Drug-loaded Scaffolds Research Articles

3D printed bioinspired scaffolds integrating doxycycline nanoparticles: Customizable implants for in vivo osteoregeneration

3D printing has revolutionized pharmaceutical research, with applications encompassing tissue regeneration and drug delivery. Adopting 3D printing for pharmaceutical drug delivery personalization via nanoparticle-reinforced hydrogel scaffolds promises great regenerative potential. Herein, we engineered novel core/shell, bio-inspired, drug-loaded polymeric hydrogel scaffolds for pharmaceutically personalized drug delivery and superior osteoregeneration. Scaffolds were developed using biopolymeric blends of gelatin, polyvinyl alcohol and hyaluronic acid and integrated with composite doxycycline/hydroxyapatite/polycaprolactone nanoparticles (DX/HAp/PCL) innovatively via 3D printing. The developed scaffolds were optimized for swelling pattern and in-vitro drug release through tailoring the biphasic microstructure and wet/dry state to attain various pharmaceutical personalization platforms. Freeze-dried scaffolds with nanoparticles reinforcing the core phase (DX/HAp/PCL-LCS-FD) demonstrated favorably controlled swelling, preserved structural integrity and controlled drug release over 28 days. DX/HAp/PCL-LCS-FD featured double-ranged pore size (90.4 ± 3.9 and 196.6 ± 38.8 µm for shell and core phases, respectively), interconnected porosity and superior mechanical stiffness (74.5 ± 6.8 kPa) for osteogenic functionality. Cell spreading analysis, computed tomography and histomorphometry in a rabbit tibial model confirmed osteoconduction, bioresorption, immune tolerance and bone regenerative potential of the original scaffolds, affording complete defect healing with bone tissue. Our findings suggest that the developed platforms promise prominent local drug delivery and bone regeneration.

Dual drug release mechanisms through mesoporous silica nanoparticle/electrospun nanofiber for enhanced anticancer efficiency of curcumin.

Electrospun nanofibers (NFs)-based drug delivery approaches are of particular interest as a hopeful implantable nanoplatform for localized cancer therapy and treating tissue defect after resection, allowing the on-site drug delivery with minimal side effect to healthy cells. To maintain therapeutic concentrations of anticancer molecules for a relatively long time through a combination of burst and sustained drug release mechanisms, a hybrid of polycaprolactone and gelatin (PCL/GEL) was used for co-encapsulation of free curcumin (CUR) and CUR-loaded mesoporous silica nanoparticles (CUR@MSNs) via electrospinning, resulting in a novel drug-loaded nanofibrous scaffold, CUR/CUR@MSNs-NFs. The as-prepared MSNs and composite NFs were characterized via TGA, FTIR, FE-SEM, TEM, and BET. In vitro release profile of CUR from CUR/CUR@MSNs-NFs was examined, and the in vitro antitumor efficacy against MDA-MB-231 breast cancer cells was also evaluated through MTT, scratch assay, DAPI staining, and real-time PCR. The results disclosed that the smooth, bead-free, and randomly oriented CUR/CUR@MSNs-NFs displayed a combination of initial rapid discharge and sustained release for CUR, which led to higher cytotoxicity, lower migration as well as a more pronounced effect on apoptosis induction than CUR-NFs and CUR@MSNs-NFs. The present study illustrated that the dual drug release mechanisms through MSN/NF-mediated drug delivery systems might have a highly hopeful application as a localized implantable scaffold for potential postoperative breast cancer therapy.

The Application of 3D-Printing and Nanotechnology for the Targeted Treatment of Osteosarcoma

