setting the responses revealed by the newly proposed voxel-wise orientation implementation as the reference, we evaluated the reliability of two previous downsampling approaches by examining the downsampled fiber orientation and the computationally predicted tract-related strains secondary to one concussive impact. Two FE models with varying element sizes (i.e., 6.4 +/- 1.6 mm and 1.3 +/- 0.6 mm, respectively) were incorporated. The results showed that, for the model with a large voxelmesh resolution mismatch, the downsampled element-wise fiber orientation, with respect to its voxel-wise counterpart, exhibited an absolute deviation over 30 across the WM/gray matter interface and the pons regions. Accordingly, this orientation deviation compromised the computation of tract-related strains with normalized root-mean-square errors up to 30% and underestimated the peak tract-related strains up to 10%. For the other FE model with finer meshes, the downsampling-induced effects were lower, both on the fiber orientation and tract-related strains. Taken together, the voxel-wise orientation implementation is recommended in future studies as it leverages the DTI-delineated fiber orientation to a larger extent than the element-wise orientation implementation. Thus, this study yields novel insights on integrating neuroimaging-revealed fiber orientation into FE models and may better inform the computation of WM tract-related deformation.

The biological performance of Ti-6Al-4V implant is primarily determined by their surface properties. However, traditional surface modification methods, such as acid etching, hardly make improvement in their osseointegration ability and antibacterial capacity. In this study, we prepared a multi-scale composite structure coated with zinc oxide (ZnO) on Ti-6Al-4V implant by an innovative technology of two-step laser processing combined with solution-assistant. Compared with the acid etching method, the physicochemical properties of surface significantly improved. The in vitro results showed that the particular dimension of micro-nano structure and the multifaceted nature of ZnO synergistically affected MC3T3-E1 osteogenesis and bacterial activities: (1) The surface morphology showed a 'contact guidance' effect on cell arrangement, which was conducive to the adhesion of filopodia and cell spreading, and the osteogenesis level of MC3T3-E1 was enhanced due to the release of zinc ions (Zn2+); (2) the characterization of bacterial response revealed that periodic nanostructures and Zn2+ released could cause damage to the cell wall of E. coli and reduce the adhesion and aggregation of S. aureus. In conclusion, the modified surface showed a synergistic effect of physical topography and chemical composition, making this a promising method and providing new insight into bone defect repairment.

3D printing has been applied in the fabrication of Ti-6Al-4V implants due to its high processing efficiency and flexibility. However, the biological inertness of 3D-printed Ti-6Al-4V implant surface limits its further clinical application. This paper aims to improve the biocompatibility of 3D-printed Ti-6Al-4V implants through multi-scale composite structure and bioactive coating. The samples are prepared by selective laser melting (SLM). The multi-scale composite structure is constructed by acid etching and anodic oxidation, and then the bioactive coating is added by hydrothermal treatment. The results indicate that acid etching removes the residuals on the surface and builds micron-/sub-micron structures. Anodic oxidation superimposes TiO2 nanotube arrays with a diameter of ≈80 nm, forming the multi-scale composite structure. The polydopamine-magnesium ion coating is added by hydrothermal treatment on the basis of retaining the multi-scale composite structure. After modification, the surface wettability and corrosion resistance are improved, and the roughness is slightly reduced. Regarding the biocompatibility of the modified 3D-printed Ti-6Al-4V implant, its admirable osteogenic induction performance is verified on osteoblasts (MC3T3-E1). Also, the addition of magnesium ions achieves better antibacterial properties. The results provide new target points for the surface modification of 3D-printed Ti-6Al-4V implant to attain better clinical performance. 

Background Hyperosmotic therapy is a mainstay treatment for cerebral edema. Although often effective, its disadvantages include mainly acting on the normal brain region with limited effectiveness in eliminating excess fluid in edema region. This study investigates how to configure our previously proposed novel electroosmosis based edema treatment as a complement to hyperosmotic therapy. 

