Can porous polymeric scaffolds be functionalized by stem cells leading to osteogenic differentiation? A systematic review of in vitro studies

The aim of this study was to analyze the influence of nanoporous structure of polymeric biomaterials on the in vitro osteogenic induction of human stem cells. An electronic search in three databases (MEDLINE, SCOPUS, and Web of Science) was performed for articles that were published before May 2018. In vitro studies were included if they met the following criteria: (1) the use of polymeric scaffolds (natural or synthetic); (2) the co-culture of human stem cells with the scaffold; and (3) cell viability, proliferation, and osteogenic differentiation assays. The main characteristics of the published studies were summarized, and a quality assessment tool was used to analyze methodological features. Eighty-eight potential articles were firstly retrieved. Thirteen were eligible for qualitative analysis. Only three studies characterized cell stemness. Nanostructure of the scaffolds showed a significant influence on viability, proliferation, and osteogenic differentiation of human stem cells. Combination of porosity between 72 and 93% and a large range diameter between 50 and 224 μm resulted in more remarkable cellular proliferation and differentiation. Porous polymeric scaffolds can be functionalized by stem cells leading to osteogenic induction. High standards of laboratory practice and accurate methodological reporting are essential for the credibility of the results.     

Fibrous hydrogel scaffolds with cells embedded in the fibers as a potential tissue scaffold for skin repair

A novel approach was undertaken to create a potential skin wound dressing. L929 fibroblast cells and alginate solution were simultaneously dispensed into a calcium chloride solution using a three-dimensional plotting system to manufacture a fibrous alginate scaffold with interconnected pores. These cells were then embedded in the alginate hydrogel fibers of the scaffold. A conventional scaffold with cells directly seeded on the fiber surface was used as a control. The encapsulated fibroblasts made using the co-dispensing method distributed homogeneously within the scaffold and showed the delayed formation of large cell aggregates compared to the control. The cells embedded in the hydrogel fibers also deposited more type I collagen in the extracellular matrix and expressed higher levels of fgf11 and fn1 than the control, indicating increased cellular proliferation and attachment. The results indicate that the novel co-dispensing alginate scaffold may promote skin regeneration better than the conventional directly-seeded scaffold.     

Ⅰ型胶原/海藻酸钠/透明质酸复合水凝胶用于血管组织工程细胞负载与3D培养EI北大核心CSCD

胶原、海藻酸钠和透明质酸是天然来源的高分子材料,具有良好的细胞相容性与生物安全性,在细胞培养、组织工程、药物负载等方面具有广泛应用。单纯的胶原力学性能较差,将胶原与海藻酸钠制备成复合水凝胶材料后,可以通过调节海藻酸钠与Ca^(2+)交联程度来改变水凝胶支架的力学性能和孔隙率,模拟细胞培养的力学环境和细胞微环境。本研究通过PIUMA纳米压痕仪和DHR流变仪表征Ⅰ型胶原/海藻酸钠/透明质酸水凝胶的杨氏模量和溶胶-凝胶转变温度。并将内皮细胞与间充质干细胞在水凝胶微环境内进行3D培养,倒置荧光显微镜观察细胞培养0,3,5,7 d时细胞的活力情况,表征Ⅰ型胶原/海藻酸钠/透明质酸水凝胶的细胞相容性,并在内皮细胞与间充质干细胞培养0,1,4,6 d时,观察内皮细胞的迁移、成血管情况,在培养1,6,9 d时,观察内皮细胞的生长扩散情况。结果表明:水凝胶杨氏模量为(600±81)Pa,水凝胶的溶胶-凝胶转变温度为23.2℃。细胞培养0,3,5,7 d时,活力持续增强,培养4,6 d时,观测到共培养下内皮细胞的迁移,培养1,6,9 d时,水凝胶内的内皮细胞球体持续生长扩散。本工作表明,Ⅰ型胶原/海藻酸钠/透明质酸水凝胶对内皮细胞与间充质干细胞具有良好的细胞相容性,可用于细胞3D培养的理想支架材料。水凝胶的杨氏模量和溶胶-凝胶转变温度对细胞活力无损害,可作为研究血管新生的相关体外模型,在血管组织工程研究中具有重要的应用前景。     

A covalently crosslinked polysaccharide hydrogel for potential applications in drug delivery and tissue engineering

