RESUMEN
Implants of bioresorbable materials combined with osteoconductive calcium phosphate ceramics show promising results to replace and repair damaged bone tissue. Here we present additive manufacturing of patient-specific porous scaffolds of poly(trimethylene carbonate) (PTMC) including high amounts of ß-tricalcium phosphate (ß-TCP). Tensile testing of composite networks showed that addition of ß-tricalcium phosphate reinforces the composites significantly. Three-dimensional structures containing up to 60 wt % ß-TCP could be built by stereolithography. By lowering the content to 51 wt %, manufacturing of a large-sized patient-specific prototype was possible at high resolution. Closer examination revealed that the created scaffolds contained more ß-TCP on the surface of the builds. Stereolithography therefore provides a manufacturing technique where the bioactive agent is directly available for creating an enhanced microenvironment for cell growth. The biocompatibility and bioresorption of PTMC coupled with the osteoconductivity of ß-TCP are an important candidate to consider in additive manufacturing of bone regeneration implants.
Asunto(s)
Regeneración Ósea , Fosfatos de Calcio/química , Dioxanos/química , Polímeros/química , Estereolitografía , Andamios del Tejido/química , Rastreo Diferencial de Calorimetría , Ensayo de Materiales , Polimerizacion , Porosidad , Resistencia a la Tracción , TermogravimetríaRESUMEN
Despite their sustainable appeal, biomass components are currently undervalued in nanotechnology because means to control the assembly of bio-based nanoparticles are lagging behind the synthetic counterparts. Here, micrometer-sized particles consisting of aligned cellulose nanocrystals (CNCs) are prepared by crosslinking cellulose in cotton linter fibers that are prehydrolyzed with gaseous HCl, resulting in chemical cleavage necessary for CNC formation but retaining the morphology of the native fibers. That way, the intrinsic alignment of cellulose microfibrils within the fiber cell wall can be retained and utilized for top-down CNC alignment. Subsequent crosslinking with citric acid cements the alignment and preserves it, following the dispersion of CNCs trapped end-to-end, connected, and crosslinked within the colloidally stable micrometer-sized particles. Furthermore, thermoporosimetry and cryogenic transmission electron microscopy (Cryo TEM) shows that the particles possess mainly nanoporous (<2 nm) character in water. The approach challenges the current paradigm of predominantly bottom-up methods for nanoparticle assembly.
Asunto(s)
Pared Celular/química , Celulosa/química , Nanopartículas/química , Hidrólisis , Microscopía de Fuerza Atómica , Microscopía Electrónica de Transmisión , Nanopartículas/ultraestructura , Nanoporos/ultraestructura , Nanotecnología , Tamaño de la Partícula , Propiedades de Superficie , Agua/químicaAsunto(s)
Materiales Biocompatibles/química , Polímeros/química , Bioimpresión/métodos , Dioxanos/química , Sistemas de Liberación de Medicamentos , Electrónica/instrumentación , Hidrogeles/química , Ácidos Nucleicos/administración & dosificación , Impresión Tridimensional , Ingeniería de Tejidos/métodosRESUMEN
Three-armed poly(trimethylene carbonate) (PTMC) and poly(trimethylene carbonate-co-Æ-caprolactone) (P(TMC-co-ε-CL)) macromers with molecular weights of approximately 30 kg mol-1 are synthesized by ring-opening polymerization and subsequent functionalization with methacrylic anhydride. Networks are then prepared by photo-crosslinking. To investigate the in vitro and in vivo degradation properties of these photo-crosslinked networks and assess the effect of ε-caprolactone content on the degradation properties, PTMC networks, and copolymer networks with two different TMC:ε-CL ratios are prepared. PTMC networks degraded slowly, via an enzymatic surface erosion process, both in vitro and in vivo. Networks prepared from P(TMC-co-ε-CL) macromers with a 74:26 ratio are found to degrade slowly as well, via a surface erosion process, albeit at a higher rate compared to PTMC networks. Increasing the ε-CL content to a ratio of 52:48, resulted in a faster degradation. These networks lost their mechanical properties much sooner than the other networks. Thus, PTMC and P(TMC-co-ε-CL) networks are interesting networks for tissue engineering purposes and the exact degradation properties can be tuned by varying the TMC:ε-CL ratio, providing researchers with a tool to obtain copolymer networks with the desired degradation rate depending on the intended application.
