Raman spectroscopic investigation of polymer based magnetic multicomponent scaffolds.

Scaffolds acting as an artificial matrix for cell proliferation are one of the bone tissue engineering approaches to the treatment of bone tissue defects. In the presented study, novel multicomponent scaffolds composed of a poly(ε-caprolactone) (PCL), phenolic compounds such as tannic (TA) and gallic acids (GA), and nanocomponents such as silica-coated magnetic iron oxide nanoparticles (MNPs-c) and functionalized multi-walled carbon nanotubes (CNTs) have been produced as candidates for such artificial substitutes. Well-developed interconnected porous structures were observed using scanning electron microscopy (SEM). Raman spectra showed that the highly crystalline nature of PCL was reduced by the addition of nanoadditives. In the case of scaffolds containing MNPs-c and TA, the formation of a Fe-TA complex was concluded because characteristic bands of chelation of the Fe3+ ion by phenolic catechol oxygen appeared. It was found that the necessary conditions for the crystallization of the PCL/MNPs-c/TA are for the catechol groups to be able to penetrate the porous silica shell of MNPs-c, as during experiment with MNPs-c and TA without polymer, no such complexation was observed. Moreover, the number of catechol groups, the spatial structure and molecular size of this phenolic compound are also crucial for complexation process because GA does not form complexes. Therefore, the PCL/CNTs/MNPs-c/TA scaffolds are interesting candidates to consider for their possible medical applications.

Physicochemical Characterization and In Vitro Activity of Poly(ε-Caprolactone)/Mycophenolic Acid Amorphous Solid Dispersions.

The obtention of amorphous solid dispersions (ASDs) of mycophenolic acid (MPA) in poly(ε-caprolactone) (PCL) is reported in this paper. An improvement in the bioavailability of the drug is possible thanks to the favorable specific interactions occurring in this system. Differential scanning calorimetry (DSC) was used to investigate the miscibility of PCL/MPA blends, measuring glass transition temperature (Tg) and analyzing melting point depression to obtain a negative interaction parameter, which indicates the development of favorable inter-association interactions. Fourier transform infrared spectroscopy (FTIR) was used to analyze the specific interaction occurring in the blends. Drug release measurements showed that at least 70% of the drug was released by the third day in vitro in all compositions. Finally, preliminary in vitro cell culture experiments showed a decreased number of cancerous cells over the scaffolds containing MPA, presumably arising from the anti-cancer activity attributable to MPA.

3D printing modality effect: Distinct printing outcomes dependent on selective laser sintering (SLS) and melt extrusion.

A direct and comprehensive comparative study on different 3D printing modalities was performed. We employed two representative 3D printing modalities, laser- and extrusion-based, which are currently used to produce patient-specific medical implants for clinical translation, to assess how these two different 3D printing modalities affect printing outcomes. The same solid and porous constructs were created from the same biomaterial, a blend of 96% poly-ε-caprolactone (PCL) and 4% hydroxyapatite (HA), using two different 3D printing modalities. Constructs were analyzed to assess their printing characteristics, including morphological, mechanical, and biological properties. We also performed an in vitro accelerated degradation study to compare their degradation behaviors. Despite the same input material, the 3D constructs created from different 3D printing modalities showed distinct differences in morphology, surface roughness and internal void fraction, which resulted in different mechanical properties and cell responses. In addition, the constructs exhibited different degradation rates depending on the 3D printing modalities. Given that each 3D printing modality has inherent characteristics that impact printing outcomes and ultimately implant performance, understanding the characteristics is crucial in selecting the 3D printing modality to create reliable biomedical implants.

Silica Aerogel-Polycaprolactone Scaffolds for Bone Tissue Engineering.

Silica aerogel is a material composed of SiO2 that has exceptional physical properties when utilized for tissue engineering applications. Poly-ε-caprolactone (PCL) is a biodegradable polyester that has been widely used for biomedical applications, namely as sutures, drug carriers, and implantable scaffolds. Herein, a hybrid composite of silica aerogel, prepared with two different silica precursors, tetraethoxysilane (TEOS) or methyltrimethoxysilane (MTMS), and PCL was synthesized to fulfil bone regeneration requirements. The developed porous hybrid biocomposite scaffolds were extensively characterized, regarding their physical, morphological, and mechanical features. The results showed that their properties were relevant, leading to composites with different properties. The water absorption capacity and mass loss were evaluated as well as the influence of the different hybrid scaffolds on osteoblasts' viability and morphology. Both hybrid scaffolds showed a hydrophobic character (with water contact angles higher than 90°), low swelling (maximum of 14%), and low mass loss (1-7%). hOB cells exposed to the different silica aerogel-PCL scaffolds remained highly viable, even for long periods of incubation (7 days). Considering the obtained results, the produced hybrid scaffolds may be good candidates for future application in bone tissue engineering.