The development of non-cytotoxic hydrogels that can allow for the controlled release of molecules has important clinical and therapeutic applications. In this paper, we developed a series of in situ hydrogels by combining N,O-carboxymethyl chitosan and oxidized alginate without additional crosslinking agents. The rheological properties of these hydrogels as well as their gelling time, swelling ratio, and in vitro degradation behavior were investigated. We observed that although gelation was rapid at physiological temperature, it was even faster in the presence of higher oxidization degree of alginate. In vitro cytotoxicity study showed that the developed hydrogels were not cytotoxic after 24?h of culturing with NIH-3T3 cells. Additionally, bovine serum albumin was released from the hydrogels initially by diffusion at early stages followed by a degradation-dependent mechanism at later stages. In conclusion, the developed hydrogel might have potential application in the drug delivery system and tissue engineering.     

Small functional groups for controlled differentiation of hydrogel-encapsulated human mesenchymal stem cells

Cell-matrix interactions have critical roles in regeneration, development and disease. The work presented here demonstrates that encapsulated human mesenchymal stem cells (hMSCs) can be induced to differentiate down osteogenic and adipogenic pathways by controlling their three-dimensional environment using tethered small-molecule chemical functional groups. Hydrogels were formed using sufficiently low concentrations of tether molecules to maintain constant physical characteristics, encapsulation of hMSCs in three dimensions prevented changes in cell morphology, and hMSCs were shown to differentiate in normal growth media, indicating that the small-molecule functional groups induced differentiation. To our knowledge, this is the first example where synthetic matrices are shown to control induction of multiple hMSC lineages purely through interactions with small-molecule chemical functional groups tethered to the hydrogel material. Strategies using simple chemistry to control complex biological processes would be particularly powerful as they could make production of therapeutic materials simpler, cheaper and more easily controlled.     

氧化海藻酸钠/聚丙烯酰胺水凝胶的制备与表征

通过水-乙醇和水-正丙醇两种不同的溶剂体系制备高分子量和不同氧化度的氧化海藻酸钠(OSA),然后引入聚丙烯酰胺(PAM)交联网络结构,通过二步法获得OSA/PAM复合水凝胶。探讨了不同反应体系下,HCl体积分数对OSA分子量的影响以及氧化剂(高碘酸钠NaIO_4)添加量、反应时间对OSA氧化度的影响规律。结果表明:在水-正丙醇体系下,HCl体积分数为24vol%时,氧化海藻酸钠的分子量达到170 000;调节NaIO_4的添加量和反应时间可以控制OSA的氧化度在10%~85%范围内变化。在此基础上对OSA/PAM复合水凝胶的溶胀率和力学性能进行了探讨,发现氧化度10%的复合水凝胶48h后的溶胀率达1 777%,断裂强度为0.11MPa,随着OSA氧化度的增大,OSA/PAM复合水凝胶的溶胀率增大,而拉伸强度逐渐减小。     

Novel macro-microporous gelatin scaffold fabricated by particulate leaching for soft tissue reconstruction with adipose-derived stem cells

The restoration of body contours as shaped by adipose tissue remains a clinical challenge specifically in patients who have experienced loss of contour due to trauma, surgical removal of tumours or congenital abnormalities. We have developed a novel macro-microporous biomaterial for use in soft tissue re-bulking and augmentation. Alginate beads provided the pore template for the construct. Incorporation, and subsequent dissolution, of the beads within a 7 % (w/v) gelatin matrix, produced a highly porous scaffold with an average pore size of 2.01 ± 0.08 mm. The ability of this scaffold to support the in vitro growth and differentiation of human adipose-derived stem cells (ADSCs) was then investigated. Histological analysis confirmed that the scaffold itself provided a suitable environment to support the growth of ADSCs on the scaffold walls. When delivered into the macropores in a fibrin hydrogel, ADSCs proliferated and filled the pores. In addition, ADSCs could readily be differentiated along the adipogenic lineage. These results therefore describe a novel scaffold that can support the proliferation and delivery of ADSCs. The scaffold is the first stage in developing a clinical alternative to current treatment methods for soft tissue reconstruction.     