Osteosarcoma is a malignant bone neoplasm prevalent in adolescents. Current therapies include chemotherapy and surgery. Surgical resection of osteosarcoma induces a large bone defect which may be overcome by employing scaffolds for bone tissue engineering. This review details the polymers and bioceramics that may be used to fabricate 3D printed scaffolds for bone regeneration and the nanotechnology strategies that may be incorporated into such scaffolds. Natural polymers discussed include chitosan, alginate, collagen, gelatin, and silk fibroin. Synthetic polymers discussed include polycaprolactone, polyurethane, poly(lactic)acid and poly(vinyl) alcohol. Bioceramics that are utilized in bone regeneration such as calcium phosphate, calcium silicate and bioglass are elaborated on. Furthermore, comparison data between different types of 3D printed scaffolds for bone regeneration are presented. A discussion on Photo-responsive and magneto-responsive 3D printed scaffolds that have been fabricated for bone regeneration is included. Research concerning drug-loaded scaffolds as well as the incorporation of nanocarriers into scaffolds for bone regeneration is provided. Chemotherapy utilized in osteosarcoma therapy has severe adverse effects due to being non-selective between healthy cells and tumor cells. A possible way to overcome this is to utilize nanotechnology. Therefore, research detailing other types of nanocarriers that have the potential to be incorporated into 3D printed scaffolds for localized adjuvant therapy is presented.

Preparation and performance of porous hydroxyapatite/poly(lactic-co-glycolic acid) drug-loaded microsphere scaffolds for gentamicin sulfate delivery

Preparation and performance of porous hydroxyapatite/poly(lactic-co-glycolic acid) drug-loaded microsphere scaffolds for gentamicin sulfate delivery

Melt Electrospinning of Polymers: Blends, Nanocomposites, Additives and Applications

Melt electrospinning has been developed in the last decade as an eco-friendly and solvent-free process to fill the gap between the advantages of solution electrospinning and the need of a cost-effective technique for industrial applications. Although the benefits of using melt electrospinning compared to solution electrospinning are impressive, there are still challenges that should be solved. These mainly concern to the improvement of polymer melt processability with reduction of polymer degradation and enhancement of fiber stability; and the achievement of a good control over the fiber size and especially for the production of large scale ultrafine fibers. This review is focused in the last research works discussing the different melt processing techniques, the most significant melt processing parameters, the incorporation of different additives (e.g., viscosity and conductivity modifiers), the development of polymer blends and nanocomposites, the new potential applications and the use of drug-loaded melt electrospun scaffolds for biomedical applications.

Preparation and characterisation of a novel polylactic acid/hydroxyapatite/graphene oxide/aspirin drug-loaded biomimetic composite scaffold

The prepared scaffold has good cytocompatibility, hemocompatibility and controlled drug release, and has biomimetic structure and drug loaded function.

Development of electrospun polymer scaffolds for the localized and controlled delivery of siponimod for the management of critical bone defects.

Sphingosine 1-phosphate (S1P) receptor modulators can influence bone regeneration owing to their positive impact on osteoblast differentiation and neovascularisation. While previous studies have utilised non-specific S1P and fingolimod, this study aims to design and characterise a controlled release vehicle to deliver the specific S1P1 & 5 receptor modulator siponimod and test its effectiveness in rat critical cranial defects. Electrospun scaffolds of poly lactide-co-glycolide (PLGA) were loaded with siponimod at drug:polymer mass ratios of 0.5:100 to 2:100. Where indicated, collagen was co-spun at a collagen:polymer mass ratio of 2:100. Thereafter, scaffolds underwent in vitro physicochemical characterisation and in vivo assessment using a rat cranial defect model. Drug-loaded scaffolds showed controlled release of siponimod, -cytocompatibility with endothelial and osteoblast cells in vitro, and furthermore, showed that released siponimod stimulated osteoblast differentiation and endothelial cell migration. The in vivo cranial defect repair study showed regeneration was occurring in the defect, although there was no significant difference in the extent of mineralisation between scaffold experimental groups. To our knowledge, this is the first study investigating siponimod in bone regeneration. In vitro studies confirm a positive impact on key cells involved in bone regeneration, however, the scaffolds did not result in significant repair of critical cranial defects.