UV-Blocking and Light-Responsive Poly (ϵ-Caprolactone)/ZIF-8 Multifunctional Composite Films for Efficient Antibacterial Activities.

Antibacterial photodynamic therapy (APDT) has received considerable attention owing to its superiority. ZIF-8 was used to address the poor stability of the photosensitizer Rose Bengal (RB) encapsulation to synthesize RB@ZIF-8 NPs, which were doped into a composite film with poly (ϵ-caprolactone) (PCL) and polyvinyl alcohol-quaternary ammonium chitosan (PVA-QCS) as substrates to form composite films (PQZ). The composite films exhibited excellent photodynamic sterilization and good resistance to bacterial adhesion. The tensile strength of the film increased to 43.4 MPa, which was approximately 1.8 times that of the PCL film. With the addition of SiO2 and RB@ZIF-8 NPs, the film exhibited water repellency and UV-blocking properties. RAW264.7 cells were selected using the MTT method to confirm that the composite films had excellent biocompatibility and had no significant inhibitory effect on cell growth and reproduction. PQZ multifunctional composite films show potential as novel APDT antimicrobial materials for food packaging.

A study of the interactions between human osteoblast-like cells and polymer composites with functionalized graphene derivatives using 2D correlation spectroscopy (2D-COS).

In response to the growing need for development of modern biomaterials for applications in regenerative medicine strategies, the research presented here investigated the biological potential of two types of polymer nanocomposites. Graphene oxide (GO) and partially reduced graphene oxide (rGO) were incorporated into a poly(ε-caprolactone) (PCL) matrix, creating PCL/GO and PCL/rGO nanocomposites in the form of membranes. Proliferation of osteoblast-like cells (human U-2 OS cell line) on the surface of the studied materials confirmed their biological activity. Fluorescence microscopy was able to distinguish the different patterns of interaction between cells (depending on the type of material) after 15 days of the test run. Raman micro-spectroscopy and two-dimensional correlation spectroscopy (2D-COS) applied to Raman spectra distinguished the nature of cell-material interactions after only 8 days. Combination of these two techniques (Raman micro-spectroscopy and 2D-COS analysis) facilitated identification of a much more complex cellular response (especially from proteins) on the surface of PCL/GO. The presented approach can be regarded as a method for early study of the bioactivity of membrane materials.

The Effect of Various Polyhedral Oligomeric Silsesquioxanes on Viscoelastic, Thermal Properties and Crystallization of Poly(ε-caprolactone) Nanocomposites.

Polyhedral oligomeric silsesquioxane POSS nanoparticles can be applied as reinforcing additives modifying various properties of biodegradable polymers. The effects of aminopropylisobutyl POSS (amine-POSS), trisilanolisooctyl-POSS (HO-POSS) and glycidyl-POSS (Gly-POSS) on the viscoelastic, thermal properties and crystallization of biodegradable poly(ε-caprolactone) PCL were studied. The analysis of the viscoelastic properties at ambient temperature indicated that aminopropylisobutyl POSS (amine-POSS) and glycidyl-POSS (Gly-POSS) enhanced the dynamic mechanical properties of PCL. The increase in the storage shear modulus G' and loss modulus G″ was observed. The plasticizing effect of trisilanolisooctyl POSS (HO-POSS) due to the presence of long isoctyl groups was confirmed. As a result, the crystallization of PCL was facilitated and the degree of crystallinity of χc increased up to 50.9%. The damping properties and the values of tan δ for PCL/HO-POSS composition increased from 0.052 to 0.069. The TGA results point out the worsening of the PCL thermal stability, with lower values of T0.5%, T1% and T3%. Both HO-POSS and Gly-POSS facilitated the relaxation of molten PCL. The presence of Gly-POSS influenced the changes that occurred in the viscoelastic properties of the molten PCL due to the thermo-mechanical degradation of the material; a positive impact was observed.

3D-Braided Poly-ε-Caprolactone-Based Scaffolds for Ligament Tissue Engineering.