Fabrication and development of artificial osteochondral constructs based on cancellous bone/hydrogel hybrid scaffold

Using tissue engineering techniques, an artificial osteochondral construct was successfully fabricated to treat large osteochondral defects. In this study, porcine cancellous bones and chitosan/gelatin hydrogel scaffolds were used as substitutes to mimic bone and cartilage, respectively. The porosity and distribution of pore size in porcine bone was measured and the degradation ratio and swelling ratio for chitosan/gelatin hydrogel scaffolds was also determined in vitro. Surface morphology was analyzed with the scanning electron microscope (SEM). The physicochemical properties and the composition were tested by using an infrared instrument. A double layer composite scaffold was constructed via seeding adipose-derived stem cells (ADSCs) induced to chondrocytes and osteoblasts, followed by inoculation in cancellous bones and hydrogel scaffolds. Cell proliferation was assessed through Dead/Live staining and cellular activity was analyzed with IpWin5 software. Cell growth, adhesion and formation of extracellular matrix in composite scaffolds blank cancellous bones or hydrogel scaffolds were also analyzed. SEM analysis revealed a super porous internal structure of cancellous bone scaffolds and pore size was measured at an average of 410 ± 59 μm while porosity was recorded at 70.6 ± 1.7 %. In the hydrogel scaffold, the average pore size was measured at 117 ± 21 μm and the porosity and swelling rate were recorded at 83.4 ± 0.8 % and 362.0 ± 2.4 %, respectively. Furthermore, the remaining hydrogel weighed 80.76 ± 1.6 % of the original dry weight after hydration in PBS for 6 weeks. In summary, the cancellous bone and hydrogel composite scaffold is a promising biomaterial which shows an essential physical performance and strength with excellent osteochondral tissue interaction in situ. ADSCs are a suitable cell source for osteochondral composite reconstruction. Moreover, the bi-layered scaffold significantly enhanced cell proliferation compared to the cells seeded on either single scaffold. Therefore, a bi-layered composite scaffold is an appropriate candidate for fabrication of osteochondral tissue.     

Interactions of total bone marrow cells with increasing quantities of macroporous calcium phosphate ceramic granules

The biological properties of synthetic calcium phosphate bioceramics have made them the third choice of material for bone reconstructive surgery, after autologous bone and allografts. Nevertheless, bioceramics lack the osteogenic properties that would allow them to repair large bone defects. One strategy in bone tissue engineering consists of associating a synthetic scaffold with osteogenic cells. Mesenchymal stem cells (MSC) are usually isolated from bone marrow cultured for several weeks and seeded on to a small quantity of bioceramic. We have studied the association of total bone marrow cells, harvested from femurs of rats, with increasing amounts of calcium phosphate ceramic granules (50–250 mg). A cell viability test indicated that a little quantity of bioceramics granules (50 mg) was less detrimental for culturing 1 million nucleated cells from the whole bone marrow population. Cell morphology, viability, adhesion and differentiation were studied after different culture periods. Among the heterogeneous population of bone marrow cells, only a limited amount of cells attached and differentiated on the bioceramics. To explain the influence of the amount of synthetic scaffold on cell viability, media calcium concentrations were measured. Low cell viability could be explained by calcium phosphate precipitation leading to a decrease in calcium concentrations observed with relatively large amounts of scaffold. This study showed that the chemical stability of the ceramic plays a critical role in the viability of bone marrow cells.     

The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder

A key tenet of bone tissue engineering is the development of scaffold materials that can stimulate stem cell differentiation in the absence of chemical treatment to become osteoblasts without compromising material properties. At present, conventional implant materials fail owing to encapsulation by soft tissue, rather than direct bone bonding. Here, we demonstrate the use of nanoscale disorder to stimulate human mesenchymal stem cells (MSCs) to produce bone mineral in vitro, in the absence of osteogenic supplements. This approach has similar efficiency to that of cells cultured with osteogenic media. In addition, the current studies show that topographically treated MSCs have a distinct differentiation profile compared with those treated with osteogenic media, which has implications for cell therapies.     