Accelerated diabetic wound healing by topical application of combination oral antidiabetic agents-loaded nanofibrous scaffolds: An in vitro and in vivo evaluation study

The combination of oral antidiabetic drugs, pioglitazone, metformin, and glibenclamide, which also exhibit the strongest anti-inflammatory action among oral antidiabetic drugs, were loaded into chitosan/gelatin/polycaprolactone (PCL) by electrospinning and polyvinyl pyrrolidone (PVP)/PCL composite nanofibrous scaffolds by pressurized gyration to compare the diabetic wound healing effect. The combination therapies significantly accelerated diabetic wound healing in type-1 diabetic rats and organized densely packed collagen fibers in the dermis, it also showed better regeneration of the dermis and epidermis than single drug-loaded scaffolds with less inflammatory cell infiltration and edema. The formation of the hair follicles started in 14 days only in the combination therapy and lower proinflammatory cytokine levels were observed compared to single drug-loaded treatment groups. The combination therapy increased the wettability and hydrophilicity of scaffolds, demonstrated sustained drug release over 14 days, has high tensile strength and suitable cytocompatibility on L929 (mouse fibroblast) cell and created a suitable area for the proliferation of fibroblast cells. Consequently, the application of metformin and pioglitazone-loaded chitosan/gelatin/PCL nanofibrous scaffolds to a diabetic wound area offer high bioavailability, fewer systemic side effects, and reduced frequency of dosage and amount of drug.

Tanshinone IIA-loaded aligned microfibers facilitate stem cell recruitment and capillary formation by inducing M2 macrophage polarization

Direct implantation of cell-free scaffolds capable of promoting tissue regeneration by manipulating immune responses has proven to be a promising therapeutic strategy for regenerative medicine. Here, we developed aligned microfiber scaffolds with sustained release of tanshinone ⅡA (Tan ⅡA) to modulate macrophages phenotypic transition, which subsequently promoted stem cell recruitment and capillary formation. Aligned microfibers scaffolds loaded with 1μM Tan ⅡA (AF-1) significantly down-regulated the expression of proinflammatory genes and proteins, while they upregulated anti-inflammatory genes and proteins, in RAW 264.7 macrophages. Conditioned medium collected from macrophages cultured on AF-1 scaffolds enhanced bone marrow-derived mesenchymal stem cell (BMSC) proliferation and migration, and also regulated their multiple biological functions as evidenced by RNA-Seq assays. Moreover, the conditioned medium also promoted human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation. Enhancement of endogenous stem cell recruitment and vascularization by regulating macrophage phenotype transition was further confirmed by utilizing rat subcutaneous implantation of the scaffolds. These results support the use of drug-loaded aligned microfiber scaffolds to enable immune modulation to stimulate stem cell recruitment and vascularization, which could potentially result in successful cell-free, scaffold-guided tissue regeneration.

Effect of poly(ethylene glycol) on drug delivery, antibacterial, biocompatible, physico-chemical and thermo-mechanical properties of PCL-chloramphenicol electrospun nanofiber scaffolds

The present study investigates the effect of poly(ethylene glycol) (PEG) addition on physico-chemical, thermo-mechanical, drug release, antibacterial and biocompatible properties of poly(ε-caprolactone) (PCL)-chloramphenicol (CAP) electrospun nanofiber scaffolds. Incorporation of PEG imparted enhanced hydrophilicity, crystallinity, glass transition temperature and cell growth ability and reduced cytotoxicity in PCL. In vitro drug release studies reveal that PEG addition in PCL-CAP facilitated well-defined release kinetics and the release profiles follow the Ritger–Peppas and Korsmeyer–Peppas model. The drug-loaded scaffolds showed antibacterial properties against both Gram-positive and Gram-negative bacterial strains. Further, addition of PEG significantly improved the biocompatibility of the PCL-CAP scaffolds.

Drug-loading three-dimensional scaffolds based on hydroxyapatite-sodium alginate for bone regeneration.

Bone tissue engineering is a promising approach for tackling clinical challenges. Osteoprogenitor cells, osteogenic factors, and osteoinductive/osteoconductive scaffolds are employed in bone tissue engineering. However, scaffold materials remain limited due to their source, low biocompatibility, and so on. In this study, a composite hydrogel scaffold composed of hydroxyapatite (HA) and sodium alginate (SA) was manufactured using three-dimensional printing. Naringin (NG) and calcitonin-gene-related peptide (CGRP) were used as osteogenic factors in the fabrication of drug-loaded scaffolds. Investigation using animal experiments, as well as scanning electron microscopy, cell counting kit-8 testing, alkaline phosphatase staining, and alizarin red-D staining of bone marrow mesenchymal stem cell culture showed that the three scaffolds displayed similar physicochemical properties and that the HA/SA/NG and HA/SA/CGRP scaffolds displayed better osteogenesis than that of the HA/SA scaffold. Thus, the HA/SA scaffold could be a biocompatible material with potential applications in bone regeneration. Meanwhile, NG and CGRP doping could result in better and more positive proliferation and differentiation.