Methods Three electrode configurations are designed to drive the excess fluid out of the edema region, including a 2-electrode, 3-electrode, and 5-electrode design. The focality and directionality of the induced electroosmotic flow (EOF) are then investigated using the same patient-specific head model with localized edema. 

Results The 5-electrode design shows improved EOF focality with reduced effect on the normal brain region than the other two designs. Importantly, this design also achieves better directionality driving excess edema tissue fluid to a larger region of surrounding normal brain where hyperosmotic therapy functions better. Thus, the 5-electrode design is suggested to treat edema more efficiently via a synergic effect: the excess fluid is first driven out from the edema to surrounding normal brain via EOF, where can then be treated with hyperosmotic therapy. Meanwhile, the 5-electrode design drives 2.22 mL excess fluid from the edema region in an hour comparable to the other designs, indicating a similar efficiency of EOF. 

Conclusions The results show the promise of our previously proposed novel electroosmosis based edema treatment can be designed to achieve better focality and directionality towards a complement to hyperosmotic therapy. 

Objective: Cerebral edema characterized as an abnormal accumulation of interstitial fluid has not been treated effectively. We propose a novel edema treatment approach to drive edematous fluid out of the brain by direct current utilizing brain tissue’s electroosmotic property. Methods: A finite element (FE) head model is developed and employed to assess the feasibility of the approach. First, the capacity of the model for electric field prediction is validated against human experiments. Second, two electrode configurations (S and D-montage) are designed to evaluate the distribution of the electric field, electroosmotic flow (EOF), current density, and temperature across the brain under an applied direct current. Results: The S-montage is shown to induce an average EOF velocity of 7e-4 mm/s underneath the anode by a voltage of 15 V, and the D-montage induces a velocity of 9e-4 mm/s by a voltage of 5 V. Meanwhile, the brain temperature in both configurations is below 38 °C, which is within the safety range. Further, the magnitude of EOF is proportional to the electric field, and the EOF direction follows the current flow from anode to cathode. The EOF velocity in the white matter is significantly higher than that in the gray matter under the anode where the fluid is to be drawn out. Conclusion: The proposed electroosmosis based approach allows alleviating brain edema within the critical time window by direct current. Significance: The approach may be further developed as a new treatment solely or as a complement to existing conventional treatments of edema.  

Cerebral edema characterized as an abnormal accumulation of excess fluid in the intracellular or extracellular spaces has not been treated effectively despite aggressive treatments. As a result, cerebral edema often leads to intracranial pressure (ICP) elevation with potentially severe consequences unless treated effectively. Hyperosmotic therapy is a mainstay of pharmacologic treatment for cerebral edema by drawing fluid out of the brain into the vascular system by osmotic gradient between the two; however, it usually causes side effects such as decreased cerebral perfusion and renal failure. For patients with severe cerebral edema, decompressive craniectomy (DC) is commonly considered a last resort to reduce raised ICP, although DC causes stretching of the brain tissue, which has been suggested to contribute to unfavorable patient outcomes, vegetative state, and even death. Therefore, cerebral edema treatment is still an arduous task and new innovative therapies are to be sought to improve patient outcomes.

This thesis attempts to develop a novel edema treatment approach to drive edematous fluid out of the brain parenchyma by applying an external direct current utilizing the brain’s electroosmotic property. Given the advantage of the finite element (FE) method to handle complex geometries and solve partial differential equations within neuroscience, FE head models were employed to explore the distribution of electric field, current density, temperature, and electroosmotic flow (EOF) across the brain during the electroosmosis based treatment. 