A 3D biodegradable protein based matrix for cartilage tissue engineering and stem cell differentiation to cartilage

A protein based 3D porous scaffold is fabricated by blending gelatin and albumin. The biomimetic biodegradable gelatin, promoted good cell adhesion and its hydrophilic nature enabled absorption of culture media. Albumin is proposed to serve as a nontoxic foaming agent and also helped to attain a hydrophobic-hydrophilic balance. The hydrophobic-hydrophilic balance and appropriate crosslinking of the scaffold avoided extensive swelling, as well as retained the stability of scaffold in culture medium for long period. The scaffold is found to be highly porous with open interconnected pores. The adequate swelling and mechanical property of the scaffold helped to withstand the loads imparted by the cells during in vitro culture. The scaffold served as a nontoxic material to monolayer of fibroblast cells and is found to be cell compatible. The suitability of scaffold for chondrocyte culture and stem cell differentiation to chondrocytes is further explored in this work. The scaffold provided appropriate environment for chondrocyte culture, resulting in deposition of cartilage specific matrix molecules that completely masked the pores of the porous scaffold. The scaffold promoted the proliferation and differentiation of mesenchymal stem cells to chondrocytes in presence of growth factors. The transforming growth factor, TGFbeta3 promoted better chondrogenic differentiation than its isoform TGFbeta1 in this scaffold.     

3D Bioplotting of Gelatin/Alginate Scaffolds for Tissue Engineering:Influence of Crosslinking Degree and Pore Architecture on Physicochemical Properties

Gelatin/Alginate hydrogels were engineered for bioplotting in tissue engineering. One major drawback of hydrogel scaffolds is the lack of adequate mechanical properties. In this study, using a bioplotter, we constructed the scaffolds with different pore architectures by deposition of gelatin/alginate hydrogels layerby-layer. The scaffolds with different crosslinking degree were obtained by post-crosslinking methods.Their physicochemical properties, as well as cell viability, were assessed. Different crosslinking methods had little influence on scaffold architecture, porosity, pore size and distribution. By contrast, the water absorption ability, degradation rate and mechanical properties of the scaffolds were dramatically affected by treatment with various concentrations of crosslinking agent(glutaraldehyde). The crosslinking process using glutaraldehyde markedly improved the stability and mechanical strength of the hydrogel scaffolds. Besides the post-processing methods, the pore architecture can also evidently affect the mechanical properties of the scaffolds. The crosslinked gelatin/alginate scaffolds showed a good potential to encapsulate cells or drugs.     

Preparation and characterization of oxidized alginate covalently cross-linked galactosylated chitosan scaffold for liver tissue engineering

Liver tissue engineering (LTE) requires a perfect extracellular matrix (ECM) for hepatocytes culture to maintain high level of liver-specific functions. Here, we reported a LTE scaffold derived from oxidized alginate covalently cross-linked galactosylated chitosan via Schiff base reaction, without employing any extraneous chemical cross-linking agent. The structure of galactosylated chitosan (GC) and oxidized alginate was confirmed by Fourier transformed infrared (FTIR) spectra, proton nuclear magnetic resonance (¹H-NMR) spectroscopy, X-ray diffraction (XRD) or thermogravimetric (TG) analysis. The structure and properties of a series of the scaffolds were characterized by FTIR, XRD, scanning electron microscopy (SEM), porosity, equilibrium swelling, mechanical properties, thermal stability and in vitro degradation. FTIR spectra confirmed the characteristic peak of Schiff base groups in the scaffolds and XRD indicated the scaffolds could be amorphous. SEM analysis showed that the scaffolds displayed highly porous surfaces with average pore size of 50-150 μm and interconnected pore structure in the internal structure with average pore size of 100-250 μm. Porosity measurement suggested the scaffolds had a porosity of about 70%. The compressive modulus of the scaffolds (hydrated) was in the range of 4.2-6.3 kPa. Further studies showed that, with the increase of the oxidized alginate content, the equilibrium swelling and in vitro degradation rate of the scaffolds decreased and the thermal stability slightly increased, which might mainly attribute to the difference of the degree of cross-linking and the nature properties of the raw materials. Additionally, the biocompatibility of the scaffolds was evaluated in vitro. The results showed that the hepatocytes cultured on the scaffolds had a typical spheroidal morphology, formed multi-cellular aggregates and presented perfect integration with the scaffolds, which suggested that the scaffolds may be potential candidates for LTE strategies.     