Selective laser sintered nano-HA/PDLLA composite microspheres for bone scaffolds applications

Purpose The main cause of aseptic inflammation after an in vivo implantation is that Poly(L-lactide) (PLLA) and Poly(D-lactide) have a slower degradation and absorption rate, while Poly(D, L-lactide) (PDLLA) has a much faster degradation rate than PLLA because of its amorphous structure. Also, the hydrolyzate of Hydroxyapatite (HA) is alkaline, which can neutralize local tissue peracid caused by hydrolysis of Polylactic acid. Design/methodology/approach In this study, the selective laser sintering (SLS) technique was chosen to prepare bone scaffolds using nano-HA/PDLLA composite microspheres, which were prepared by the solid-in-oil-in-water (S/O/W) method. First, the SLS parameters range of bulk was determined by the result of a single-layer experiment and the optimized parameters were then obtained by the orthogonal experiment. The tensile property, hydrophobicity, biocompatibility, biological toxicity and in vitro degradation of the samples with optimized SLS parameters were characterized. Findings As a result, the samples showed a lower tensile strength because of the many holes in their interior, which was conducive to better cell adhesion and nutrient transport. In addition, the samples retained their inherent properties after SLS and the hydrophobicity was improved after adding nano-HA because of the OH group. Furthermore, the samples showed good biocompatibility with the large number of cells adhering to the material through pseudopods and there was no significant difference between the pure PDLLA and 10% HA/PDLLA in terms of biological toxicity. Finally, the degradation rate of the composites could be tailored by the amount of nano-HA. Originality/value This study combined the S/O/W and SLS technique and provides a theoretical future basis for the preparation of drug-loaded microsphere scaffolds through SLS using HA/PDLLA composites.

Degradable porous drug-loaded polymer scaffolds for localized cancer drug delivery and breast cell/tissue growth.

This paper presents the results of a combined experimental and analytical study of blended FDA-approved polymers [polylactic-co-glycolic acid (PLGA), polyethylene glycol (PEG) and polycaprolactone (PCL)] with the potential for sustained localized cancer drug release. Porous drug-loaded 3D degradable PLGA-PEG and PLGA-PCL scaffolds were fabricated using a multistage process that involved solvent casting and particulate leaching with lyophilization. The physicochemical properties including the mechanical, thermal and biostructural properties of the drug-loaded microporous scaffolds were characterized. The release of the encapsulated prodigiosin (PG) or paclitaxel (PTX) drug (from the drug-loaded polymer scaffolds) was also studied experimentally at human body temperature (37 °C) and hyperthermic temperatures (41 and 44 °C). These characteristic controlled and localized in vitro drug release from the properties of the microporous scaffold were analyzed using kinetics and thermodynamic models. Subsequently, normal breast cells (MCF-10A) were cultured for a 28-day period on the resulting 3D porous scaffolds in an effort to study the possible regrowth of normal breast tissue, following drug release. The effects of localized cancer drug release on breast cancer cells and normal breast cell proliferation are demonstrated for scenarios that are relevant to palliative breast tumor surgery for 16 weeks under in vivo conditions. Results from the in vitro drug release show a sustained anomalous (non-Fickian) drug release that best fits the Korsmeyer-Peppas (KP) kinetic model with a non-spontaneous thermodynamic process that leads to a massive decrease in breast cancer cell (MDA-MB-231) viability. Our findings from the animal suggest that localized drug release from drug-based 3D resorbable porous scaffolds can be used to eliminate/treat local recurred triple negative breast tumors and promote normal breast tissue regeneration after surgical resection.

