心肌梗塞是一種急性的心臟疾病，成因為冠狀動脈狹窄，下游心肌細胞無法獲得足夠的氧氣和養分而壞死。壞死的心肌細胞會逐漸形成纖維化的成疤組織，進而缺乏電訊號傳遞的功能，容易導致心律不整，損害心臟的功能。因此，開發一導電性聚合物，能協助梗塞處生理電訊號的傳遞，治療其所引發心律不整的現象，可以近一步的改善心臟的功能。在第一個部分的研究裡，我們將具自我摻雜特性之導電性高分子聚3-胺基-4-甲氧基苯甲酸(poly-3-amino-4-methoxybenzoic acid, PAMB)接枝於明膠(gelatin)上後，進行化學交聯製備出具生物相容性的自我摻雜導電性水膠(PAMB-G)，以協助心肌電訊號的傳遞，改善心臟的功能。在傅立葉轉換紅外光譜以及核磁共振儀的實驗結果裡，我們證明了自我摻雜導電性高分子PAMB成功地接枝到gelatin上，且其導電度有顯著的提升。在機械性質的實驗結果裡，自我摻雜導電性水膠PAMB-G的楊氏模數和心肌組織相似，因此適合用於心肌組織的修復上。在體外的實驗結果裡，我們發現PAMB-G不會對新生幼鼠的心肌細胞造成細胞毒性，並且能夠協助心肌細胞進行同步收縮。在動物實驗裡，我們將PAMB-G注射於大鼠心臟的梗塞處後，測量手術後大鼠心臟功能的變化。我們發現PAMB-G能夠協助大鼠心臟梗塞處的電訊號傳遞、減少自發性心律不整的情形、改善心室收縮功能。在第二個部分的研究裡，我們開發一導電性生物工程補綴片，協助心肌梗塞處的電訊號傳遞、並同步化植入心肌細胞與宿主心肌細胞的收縮，以改善心肌梗塞後的心臟功能。研究裡，我們將具自我摻雜特性之導電性高分子聚3-胺基-4-甲氧基苯甲酸(poly-3-amino-4-methoxybenzoic acid, PAMB)接枝於明膠海綿上(PAMB-Gel patch)，再將由新生幼鼠分離出來的心肌細胞培養於PAMB-Gel patch上製備一導電性生物工程補綴片，以應用於大鼠心肌梗塞後心臟功能的改善。我們針對製備出的導電性生物工程補綴片，進行其物、化、導電性、機械性質及其對心肌細胞的毒性的探討。體外實驗裡，我們發現導電性生物工程補綴片能夠協助心肌細胞的電訊號傳遞及使其同步收縮。在動物實驗裡，我們將導電性生物工程補綴片移植到大鼠心肌的梗塞患部。實驗的成果顯示，導電性PAMB-Gel patch能夠協助電訊號的傳遞，而心肌細胞能夠提供心肌額外的收縮功能，在這兩個效果的並行之下，導電性生物工程補綴片治療能夠同時解決心律不整的問題，並且大幅改善心臟的功能，具有應用於心肌組織工程上的潛能。維他命D為一體內重要的維生素之一。經過代謝之後能夠有效地抑制心血管以及心臟疾病的發生。由於維他命D為一親脂性藥物的關係，因此通常會搭配著油類脂肪酸來口服，增加藥物的吸收。傳統口服藥物的製備需要大型的儀器，且製備過程相當的繁瑣和耗時，因此在本部分的研究中，我們利用馬倫哥尼原理開發一快速、簡單的藥物載體製備方式。我們將維他命D、脂肪酸和乙醇混合製備成表面張力低的油相。由於油相和水相的表面張力差的關係，乙醇能夠利用馬倫哥尼原理迅速的將油相分散成許多小油珠。形成的小油珠會因為脂肪酸的相轉換性質，使得環境的溫度下降之後，能夠冷卻凝固形成包覆有維他命D的微米粒子。此一微米粒子在口服之後能夠增加於小腸內的乳化程度，進而提高藥物的吸收

Myocardial infarction leads to the necrosis of cardiomyocytes, which become replaced by fibrotic tissue. Fibrous tissue impedes electrical propagation in the infarcted heart, contributing to abnormal contraction patterns, ventricular dysfunction and arrhythmias. An electrically active biomaterial may restore the propagation of electric signals through the infarct, synchronize contraction and prevent heart failure. Poly-3-amino-4-methoxybenzoic acid (PAMB) is a carboxyl group-functionalized polyaniline, which is a self-doped conductive polymer at physiological pH. In this study, a self-doping conductive polymeric hydrogel (PAMB-G hydrogel) is synthesized by grafting the PAMB on biocompatible gelatin and then chemically crosslinking with carbodiimide is proposed. Microelectrode array results reveal that a heart that is placed on the PAMB-G hydrogel has a higher field potential amplitude than one placed on gelatin hydrogel and can pass current that can excite another heart at a distance. An infarcted rat heart that was treated with PAMB-G hydrogel exhibit remarkably improved functions, including reduced induced arrhythmia and spontaneous arrhythmia, improved conduction velocity, and increased fractional shortening, relative a gelatin-treated control. A second study proposes a cell delivery construct that contains a conductive biomaterial scaffold that is made of a self-doping conductive polymer-grafted gelfoam (PAMB-Gel patch) as a bioengineered cardiac patch for heart repair. The conductive PAMB-Gel patch can increase the propagation of electric signals between clusters of beating cardiomyocytes, facilitating their synchronous contraction. In vivo results demonstrate that the bioengineered conductive patch can significantly strengthen electrical activity in the scar tissue, improving electrical impulse propagation, reducing susceptibility to cardiac arrhythmias, and promoting the restoration of cardiac function, perhaps owing to the synergistic effects of its conductive constructs and the synchronously beating CMs. Vitamin D has received substantial interest because of its ability to prevent cardiovascular disease, and fatty acid has commonly been used as a drug carrier to solubilize and deliver it. Such drug carriers are usually prepared by emulsification, which is complicated and time-consuming and requires much energy input. To address these concerns, in a