Asunto(s)
Caproatos , Lactonas , Poliésteres , Polímeros , Polímeros/metabolismo , DioxanosRESUMEN
We propose an injectable nanocomposite hydrogel that is photo-curable via light-induced thiol-ene addition between methacrylate modified O-acetyl-galactoglucomannan (GGMMA) and thiolated cellulose nanocrystal (CNC-SH). Compared to free-radical chain polymerization, the orthogonal step-growth of thiol-ene addition allows a less heterogeneous hydrogel network and more rapid crosslinking kinetics. CNC-SH reinforced the GGMMA hydrogel as both a nanofiller and a crosslinker to GGMMA resulting in an interpenetrating network via thiol-ene addition. Importantly, the mechanical stiffness of the GGMMA/CNC-SH hydrogel is mainly determined by the stoichiometric ratio between the thiol groups on CNC-SH and the methacrylate groups in GGMMA. Meanwhile, the bioactive glass nanoparticle (BaGNP)-laden hydrogels of GGMMA/CNC-SH showed a sustained release of therapeutic ions in simulated body fluid in vitro, which extended the bioactive function of hydrogel matrix. Furthermore, the suitability of the GGMMA/CNC-SH formulation as biomaterial resin to fabricate digitally designed hydrogel constructs via digital light processing (DLP) lithography printing was evaluated.
Asunto(s)
Celulosa/química , Vidrio/química , Mananos/química , Nanogeles/química , Nanopartículas/química , Compuestos de Sulfhidrilo/química , Materiales Biocompatibles/química , Sistemas de Liberación de Medicamentos/métodos , Humanos , Hidrogeles/química , Inyecciones/métodos , Iones/química , Metacrilatos/química , Polimerizacion , Impresión Tridimensional , Ingeniería de Tejidos/métodosRESUMEN
A major challenge with extensive craniomaxillofacial bone reconstruction is the limited donor-site availability to reconstruct defects predictably and accurately according to the anatomical shape of the patient. Here, patient-specific composite bioimplants, consisting of cross-linked poly(trimethylene carbonate) (PTMC) networks and ß-tricalcium phosphate (ß-TCP), are tested in vivo in twelve Göttingen minipigs in a large mandibular continuity defect model. The 25 mm defects are supported by patient-specific titanium reconstruction plates and receive either osteoconductive composite bioimplants (PTMC+TCP), neat polymer network bioimplants (PTMC), autologous bone segments (positive control), or are left empty (negative control). Postoperatively, defects treated with bioimplants show evident ossification at 24 weeks. Histopathologic evaluation reveals that neat PTMC bioimplant surfaces are largely covered with fibrous tissue, while in the PTMC+TCP bioimplants, bone attached directly to the implant surface shows good osteoconduction and histological signs of osteoinductivity. However, PTMC+TCP bioimplants are associated with high incidence of necrosis and infection, possibly due to rapid resorption and/or particle size of the used ß-TCP. The study highlights the importance of testing bone regeneration implants in a clinically relevant large animal model and at the in situ reconstruction site, since results on small animal models and studies in nonloadbearing areas do not translate directly.
Asunto(s)
Sustitutos de Huesos , Fosfatos de Calcio , Animales , Regeneración Ósea , Huesos , Humanos , Modelos Animales , Porcinos , Porcinos Enanos , Flujo de TrabajoRESUMEN
Additive manufacturing (AM) is gaining interests in drug delivery applications, offering innovative opportunities for the design and development of systems with complex geometry and programmed controlled release profile. In addition, polymer-based drug delivery systems can improve drug safety, efficacy, patient compliance, and are the key materials in AM. Therefore, combining AM and polymers can be beneficial to overcome the existing limitations in the development of controlled release drug delivery systems. Considering these advantages, here we are focusing on the recent developments in the field of polymeric drug delivery systems prepared by AM. This review provides a comprehensive overview on a holistic polymer-AM perspective for drug delivery systems with discussion on the materials, properties, design and fabrication techniques and the mechanisms used to achieve a controlled release system. The current challenges and future perspectives for personalized medicine and clinical use of these systems are also briefly discussed.