Ability of polyurethane foams to support placenta-derived cell adhesion and osteogenic differentiation: preliminary results

In bone tissue reconstruction, the use of engineered constructs created by mesenchymal stem cells (MSCs) that differentiate and proliferate into 3D porous scaffolds is an appealing alternative to clinical therapies. Human placenta represents a possible source of MSCs, as it is readily available without invasive procedures and because of the phenotypic plasticity of many of the cell types isolated from this tissue. The scaffold considered in this work is a slowly degradable polyurethane foam (EF PU foam), synthesized and characterized for morphology and in vitro interaction with chorion mesenchymal cells (CMCs). These cells were isolated from human term placenta and cultured onto the EF PU foam using two different culture media (EMEM and NH osteogenic differentiation medium). Synthesized EF PU foam showed homogeneous pore size and distribution, with 89% open porosity. In vitro tests showed CMCs scaffold colonization, as confirmed by Scanning Electron Microscopy (SEM) observations and hematoxylin–eosin staining. Alizarin Red staining revealed the presence of a small amount of calcium deposition for the samples treated with the osteogenic differentiation medium. Therefore, the proposed EF PU foam appears to stimulate cell adhesion in vitro, sustaining CMCs growth and differentiation into the osteogenic lineage.     

Differentiation of human adipose-derived stem cells seeded on mineralized electrospun co-axial poly(ε-caprolactone) (PCL)/gelatin nanofibers

Mineralized poly(ε-caprolactone)/gelatin core–shell nanofibers were prepared via co-axial electrospinning and subsequent incubation in biomimetic simulated body fluid containing ten times the calcium and phosphate ion concentrations found in human blood plasma. The deposition of calcium phosphate on the nanofiber surfaces was investigated through scanning electronic microscopy and X-ray diffraction. Energy dispersive spectroscopy results indicated that calcium-deficient hydroxyapatite had grown on the fibers. Fourier transform infrared spectroscopy analysis suggested the presence of hydroxyl-carbonate-apatite. The results of a viability assay (MTT) and alkaline phosphatase activity analysis suggested that these mineralized matrices promote osteogenic differentiation of human adipose-derived stem cells (hASCs) when cultured in an osteogenic medium and have the potential to be used as a scaffold in bone tissue engineering. hASCs cultured in the presence of nanofibers in endothelial differentiation medium showed lower rates of proliferation than cells cultured without the nanofibers. However, endothelial cell markers were detected in cells cultured in the presence of nanofibers in endothelial differentiation medium.     

Tissue-engineered fibrin scaffolds containing neural progenitors enhance functional recovery in a subacute model of SCI

Two recurring problems with stem/neural progenitor cell (NPC) transplantation therapies for spinal cord injury (SCI) are poor cell survival and uncontrolled cell differentiation. The current study evaluated the viability and differentiation of embryonic stem cell-derived neural progenitor cells (ESNPCs) transplanted within fibrin scaffolds containing growth factors (GFs) and a heparin-binding delivery system (HBDS) to enhance cell survival and direct differentiation into neurons. Mouse ESNPCs were generated from mouse embryonic stem cells (ESCs) using a 4-/4+ retinoic acid (RA) induction protocol that resulted in a population of cells that was 70% nestin positive NPCs. The ESNPCs were transplanted directly into a rat subacute dorsal hemisection lesion SCI model. ESNPCs were either encapsulated in a fibrin scaffold; encapsulated in fibrin containing the HBDS, neurotrophin-3 (NT-3) and platelet derived growth factor (PDGF-AA); or encapsulated in fibrin scaffolds with NT-3 and PDGF-AA without the HBDS. We report that the combination of GFs and fibrin scaffold (without HBDS) enhanced the total number of ESNPCs present in the treated spinal cords and increased the number of ESNPC-derived NeuN positive neurons 8 weeks after transplantation. All experimental groups treated with ESNPCs exhibited an increase in behavioral function 4 weeks after transplantation. In a subset of animals, the ESNPCs over-proliferated as evidenced by SSEA-1 positive/Ki67 positive ESCs found at 4 and 8 weeks. These results demonstrate the potential of tissue-engineered fibrin scaffolds to enhance the survival of NPCs and highlight the need to purify cell populations used in therapies for SCI.     