third study, a fast and facile method for fabricating lipid-based oil droplets, using propulsive forces powered by the chemical Marangoni effect, is developed for the oral delivery of vitamin D. The oil droplets are prepared by solubilizing vitamin D in a phase-changeable fatty acid and ethanol as an oil phase, which is then deposited on the surface of a water bath. Due to the difference between the surface tensions of water and ethanol (chemical energy), Marangoni propulsion is produced (kinetic energy), quickly spreading the oil phase into numerous tiny oil droplets. To prevent their coalescence, the formed oil droplets are solidified by reducing their environmental temperature. Following oral treatment, the fluidity of the exposed microparticles increases at body temperature, and the microparticles can be further emulsified into the vitamin D-containing micelles by intestinal bile salts, improving its oral bioavailability.

Table of Contents
中文摘要 I
Abstract III
Contents V
List of Figures X
List of Tables XVI
Chapter 1 Introduction 1
Chapter 2 A Self-Doping Conductive Polymer Hydrogel that Can Restore Electrical Impulse Propagation at Myocardial Infarct to Prevent Cardiac Arrhythmia and Preserve Ventricular Function
2-1 Introduction 5
2-2. Results and discussion 7
2-2.1. Characteristics of PAMB-G copolymer 7
2-2.2. Characteristics of PAMB-G hydrogel 9
2-2.3. Physical structure of PAMB-G hydrogel and its cell compatibility 10
2-2.4. Electrical conduction through PAMB-G hydrogel 13
2-2.5. Ca2+ transient propagation through distinct CM clusters 14
2-2.6. Regional and global electrical field potential amplitudes in scar tissues 15
2-2.7. Spontaneous and induced arrhythmias in infarcted hearts 17
2-2.8. Electrical impulse conduction velocity across infarct scar region 18
2-2.9. Cardiac function and histological findings 19
2-3. Conclusions 22
2-4. Materials and methods 22
2-4.1. Synthesis and characterization of PAMB-G copolymer 22
2-4.2. Formation and characterization of PAMB-G hydrogel 23
2-4.3. Animal studies 23
2-4.4. Cardiomyocyte isolation and cell compatibility analysis 24
2-4.5. Identification of expression of cardiac functional proteins in CMs 24
2-4.6. Evaluation of electrical conduction through PAMB-G hydrogel 25
2-4.7. In vitro and ex vivo imaging of calcium (Ca2+) transient and electrical signal propagation 26
2-4.8. Hydrogel injection and electrical activity analysis in an acute MI model 27
2-4.9. Cardiac function assessment and histological examination 28
2-4.10. Statistical analysis 29
Chapter 3 A Conductive Cell-Delivery Construct as a Bioengineered Patch that Can Improve Electrical Propagation and Synchronize Cardiomyocyte Contraction for Heart Repair
3-1 Introduction 31
3-2. Results and discussion 33
3-2.1. Characteristics of PAMB-Gel patch 34
3-2.2. Cell compatibility of PAMB-Gel patch 37
3-2.3. Ca2+ transient propagation in PAMB-Gel patch 37
3-2.4. Electrical impulse propagation in CMs grown in PAMB-Gel patch 39
3-2.5. Electrical impulse propagation in infarcted hearts 39
3-2.6. QRS duration in infarcted hearts 41
3-2.7. Inducibility of cardiac arrhythmias in infarcted hearts 41
3-2.8. Electrical conduction velocity across infarcted hearts 42
3-2.9. Cardiac function and histological findings 43
3-3. Conclusions 45
3-4. Materials and methods 46
3-4.1. Preparation of PAMB-Gel patch 46
3-4.2. Characterization of PAMB-Gel patch 46
3-4.3. Animal studies 48
3-4.4. Preparation of cell-delivery construct (cell-seeded PAMB-Gel patch) 48
3-4.5. Immunofluorescent staining of cell-seeded PAMB-Gel patch 48
3-4.6. Conductive properties of cell-seeded PAMB-Gel patch 49
3-4.7. CM Ca2+ transient and electrical impulse propagation 49
3-4.8. Epicardial implantation of cell-seeded PAMB-Gel patch and analysis of its electrical activity 50