Bioactive ophiopogonin release form bioglass-collagen-phosphatidylserine scaffolds to enhance bone repair in vitro

The goal of this study is to construct bone scaffolds with neuroregulatory function. The scaffolds were prepared using bioglass (BG) powder, collagen (COL) solution, phosphatidylserine (PS) and ophiopogonin loaded COL microspheres as the main components. Combinatorial processing techniques involving chemical-crosslinking and freeze-drying were used. The resultant scaffold constructs were characterized in terms of their morphology, drug release kinetics, pharmacological and biological activities for osteoblast and neurocyte. The microporphology observation showed that the scaffolds had highly interconnected pores, favorable drug release kinetics in view of low initial release and slow average release rate. Moreover, cell studies showed that the involvement of ophiopogonin contributed to the proliferation and mineralization of MC3T3-E1 cells, and the neurite outgrowth of neuron. The drug-loaded composite scaffolds may therefore be a potential replacement in bone-tissue engineering.

Sustained release of inhibitor from bionic scaffolds for wound healing and functional regeneration.

Small molecules play remarkable roles in promoting tissue regeneration, but are limited by their burst release. Small molecules such as deferoxamine (DFO) have been released slowly from silk hydrogels and stimulated angiogenesis and wound healing, but failed to achieve functional recovery of skin. Various bioactive molecules are required to create a suitable niche for better skin regeneration by controlling their release behaviors. Herein, a small molecule SB216763, a GSK-3 inhibitor, was loaded on silk fibroin nanofibers (SNF), and then mixed with chitosan (CS) to prepare the small molecule-loaded composite bionic scaffolds (CSNF-SB). Given the interaction of SNF and SB216763, the sustained release of SB216763 for more than 21 days was achieved for SNF and CSNF-SB composite scaffolds. Compared to drug-free CSNF scaffolds, CSNF-SB showed better cell adhesion and proliferation capacity, suggesting bioactivity. The upregulated expression of β-catenin in fibroblasts in vitro revealed that the released small molecules maintained their function in composite scaffolds. Quicker and better wound healing was realized with the drug-loaded scaffolds, which was significantly superior to that treated with drug-free scaffolds. Unlike the DFO-loaded silk hydrogel system, hair follicle neogenesis was also found in the drug-loaded-scaffold treatment wounds, demonstrating functional recovery. Therefore, silk nanofibers as versatile carriers for different small bioactive molecules could be used to fabricate scaffolds with optimized niches and then achieve functional recovery of tissues. The small molecule-loaded bionic scaffolds have a promising future in skin tissue regeneration.

Sustained delivery of 17β-estradiol by human amniotic extracellular matrix (HAECM) scaffold integrated with PLGA microspheres for endometrium regeneration

The endometrial injury usually results in intrauterine adhesions (IUAs). However, there is no effective treatment to promote the regeneration of the endometrium currently. The decellularized amnion membrane (AM) is a promising material in human tissue repair and regeneration due to its biocompatibility, biodegradability, as well as the preservation of abundant bioactive components. Here, an innovative drug-delivering system based on human amniotic extracellular matrix (HAECM) scaffolds were developed to facilitate endometrium regeneration. The 17β-estradiol (E2) loaded PLGA microspheres (E2-MS) were well dispersed in the scaffolds without altering their high porosity. E2 released from E2-MS-HAECM scaffolds in vitro showed a decreased initial burst release followed with a sustained release for 21 days, which coincided with the female menstrual cycle. Results of cell proliferation suggested E2-MS-HAECM scaffolds had good biocompatibility and provided more biologic guidance of endometrial cell proliferation except for mechanical supports. Additionally, the mRNA expression of growth factors in endometrial cells indicated that HAECM scaffolds could upregulate the expression of EGF and IGF-1 to achieve endometrium regeneration. Therefore, these advantages provide the drug-loaded bioactive scaffolds with new choices for the treatments of IUAs.

Preparation and characterization of antibacterial dopamine-functionalized reduced graphene oxide/PLLA composite nanofibers.

Electrospun poly(l)-lactide (PLLA) ultrafine fibers are a biodegradable and biocompatible scaffold, widely used in tissue engineering applications. Unfortunately, these scaffolds have some limitations related to the absence of bioactivity and antibacterial capacity. In this study, dopamine-functionalized reduced graphene oxide (rGO)/PLLA composite nanofibers were fabricated via electrospinning. The morphology and the physicochemical and biological properties of the composite nanofibers were investigated. The results indicate that incorporating rGO improves the hydrophilic, mechanical, and biocompatibility properties of PLLA nanofibers. Tetracycline hydrochloride (TC)-loaded rGO/PLLA composite nanofibers showed better controlled drug release profiles compared to GO/PLLA and PLLA nanofibrous scaffolds. Drug-loaded nanofibrous scaffolds showed significantly improved antibacterial activity against Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus). Additionally, rGO/PLLA composite nanofibers exhibited enhanced cytocompatibility. Thus, it can be concluded that rGO/PLLA composite nanofibers allow the development of multifunctional scaffolds for use in biomedical applications.