Osteogenic behavior of alginate encapsulated bone marrow stromal cells: An in vitro study

Sodium alginate is a useful polymer for the encapsulation and immobilization of a variety of cells in tissue engineering because it is biocompatible, biodegradable and easy to process into injectable microbeads. Despite these properties, little is known of the efficacy of calcium cross-linked alginate gel beads as a biodegradable scaffold for osteogenic cell proliferation and differentiation. In this study, we investigated the ability of rabbit derived bone marrow cells (BMCs) to proliferate and differentiate in alginate microbeads and compared them with BMCs cultured in poly-l-lysine (PLL) coated microbeads and on conventional 2D plastic surfaces. Results show that levels of proliferation and differentiation in microbeads and on tissue culture plastics were comparable. Cell proliferation in microbeads however diminished after fortification with a coating layer of PLL. Maximum cell numbers observed were, 3.32 × 10⁵ ± 1.72 × 103; 3.11 × 10⁵ ± 1.52 × 10³ and 3.28 × 10⁵ ± 1.21 × 10³ for the uncoated, PLL coated and plastic surface groups respectively. Alkaline phosphatase and protein expressions reflected the stage of cell differentiation. We conclude that calcium cross-linked alginate microbeads can act as a scaffold for BMC proliferation and osteogenic differentiation and has potential for use as 3D degradable scaffold.     

Encapsulation of Huh-7 cells within alginate-poly(ethylene glycol) hybrid microspheres

Novel calcium alginate poly(ethylene glycol) hybrid microspheres (Ca-alg-PEG) were developed and evaluated as potentially suitable materials for cell microencapsulation. Grafting 5–13% of the backbone units of sodium alginate (Na-alg) with α-amine-ω-thiol PEG maintained the gelling capacity in presence of calcium ions, while thiol end groups allowed for preparing chemically crosslinked hydrogel via spontaneous disulfide bond formation. The combination of these two gelling mechanisms yielded Ca-alg-PEG. Human hepatocellular carcinoma cells (Huh-7) were encapsulated in Ca-alg-PEG and calcium alginate beads (Ca-alg), and cultured for 2 weeks under agitation conditions. Immediately after completion of the microencapsulation, the cell viability was 60% and similar in Ca-alg-PEG and Ca-alg. The proliferation of Huh-7 encapsulated in Ca-alg-PEG was slightly higher than in Ca-alg. Accelerated proliferation after 2 weeks was observed for the encapsulation in Ca-alg-PEG. The production of albumin confirmed the functionality of the encapsulated Huh-7 cells. The study confirms the suitability of Ca-alg-PEG and the one-step technology for cell microencapsulation.     

The effects of vibration loading on adipose stem cell number,viability and differentiation towards bone-forming cells

Mechanical stimulation is an essential factor affecting the metabolism of bone cells and their precursors. We hypothesized that vibration loading would stimulate differentiation of human adipose stem cells (hASCs) towards bone-forming cells and simultaneously inhibit differentiation towards fat tissue. We developed a vibration-loading device that produces 3g peak acceleration at frequencies of 50 and 100 Hz to cells cultured on well plates. hASCs were cultured using either basal medium (BM), osteogenic medium (OM) or adipogenic medium (AM), and subjected to vibration loading for 3 h d^–1 for 1, 7 and 14 day. Osteogenesis, i.e. differentiation of hASCs towards bone-forming cells, was analysed using markers such as alkaline phosphatase (ALP) activity, collagen production and mineralization. Both 50 and 100 Hz vibration frequencies induced significantly increased ALP activity and collagen production of hASCs compared with the static control at 14 day in OM. A similar trend was detected for mineralization, but the increase was not statistically significant. Furthermore, vibration loading inhibited adipocyte differentiation of hASCs. Vibration did not affect cell number or viability. These findings suggest that osteogenic culture conditions amplify the stimulatory effect of vibration loading on differentiation of hASCs towards bone-forming cells.     

PSY-g-PAA/APT/SA载药复合凝胶小球的制备及释药性能

采用离子凝胶法制备了欧车前胶-g-聚丙烯酸/凹凸棒黏土/海藻酸钠(PSY-g-PAA/APT/SA)载药复合凝胶小球,以双氯芬酸钠为模型药物,考察了pH敏感性和凹凸棒黏土含量对凝胶小球的包封率、载药率、溶胀性能和药物释放行为的影响。结果表明,当释放介质为模拟胃液(pH=1.2)时,药物基本不释放;而为模拟肠液(pH=6.8)时,5h后累积释放率超过90%,复合凝胶小球具有明显的pH敏感性。随着凝胶小球中凹凸棒黏土含量的增加,溶胀率和药物累积释放率均减小,表明凹凸棒黏土的引入可以减缓药物的突释效应。