3-4.9. Cardiac function assessment and histological evaluation 51
3-4.10. Statistical analysis 52
Chapter 4 A Fast and Facile Platform for Fabricating Phase-Change Materials-Based Drug Carriers Powered by Chemical Marangoni Effect
4-1 Introduction 54
4-2. Results and discussion 57
4-3. Conclusions 66
4-4. Materials and methods 66
4-4.1. Preparation and characterization of MCFA-based MPs 66
4-4.2. Cytotoxicity of C12 MPs 68
4-4.3. In vitro micellarization of C12 MPs. 68
4-4.4. Animal study. 68
4-4.5. Histological analyses. 69
4-4.6. Statistical analysis. 69
Chapter 5 References 70
Publications 79
 
List of Figures

Figure 2-1. Synthesis and structure of PAMB hydrogel and mechanism of its restoring electrical impulse propagation and synchronizing myocardial contraction following a myocardial infarction 6
Figure 2-2. (a) FT–IR and (b) 1H NMR spectra of gelatin, PAMB, and PAMB-G copolymer, showing successful conjugation of PAMB on gelatin backbone. (c) UV-vis spectra of PAMB-G copolymer at various pH values, demonstrating its self-doping characteristics under physiological pH conditions. Rheological behaviors of gelatin and PAMB-G hydrogels in (d) time sweep and (e) frequency sweep mode. (f) Stress–strain curves and (g) Young’s moduli of gelatin and PAMB-G hydrogels (n = 7 each group). (h) Conductivities of gelatin and PAMB-G hydrogels (n = 7 each group). *P < 0.05; n.s.: not significant 9
Figure 2-3. (a) SEM micrographs of gelatin and PAMB-G hydrogels, showing their physical structures. (b) CMs grown on gelatin or PAMB-G hydrogel at day three following cell seeding, showing normal cell morphology. (c) Numbers of CMs grown on culture dish (CD) alone or with a coating of gelatin or PAMB-G hydrogel during five days in culture, showing that both gelatin and PAMB-G hydrogels supported CM growth (n = 3 each group). (d) Representative fluorescence photomicrographs of SARC and connexin 43 staining of CMs that were cultured on CD, or had a coating of gelatin or PAMB-G hydrogel, captured three days following seeding. n.s.: not significant 11
Figure 2-4. Neonatal rat CMs were seeded on CDs alone or with a coating of gelatin or PAMB-G hydrogel. Cells were grown for up to 7 days and then stained with DAPI to show nuclei. BF: bright field image 12
Figure 2-5. (a) An ex vivo beating rat heart was placed on gelatin or PAMB-G hydrogel with a thickness of 2, 4, or 6 mm. Local field potential amplitudes that were detected through test hydrogels using a MEA (n = 4 each group). (b) Representative ECG recordings of stimulation signals from an ex vivo beating heart (Heart 1) that passed through gelatin or PAMB-G hydrogel with a thickness of 1, 2, 3, or 4 mm to a non-beating heart (Heart 2); local field potential ratios of non-beating hearts (Heart 2)/beating hearts (Heart 1) (n = 4 each group). *P < 0.05; n.s.: not significant 14
Figure 2-6. Ca2+ transient propagation through distinct clusters of spontaneously beating CMs grown on gelatin or PAMB-G hydrogel at day three following cell seeding; CMs grown on PAMB-G hydrogel exhibit better synchronization than those grown on gelatin hydrogel 15
Figure 2-7. (a) Regional field potential amplitude of fibrotic scar tissue at four weeks post-injection of gelatin or PAMB-G hydrogel, measured by a 36-lead flexible microelectrode array (MEA). (b) Representative electrograms and (c) regional field potential amplitudes measured in fibrotic scar tissues (n = 6 each group). (d) Global field potential amplitude across fibrotic scar tissue at four weeks post-injection of gelatin or PAMB-G hydrogel, measured by an 8-lead catheter. (e) Representative electrograms detected at remote, border, and scar areas and (f) ratios of scar/remote field potential amplitudes (n = 5 each group). *P < 0.05 16