Silk based scaffolds with immunomodulatory capacity: anti-inflammatory effects of nicotinic acid.

Implantation of temporary and permanent biomaterials in the body leads to a foreign body reaction (FBR), which may adversely affect tissue repair processes and functional integration of the biomaterial. However, modulation of the inflammatory response towards biomaterials can potentially enable a favorable healing response associated with functional tissue formation and tissue regeneration. In this work, incorporation of nicotinic acid in 3D silk scaffolds is explored as an immunomodulatory strategy for implantable biomaterials. Silk scaffolds were fabricated from dissolved Bombyx mori silk fibers by freeze-drying, resulting in silk scaffolds with high porosity (>94%), well-connected macropores, a high swelling degree (>550%) and resistance to in vitro degradation. Furthermore, drug-loaded scaffolds displayed a sustained drug release and excellent cytocompatibility could be observed with osteoblast-like MG63 cells. Cultivating M1-like macrophages on the scaffolds revealed that scaffolds loaded with nicotinic acid suppress gene expression of pro-inflammatory markers TNF-α, CXCL10 and CD197 as well as secretion of TNF-α in a concentration dependant manner. Hence, this study provides insights into the possible application of nicotinic acid in tissue engineering to control inflammatory responses towards biomaterials and potentially help minimizing FBR.

Experimental study on preparation of coaxial drug-loaded tissue-engineered bone scaffold by 3D printing technology.

In order to combine the drug with the tissue-engineered bone scaffold and make the drugs on the scaffolds stable to achieve sustained-release stepwise function, a new method for preparing coaxial drug-loaded tissue engineering bone scaffolds using coaxial three-dimensional printing technology is proposed, in which inner layer material can carry drugs and the outer material can adjust the drug sustained-release rate. The coupling mechanism of both shape control and property control in the process of coaxial three-dimensional printing micro-structural unit is presented. Design-Expert software is introduced for experimental design. The influences of extrusion speed, filling speed, and delamination height on the forming quality are analyzed, and a coaxial gradient composite scaffold model with controllable micro-structure is established. The macro-structure, mechanical properties, in vitro degradation rate, and drug release rate of the scaffolds were analyzed. The experimental results show that the proposed forming technology and process parameter optimization can effectively improve the forming quality of the coaxial scaffold. At the same time, this design of the coaxial structure can effectively slow down the degradation rate of the scaffold and enables stable and long-time drug release. Furthermore, the presented method provides a new technical approach for the further implementation of implantable drug delivery systems for the effective treatment of bone tuberculosis.

E-jet 3D printed drug delivery implants to inhibit growth and metastasis of orthotopic breast cancer

Drug-loaded implants have attracted considerable attention in cancer treatment due to their precise delivery of drugs into cancer tissues. Contrary to injected drug delivery, the application of drug-loaded implants remains underutilized given the requirement for a surgical operation. Nevertheless, drug-loaded implants have several advantages, including a reduction in frequency of drug administration, minimal systemic toxicity, and increased delivery efficacy. Herein, we developed a new, precise, drug delivery device for orthotopic breast cancer therapy able to suppress breast tumor growth and reduce pulmonary metastasis using combination chemotherapy. Poly-lactic-co-glycolic acid scaffolds were fabricated by 3D printing to immobilize 5-fluorouracil and NVP-BEZ235. The implantable scaffolds significantly reduced the required drug dosages and ensured curative drug levels near tumor sites for prolonged period, while drug exposure to normal tissues was minimized. Moreover, long-term drug release was achieved, potentially allowing one-off implantation and, thus, a major reduction in the frequency of drug administration. This drug-loaded scaffold has great potential in anti-tumor treatment, possibly paving the way for precise, effective, and harmless cancer therapy.