Asunto(s)
Sistemas de Liberación de Medicamentos , Polímeros/química , Impresión Tridimensional , HumanosRESUMEN
Large critical size bone defects are complicated to treat, and in many cases, autografts become a challenge due to size and availability. In such situations, a synthetic bone implant that can be patient-specifically designed and fabricated with control over parameters such as porosity, rigidity, and osteogenic cues can act as a potential synthetic bone substitute. In this study, we produced photocuring composite resins with poly(trimethylene carbonate) containing high ratios of bioactive ceramics and printed porous 3D composite scaffolds to be used as bone grafts. To enhance the overall surface area available for cell infiltration, the scaffolds were also filled with a macroporous cryogel. Furthermore, the scaffolds were functionalized with osteoactive factors: bone morphogenetic protein and zoledronic acid. The scaffolds were evaluated in vitro for biocompatibility and for functionality in vivo in critical bone defects (â¼8 mm) in two clinically relevant rabbit models. These studies included a smaller study in rabbit tibia and a larger study in the rabbit cranium. It was observed that the bioactive molecule-functionalized 3D printed porous composite scaffolds provide an excellent conductive surface inducing higher bone formation and improved defect healing in both critical size long bones and cranial defects. Our findings provide strong evidence in favor of these composites as next generation synthetic bone substitutes.
Asunto(s)
Materiales Biocompatibles/química , Sustitutos de Huesos/química , Impresión Tridimensional , Andamios del Tejido/química , Animales , Regeneración Ósea , Masculino , Osteogénesis , Tamaño de la Partícula , Porosidad , Conejos , Propiedades de SuperficieRESUMEN
Photo-crosslinked synthetic biodegradable polymer networks are highly interesting materials for utilization in biomedical applications such as drug delivery, cell encapsulation and tissue engineering scaffolds. Varying the architecture, chemistry, degree of functionalization and molecular weight of the macromer precursor molecules results in networks with a wide range of physical- and mechanical properties, crosslinking densities, degradation characteristics and thus in potential applications. Photo-crosslinked networks can easily be prepared and have the possibility to entrap a wide range of (biologically active) substances and cells. Additionally, spatial and temporal control over the crosslinking process when using additive manufacturing processes, allows for the preparation of network structures with complex shapes. Photo-crosslinked networks have been used to prepare drug delivery devices, as these networks allow for drug delivery in a controlled way over a prolonged period of time. Furthermore, additive manufacturing techniques such as extrusion-based additive manufacturing and stereolithography have been used to prepare photo-crosslinked tissue engineering scaffolds. This allows for the preparation of designed porous structures with precise control over the pore size and pore architecture and optimal mechanical properties. In particular for stereolithography, a wide variety of resins based on biodegradable photo-crosslinkable macromers has been developed.
Asunto(s)
Materiales Biocompatibles/síntesis química , Plásticos Biodegradables/síntesis química , Reactivos de Enlaces Cruzados/química , Procesos Fotoquímicos , Animales , Línea Celular , Portadores de Fármacos/química , Humanos , Fenómenos Mecánicos , Polimerizacion , Porosidad , Impresión Tridimensional , Ingeniería de Tejidos , Andamios del Tejido/químicaRESUMEN
Three-armed poly(trimethylene carbonate) macromers with a relatively high molecular weight of 28.9 kg mol-1 are prepared by ring opening polymerization and subsequent functionalization with methacrylate end groups. A resin suitable for processing by stereolithography is developed using propylene carbonate as a diluent, a photoinitiator, and a dye to control the curing characteristics. The difficulties in building designed structures with digital light processing stereolithography and the ways of optimizing the resin compositions are described in detail. Using an optimized resin composition, which contained 50 wt% macromer, 50 wt% diluent, 0.05 wt% (relative to the macromer) dye, and 5 wt% (relative to the macromer) photoinitiator, designed 3D porous structures with a gyroid pore network geometry are manufactured. By varying pore sizes and porosities between, respectively, 300 and 1000 µm and 60% and 90%, cylindrical porous poly(trimethylene carbonate) network structures with compression moduli of 85-2320 kPa are prepared. A porous poly(trimethylene carbonate) network meniscus implant is designed on the basis of computed tomography imaging data. By adjusting the characteristics of the gyroid pore architecture, an implant with a compression modulus close to 400 kPa, which fits the compression modulus of human meniscal tissue, is manufactured by stereolithography.