The electroosmosis based treatment was first proposed and evaluated systematically via a baseline head model in the first study. The proposed approach was verified to allow alleviating brain edema within a critical time window by a direct current, in which the excess fluid was driven from the edema region to subarachnoid space (SAS) along the direction of electric current flow. In the second study, three representative anisotropic conductivity algorithms were employed for the white matter (WM) and compared with isotropic WM. The extent of EOF velocity variation was highly correlated with the degree of the anisotropic ratio of the WM regions, and EOF in anisotropic models tended to move along the principal fiber direction. The results suggested the importance of incorporating WM anisotropic conductivity for a more reliable prediction of electric field and EOF inside the brain. In the third study, the capability of the electroosmosis based approach for edema treatment was further evaluated with three patient-specific head models with various types of edema. The electroosmosis based treatment was shown to reduce excess fluid at a rate of 1.8, 2.38, 0.73 mL/hour for patients with diffuse, localized, and expanded edema, respectively; thus, the estimated treatment time for the respective patient was around 15.4, 2.0, and 26 hours. In the fourth study, the application of electroosmosis based treatment in different age groups was investigated. The results demonstrated that anatomical structure (e.g., fontanel, brain volume, and brain atrophy) significantly affected the EOF distribution across the brain, suggesting that special attention should be paid to select appropriate treatment dosage for infants and adults with relatively smaller brains to avoid brain injury caused by high current density. The final study aimed at investigating the possibility of configuring the proposed approach as a complement to hyperosmotic therapy for cerebral edema. Through redesigning electrode configuration, the proposed approach improved EOF focality with a reduced effect on normal brain regions, and better directionality allowing driving the fluid from the edema region into the surrounding tissues more evenly where it could be absorbed by a larger volume of tissue during hyperosmotic therapy.

In conclusion, this thesis describes a novel edema treatment approach to alleviate the abnormal accumulation of excess fluid in brain parenchyma by applying an external direct current, and then demonstrates its capacity utilizing FE head models. It is hoped that this research has made a valuable and lasting contribution to cerebral edema treatment.

Cerebralt ödem som kännetecknas av en onormal ackumulering av överskott av vätska i deintracellulära eller extracellulära utrymmena har hittills inte behandlats effektivt. Ökningen avvattenhalten i det extracellulära utrymmet kan leda till förhöjt intrakraniellt tryck (ICP) medpotentiellt skadlig påverkan om det inte behandlas effektivt. Hyperosmotisk terapi betraktas som enfarmakologisk grundsten för behandling av cerebralt ödem genom att det suger ut vätska frånhjärnan in i kärlsystemet med en osmotisk gradient. Vanliga biverkningar är minskadhjärnperfusion och njursvikt. För allvarliga cerebrala ödem anses dekompressiv kraniektomi (DC)vara en sista utväg för att snabbt minska förhöjt ICP, även om hjärnvävnad som deformerar vid detexpanderade området har föreslagits bidra till ogynnsamt patientresultat, vegetativt tillstånd och tilloch med dödsfall. Därför är cerebral ödembehandling fortfarande en svår uppgift och nyainnovativa behandlingar ska sökas för att förbättra terapins effektivitet.  

Den aktuella avhandlingen försökte utveckla en ny metod för ödembehandling för att driva vätskan iödemet ur hjärnvävnaden genom att applicera en extern likström genom att utnyttja hjärnanselektroosmotiska egenskap. Med tanke på fördelen med finite element (FE) -metoden för atthantera komplexa geometrier och lösa patialdifferentialekvationer inom neurovetenskap, användsen FE-huvudmodell för att utforska elektriskt fält, strömtäthet och elektroosmotiskt flöde (EOF)över hjärnan under elektroosmosbaserad behandling med likström. 

