A Novel Resorbable Composite Material Containing Poly(ester-co-urethane) and Precipitated Calcium Carbonate Spherulites for Bone Augmentation-Development and Preclinical Pilot Trials.

Polyurethanes have the potential to impart cell-relevant properties like excellent biocompatibility, high and interconnecting porosity and controlled degradability into biomaterials in a relatively simple way. In this context, a biodegradable composite material made of an isocyanate-terminated co-oligoester prepolymer and precipitated calcium carbonated spherulites (up to 60% w/w) was synthesized and investigated with regard to an application as bone substitute in dental and orthodontic application. After foaming the composite material, a predominantly interconnecting porous structure is obtained, which can be easily machined. The compressive strength of the foamed composites increases with raising calcium carbonate content and decreasing calcium carbonate particle size. When stored in an aqueous medium, there is a decrease in pressure stability of the composite, but this decrease is smaller the higher the proportion of the calcium carbonate component is. In vitro cytocompatibility studies of the foamed composites on MC3T3-E1 pre-osteoblasts revealed an excellent cytocompatibility. The in vitro degradation behaviour of foamed composite is characterised by a continuous loss of mass, which is slower with higher calcium carbonate contents. In a first pre-clinical pilot trial the foamed composite bone substitute material (fcm) was successfully evaluated in a model of vertical augmentation in an established animal model on the calvaria and on the lateral mandible of pigs.

Poly(dl-lactide) Polymer Blended with Mineral Phases for Extrusion 3D Printing-Studies on Degradation and Biocompatibility.

A promising therapeutic option for the treatment of critical-size mandibular defects is the implantation of biodegradable, porous structures that are produced patient-specifically by using additive manufacturing techniques. In this work, degradable poly(DL-lactide) polymer (PDLLA) was blended with different mineral phases with the aim of buffering its acidic degradation products, which can cause inflammation and stimulate bone regeneration. Microparticles of CaCO3, SrCO3, tricalcium phosphates (α-TCP, ß-TCP), or strontium-modified hydroxyapatite (SrHAp) were mixed with the polymer powder following processing the blends into scaffolds with the Arburg Plastic Freeforming 3D-printing method. An in vitro degradation study over 24 weeks revealed a buffer effect for all mineral phases, with the buffering capacity of CaCO3 and SrCO3 being the highest. Analysis of conductivity, swelling, microstructure, viscosity, and glass transition temperature evidenced that the mineral phases influence the degradation behavior of the scaffolds. Cytocompatibility of all polymer blends was proven in cell experiments with SaOS-2 cells. Patient-specific implants consisting of PDLLA + CaCO3, which were tested in a pilot in vivo study in a segmental mandibular defect in minipigs, exhibited strong swelling. Based on these results, an in vitro swelling prediction model was developed that simulates the conditions of anisotropic swelling after implantation.

A comparative analysis of 3D printed scaffolds consisting of poly(lactic-co-glycolic) acid and different bioactive mineral fillers: aspects of degradation and cytocompatibility.

Their excellent mechanical properties, degradability and suitability for processing by 3D printing technologies make the thermoplastic polylactic acid and its derivatives favourable candidates for biomaterial-based bone regeneration therapies. In this study, we investigated whether bioactive mineral fillers, which are known to promote bone healing based on their dissolution products, can be integrated into a poly(L-lactic-co-glycolic) acid (PLLA-PGA) matrix and how key characteristics of degradation and cytocompatibility are influenced. The polymer powder was mixed with particles of CaCO3, SrCO3, strontium-modified hydroxyapatite (SrHAp) or tricalcium phosphates (α-TCP, ß-TCP) in a mass ratio of 90 : 10; the resulting composite materials have been successfully processed into scaffolds by the additive manufacturing method Arburg Plastic Freeforming (APF). Degradation of the composite scaffolds was investigated in terms of dimensional change, bioactivity, ion (calcium, phosphate, strontium) release/uptake and pH development during long-term (70 days) incubation. The mineral fillers influenced the degradation behavior of the scaffolds to varying degrees, with the calcium phosphate phases showing a clear buffer effect and an acceptable dimensional increase. The amount of 10 wt% SrCO3 or SrHAp particles did not appear to be appropriate to release a sufficient amount of strontium ions to exert a biological effect in vitro. Cell culture experiments with the human osteosarcoma cell line SAOS-2 and human dental pulp stem cells (hDPSC) indicated the high cytocompatibility of the composites: For all material groups cell spreading and complete colonization of the scaffolds over the culture period of 14 days as well as an increase of the specific alkaline phosphatase activity, typical for osteogenic differentiation, were observed.

Development of a solvent-free polylactide/calcium carbonate composite for selective laser sintering of bone tissue engineering scaffolds.

Since large bone defects cannot be healed by the body itself, continuous effort is put into the development of 3D scaffolds for bone tissue engineering. One method to fabricate such scaffolds is selective laser sintering (SLS). However, there is a lack of solvent-free prepared microparticles suitable for SLS. Hence, the aim of this study was to develop a solvent-free polylactide/calcium carbonate composite powder with tailored material properties for SLS. Four composite powders with a composition of approximately 75 wt% polylactide (PLLA as well as PDLLA) and 25 wt% calcium carbonate (calcite) were prepared by a milling process based on GMP standards. Four different grades of polylactide were chosen to cover a broad inherent viscosity range of 1.0-3.6 dl/g. The composite material with the lowest inherent viscosity (1.0 dl/g) showed the best processability by SLS. This was caused by the small polymer particle diameter (50 µm) and the small zero-shear melt viscosity (400 Pa·s), which led to fast sintering. The SLS process parameters were developed to achieve low micro-porosity (approx. 2%) and low polymer degradation (no measurable decrease of the inherent viscosity). A biaxial bending strength of up to 75 MPa was achieved. Cell culture assays indicated good viability of MG-63 osteoblast-like cells on the SLS specimens. Finally, the manufacture of 3D scaffolds with interconnected pore structure was demonstrated. After proving the biocompatibility of the material, the developed scaffolds could have great potential to be used as patient-specific bone replacement implants.

Influence of the material properties of a poly(D,L-lactide)/ß-tricalcium phosphate composite on the processability by selective laser sintering.

Complex 3D scaffolds with interconnected pores are a promising tool for bone regeneration. Such 3D scaffolds can be manufactured by selective laser sintering (SLS) from biodegradable composite powders. However, the mechanical strength of these scaffolds is often too low for medical application. We propose that the mechanical strength of laser-sintered scaffolds can be improved through composite powders with tailored properties (e.g., suitable powder particle size and melt viscosity for SLS). To prove this, two batches of a poly(D,L-lactide) (PDLLA)/ß-tricalcium phosphate (ß-TCP) composite powder with 50 wt% PDLLA and 50 wt% ß-TCP were synthesized. The two batches differed in polymer particle size, filler particle size, and polymer molecular weight. Both batches were processed with identical SLS process parameters to study the extent to which the material properties influence how well a PDLLA/ß-TCP (50/50) composite can be processed with SLS. In the SLS process, batch 2 showed improved melting behavior due to its smaller polymer particle size (approx. 35 µm vs. 50 µm) and its lower zero-shear melt viscosity (5800 Pa∙s vs. 17,900 Pa∙s). The better melting behavior of batch 2 led to SLS test specimens with lower porosity compared to batch 1. In consequence, the batch 2 specimens exhibited a larger biaxial bending strength (62 MPa) than the batch 1 specimens did (23 MPa). We conclude that a tailored composite powder with optimized polymer particle size, filler particle size, and polymer molecular weight can increase the achievable mechanical strength of laser-sintered scaffolds.