Asunto(s)
Materiales Biocompatibles/síntesis química , Dioxanos/síntesis química , Menisco/química , Polímeros/síntesis química , Ingeniería de Tejidos/métodos , Andamios del Tejido/química , Humanos , Polimerizacion , Porosidad , Impresión Tridimensional , Resistencia a la TracciónRESUMEN
Photo-crosslinked networks prepared from three-armed methacrylate functionalized PTMC oligomers (PTMC-tMA macromers) are attractive materials for developing an anatomically correct meniscus scaffold. In this study, we evaluated cell specific biocompatibility, in vitro and in vivo degradation behavior of, and tissue response to, such PTMC networks. By evaluating PTMC networks prepared from PTMC-tMA macromers of different molecular weights, we were able to assess the effect of macromer molecular weight on the degradation rate of the PTMC network obtained after photo-crosslinking. Three photo-crosslinked networks with different crosslinking densities were prepared using PTMC-tMA macromers with molecular weights 13.3, 17.8, and 26.7 kg/mol. Good cell biocompatibility was demonstrated in a proliferation assay with synovium derived cells. PTMC networks degraded slowly, but statistically significant, both in vitro as well as subcutaneously in rats. Networks prepared from macromers with higher molecular weights demonstrated increased degradation rates compared to networks prepared from initial macromers of lowest molecular weight. The degradation process took place via surface erosion. The PTMC networks showed good tissue tolerance during subcutaneous implantation, to which the tissue response was characterized by the presence of fibrous tissue and encapsulation of the implants. Concluding, we developed cell and tissue biocompatible, photo-crosslinked PTMC networks using PTMC-tMA macromers with relatively high molecular weights. These photo-crosslinked PTMC networks slowly degrade by a surface erosion process. Increasing the crosslinking density of these networks decreases the rate of surface degradation. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2823-2832, 2016.
Asunto(s)
Materiales Biocompatibles/química , Dioxanos/química , Polímeros/química , Andamios del Tejido/química , Animales , Materiales Biocompatibles/metabolismo , Bovinos , Células Cultivadas , Dioxanos/metabolismo , Masculino , Ensayo de Materiales , Procesos Fotoquímicos , Polímeros/metabolismo , Ratas Sprague-DawleyRESUMEN
Laser-induced periodic surface structures (LIPSS) are highly regular, but at the same time contain a certain level of disorder. The application of LIPSS is a promising method to functionalize biomaterials. However, the absorption of laser energy of most polymer biomaterials is insufficient for the direct application of LIPSS. Here, we report the application of LIPSS to relevant biomaterials using a two-step approach. First, LIPSS are fabricated on a stainless steel surface. Then, the structures are replicated onto biomaterials using the steel as a mold. Results show that LIPSS can be transferred successfully using this approach, and that human mesenchymal stromal cells respond to the transferred structures. With this approach, the range of biomaterials that can be supplied with LIPSS increases dramatically.
Asunto(s)
Materiales Biocompatibles , Rayos Láser , Células Cultivadas , Humanos , Células Madre Mesenquimatosas , Nanoestructuras , Acero Inoxidable , Propiedades de SuperficieRESUMEN
The menisci fulfill key biomechanical functions in the tibiofemoral (knee) joint. Unfortunately meniscal injuries are quite common and most often treated by (partial) meniscectomy. However, some patients experience enduring symptoms, and, more importantly, it leads to an increased risk for symptomatic osteoarthritis. Over the past decades, researchers have put effort in developing a meniscal substitute able to prevent osteoarthritis and treat enduring clinical symptoms. Grossly, two categories of substitutes are observed: First, a resorbable scaffold mimicking biomechanical function which slowly degrades while tissue regeneration and organization is promoted. Second, a non resorbable, permanent implant which mimics the biomechanical function of the native meniscus. Numerous biomaterials with different (material) properties have been used in order to provide such a substitute. Nevertheless, a clinically applicable cartilage protecting material is not yet emerged. In the current review we provide an overview, and discuss, these different materials and extract recommendations regarding material properties for future developmental research.