Den elektroosmosbaserade behandlingen föreslås först och beskrivs sedan systematiskt via enbaslinjehuvudmodell i den första studien. Det är verifierat att det föreslagna tillvägagångssättet medlikström möjliggör lindring av hjärnödem inom det kritiska tidsfönstret, i vilket överflödig vätskadrivs från målregionen till Subarachnoidala Sinus (SAS) längs riktningen för elektrisk strömflödefrån anod till katod. Eftersom fiberarkitekturen för vit materia (WM) underlättar elektriskströmflöde parallellt med den huvudsakliga fiberriktningen än vinkelrät riktning, används trerepresentativa anisotropa konduktivitetsalgoritmer för att bygga en anisotrop WM vilket jämförsmed isotropisk WM i den andra studien. Resultaten visar att graden av EOF-hastighetsvariationkorrelerar med graden av det anisotropa förhållandet mellan WM-regionerna och riktningen förEOF för anisotropa modeller tenderar att avvika från dess isotropiskt definierade vägar för att rörasig längs den principiella fiberriktningen, vilket antyder att anisotrop WM bör införlivas i FEmodeller för mer tillförlitlig förutsägelse av elektriskt fält och EOF inuti hjärnan. I den tredjestudien verifieras ytterligare förmågan hos elektroosmosbaserad behandling för att lindra denonormala vätskeansamlingen för tre patientspecifika huvudmodeller med olika typer av ödem. Denkvantitativa analysen visar att den elektroosmosbaserade behandlingen uppnår en minskning avöverskottet av vätska med 1,8 ml för en patient med diffus ödem (DE), 2,4 ml för en patient medlokaliserat ödem (LE) och 0,7 ml för en patient med expanderat ödem (EE) per timme, vilketindikerar att den uppskattade behandlingstiden är cirka 15 timmar för DE, 2 timmar för LErespektive 26 timmar för EE. I den fjärde studien undersöks tillämpningen av elektroosmosbaserad behandling i olika åldersgrupper, och resultaten visar att anatomisk struktur (t.ex. fontanel,hjärnvolym, hjärnatrofi pga. ålder) påverkar EOF-fördelningen och strömtätheten över hjärnansignifikant, vilket tyder på att acceptabel behandlingsdos bör justeras för olika åldersgrupper för atthålla sig inom säkerhetsområdet. Den slutliga studien syftar till att undersöka möjligheten attkonfigurera det föreslagna tillvägagångssättet som ett komplement till hyperosmotisk behandlingför hjärnödem. Genom redesign av elektrodkonfiguration förbättrar den elektroosmosbaseradebehandlingen EOF-fokalitet med en minskad potentiell effekt på normala hjärnregioner ochriktning som gör att vätskan från ödemregionen kan dras in i omgivande vävnader där den kanabsorberas av en större volym vävnad genom hyperosmotisk terapi.Sammanfattningsvis beskriver denna avhandling en ny metod för ödembehandling för att lindraden onormala ackumuleringen av vätska i hjärnvävnaden genom att applicera en extern likström,och sedan demonstreras dess kapacitet genom simuleringar med FE-huvudmodeller.Förhoppningen är att denna forskning kan ge ett värdefullt och varaktigt bidrag tillhjärnödembehandling i framtiden.  

Treatment of cerebral edema remains a major challenge in clinical practice and new innovative therapies are needed. This study presents a novel approach for mitigating cerebral edema by inducing bulk fluid transport utilizing the brain’s electroosmotic property using an anatomically detailed finite element head model incorporating anisotropy in the white matter (WM). Three representative anisotropic conductivity algorithms are employed for the WM and compared with isotropic WM. The key results are (1) the electroosmotic flow (EOF) is driven from the edema region to the subarachnoid space under an applied electric field with its magnitude linearly correlated to the electric field and direction following current flow pathways; (2) the extent of EOFdistribution variation correlates highly with the degree of the anisotropic ratio of the WMregions; (3) the directions of the induced EOF in the anisotropic models deviate from its isotropically defined pathways and tend to move along the principal fiber direction. The results suggest WM anisotropy should be incorporated in head models for more reliable EOF evaluations for cerebral edema mitigation and demonstrate the promise of the electroosmosis based approach to be developed as a new therapy for edema treatment as evaluated with enhanced head models incorporating WM anisotropy.