Figure 2-8. (a) Electrograms of spontaneous arrhythmias recorded by ambulatory telemetry at four weeks post-injection of test hydrogel, showing that (b) PAMB-G group had a lower rate of spontaneous PVCs than gelatin group (n = 5 each group). (c) Electrograms of induced arrhythmias recorded at four weeks post-hydrogel injection after programmed electrical stimulation (PES), showing that (d) PAMB-G group had a lower induced inducibility quotient than gelatin group (n = 5 each group). (e) Optical mappings of electrical impulse propagation (red arrows) through left ventricles of normal heart or of heart treated with gelatin or PAMB-G hydrogel, indicating (f) that PAMB-G-treated hearts had a significantly higher conduction velocity than gelatin-treated hearts (n = 6 each group). *P < 0.05 18
Figure 2-9. (a) Representative M-mode echo images obtained four weeks following test hydrogel injection, showing that PAMB-G group had greater (b) fractional shortening and (c) ejection fraction with smaller (d) LVIDs and (e) LVIDd than gelatin group. (f) Representative photographs of whole sectioned hearts at four weeks following test hydrogel injection, showing that (g) scars were smaller and scar thickness and viable myocardium were greater in PAMB-G group than in gelatin group. Photomicrographs of (h) H&E and (i) Masson’s trichrome staining. (b–e, n = 8 each group; f and g, n = 6 each group). *P < 0.05 20
Figure 2-10. Representative immunofluorescence photomicrographs of SARC and connexin 43 staining of CMs in infarcted areas that were observed in gelatin and PAMB-G groups at four weeks post-hydrogel injection 21
Figure 3-1. Preparation and structure of as-proposed bioengineered conductive patch (PAMB-Gel+CMs) and mechanisms of its improvement of electrical propagation and synchronizing CM contraction for repair of infarcted rat heart 33
Figure 3-2. (a) Conductivities of PAMB-Gel patches with various formulations (n = 6 in each group). (b) FT–IR spectra of Gel patch (gelfoam), PAMB polymer, and PAMB-Gel patch, indicating that PAMB polymer had been successfully synthesized and grafted into gelfoam. (c) SEM micrographs showing that Gel and PAMB-Gel patches had similar interconnected porous structures. (d) Pore size and (e) porosity of Gel and PAMB-Gel patches, suggesting that conjugation of PAMB did not change morphological structure of Gel patch (n = 6 in each group). (f) Swelling ratios of Gel and PAMB-Gel patches. (g) Stress–strain curves, (h) Young’s moduli, (i) tensile strengths, and (j) elongations at break of Gel and PAMB-Gel patches (n = 6 in each group). (k) UV-vis absorption spectra of PAMB polymer at different pH values, showing self-doping at physiological pH. (l) Conductivities of Gel and PAMB-Gel patches (n = 6 in each group). *P < 0.05; n.s.: not significant 36
Figure 3-3. (a) Representative fluorescence images of connexin 43 staining of CMs that had been grown in Gel and PAMB-Gel patches. Nuclei were counter-stained with DAPI. (b) Numbers of CMs grown in Gel and PAMB-Gel patches during eight days in culture (n = 3 in each group). (c) Ca2+ transient propagation through CMs that had been grown in Gel and PAMB-Gel patches. Area where Ca2+ fluorescence increased first was selected as ROI #1, and area where Ca2+ fluorescence propagation stopped was selected as ROI #2. (d) Ca2+ transient velocities in CMs that had been cultured in Gel and PAMB-Gel patches were calculated from time between activation of ROI #1 and that of ROI #2 (n = 3 in each group). (e) Ca2+ transients of distinct clusters of spontaneously beating CMs that had been grown in PAMB-Gel patch, exhibiting better synchronization than those that had been grown in Gel patch. (f) Representative electrograms of CMs that had been grown in Gel and PAMB-Gel patches, detected by MEA, showing that PAMB-Gel group had (g) higher field potential amplitude and (h) greater conduction velocity than Gel group (n = 3 in each group). *P < 0.05; n.s.: not significant 38
Figure 3-4. (a) Experimental timeline. (b) Electrograms of regional field potential recorded on fibrotic scar areas using MEA and their (c) regional field potential amplitudes as well as (d) conduction velocities (n = 6 in each of Gel and PAMB-Gel groups; n = 4 in each of normal and PAMB-Gel+CMs groups). (e) Electrograms of global field potential recorded across fibrotic scar tissues using an eight-lead catheter and (f) corresponding ratios of scar/remote field potential amplitudes (n = 6 in each of Gel and PAMB-Gel groups, n = 4 in PAMB-Gel+CMs group). *P < 0.05; n.s.: not significant 40
Figure 3-5. (a) ECG recordings were taken to determine (b) QRS duration four weeks post-patch implantation (n = 6 in each of Gel and PAMB-Gel groups, n = 4 in each of normal and PAMB-Gel+CMs groups). (c) PES protocol was followed to investigate inducibility of arrhythmias of infarcted hearts. (d) Calculated inducibility quotients (n = 6 in each of Gel and PAMB-Gel groups, n = 4 in each of normal and PAMB-Gel+CMs groups). (e) Conduction velocities were calculated from optical mappings recorded at four weeks post-patch implantation (n = 6 in each of Gel and PAMB-Gel groups, n = 4 in each of normal and PAMB-Gel+CMs groups). *P < 0.05; n.s.: not significant 43
Figure 3-6. Echocardiograph at four weeks post-patch implantation, demonstrating that PAMB-Gel and PAMB-Gel+CMs patches had greater (a) fractional shortening and (b) ejection fraction but smaller (c) LVIDs and (d) LVIDd than Gel patch (n = 6 in each of Gel and PAMB-Gel groups, n = 4 in each of normal and PAMB-Gel+CMs groups). (e) Representative histological images of staining with Masson’s Trichrome of cross-sectioned hearts excised four weeks after patch implantation. (f) Scar size and (g) scar thickness of each studied group (n = 6 in each of Gel and PAMB-Gel groups, n = 4 in PAMB-Gel+CMs group). *P < 0.05 45
Figure 4-1. Schematic mechanism in preparation C12 MPs and their use in oral delivery of vitamin D in a rat model 56
Figure 4-2. (a) DSC thermograms of C10 and C12 in bulk form, empty MPs, and vitamin D-containing MPs 58
Figure 4-3. Spreading of C12 oil phase (a) with various agents with low surface tension or (b) with various ethanol concentrations, and their (c, d) displacement–time graphs and corresponding speeds of Marangoni flow. *P < 0.05; n.s.: not significant 62
Figure 4-4. (a) Photomicrograph of as-prepared C12 MPs. (b) Cytotoxicity of free C12 and C12 MPs at various concentrations as suspensions on Caco-2 cells. (c) Stability of C12 MPs in storage at 4 °C. (d) Photographs of free vitamin D, bulk C12, and C12 MPs that had been emulsified in simulated gastric fluid (SGF) and then in simulated intestinal fluid (SIF) at 37 °C, and (e) their corresponding percentages of vitamin D that partitioned into micelles. *P < 0.05; n.s.: not significant 64
Figure 4-5. (a) Plasma vitamin D level versus time following treatment with deionized water (untreated control), free vitamin D, bulk C12, and C12 MPs. (b) Histological photomicrographs of intestinal tissue sections, which were harvested from each studied group, stained with H&E or TUNEL 65

List of Tables
Table 4-1. Pharmacokinetic parameters of vitamin D in rats following oral treatment with free vitamin D, bulk C12, or C12 MPs. Cmax: maximum plasma concentration; Tmax: time at which Cmax is reached; AUC (0–24 h): area under plasma concentration as a function of time; BA: bioavailability relative to that achieved by oral treatment with free vitamin D (n = 6 for each studied group) 66

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