The anterior cruciate ligament (ACL) is the most commonly injured intra-articular ligament of the knee. Due to its limited intrinsical healing potential and vascularization, injuries of the ACL do not heal satisfactorily, and surgical intervention is usually required. The limitations of existing reconstructive grafts and autologous transplants have prompted interest in tissue-engineered solutions. A tissue engineering scaffold for ACL reconstruction must be able to mimic the mechanical properties of the native ligament, provide sufficient porosity to promote cell growth of the neoligament tissue, and be biodegradable. This study investigates long-term biodegradable poly-ε-caprolactone (PCL)-based scaffolds for ACL replacement using the 3D hexagonal braiding technique. The scaffolds were characterized mechanically as well as morphologically. All scaffolds, regardless of their braid geometry, achieved the maximum tensile load of the native ACL. The diameter of all scaffolds was lower than that of the native ligament, making the scaffolds implantable with established surgical methods. The 3D hexagonal braiding technique offers a high degree of geometrical freedom and, thus, the possibility to develop novel scaffold architectures. Based on the findings of this study, the 3D-braided PCL-based scaffolds studied were found to be a promising construct for tissue engineering of the anterior cruciate ligament.

Investigation of Molecular Weight, Polymer Concentration and Process Parameters Factors on the Sustained Release of the Anti-Multiple-Sclerosis Agent Teriflunomide from Poly(ε-caprolactone) Electrospun Nanofibrous Matrices.

In the current work, a series of PCL polyesters with different molecular weights was synthesized and used for the fabrication of nanofibrous patches via electrospinning, as sustained release matrices for leflunomide's active metabolite, teriflunomide (TFL). The electrospinning conditions for each sample were optimized and it was found that only one material with high Mn (71,000) was able to produce structures with distinct fibers devoid of the presence of beads. The successful preparation of the fibers was determined by scanning electron microscopy (SEM).TFL (10, 20 and 30 wt%) in three different concentrations was incorporated into the prepared nanofibers, which were used in in vitro drug release experiments. The drug-loaded nanofibrous formulations were further characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffractometry (XRD).It was found that TFL was incorporated in an amorphous form inside the polymeric nanofibers and that significant molecular interactions were formed between the drug and the polyester. Additionally, in vitro dissolution studies showed that the PCL/TFL-loaded nanofibers exhibit a biphasic release profile, having an initial burst release phase, followed by a sustained release until 250 h. Finally, a kinetic analysis of the obtained profiles revealed that the drug release was directly dependent on the amount TFL incorporated into the nanofibers.

Early Recognition of the PCL/Fibrous Carbon Nanocomposites Interaction with Osteoblast-like Cells by Raman Spectroscopy.

Poly(ε-caprolactone) (PCL) is a biocompatible resorbable material, but its use is limited due to the fact that it is characterized by the lack of cell adhesion to its surface. Various chemical and physical methods are described in the literature, as well as modifications with various nanoparticles aimed at giving it such surface properties that would positively affect cell adhesion. Nanomaterials, in the form of membranes, were obtained by the introduction of multi-walled carbon nanotubes (MWCNTs and functionalized nanotubes, MWCNTs-f) as well as electro-spun carbon nanofibers (ESCNFs, and functionalized nanofibers, ESCNFs-f) into a PCL matrix. Their properties were compared with that of reference, unmodified PCL membrane. Human osteoblast-like cell line, U-2 OS (expressing green fluorescent protein, GFP) was seeded on the evaluated nanomaterial membranes at relatively low confluency and cultured in the standard cell culture conditions. The attachment and the growth of the cell populations on the polymer and nanocomposite samples were monitored throughout the first week of culture with fluorescence microscopy. Simultaneously, Raman microspectroscopy was also used to track the dependence of U-2 OS cell development on the type of nanomaterial, and it has proven to be the best method for the early detection of nanomaterial/cell interactions. The differentiation of interactions depending on the type of nanoadditive is indicated by the ν(COC) vibration range, which indicates the interaction with PCL membranes with carbon nanotubes, while it is irrelevant for PCL with carbon nanofibers, for which no changes are observed. The vibration range ω(CH2) indicates the interaction for PCL with carbon nanofibers with seeded cells. The crystallinity of the area ν(C=O) increases for PCL/MWCNTs and for PCL/MWCNTs-f, while it decreases for PCL/ESCNFs and for PCL/ESCNFs-f with seeded cells. The crystallinity of the membranes, which is determined by Raman microspectroscopy, allows for the assessment of polymer structure changes and their degradability caused by the secretion of cell products into the ECM and the differentiation of interactions depending on the carbon nanostructure. The obtained nanocomposite membranes are promising bioactive materials.

Improvement of Drug Release and Compatibility between Hydrophilic Drugs and Hydrophobic Nanofibrous Composites.

Electrospinning is a flexible polymer processing method to produce nanofibres, which can be applied in the biomedical field. The current study aims to develop new electrospun hybrid nanocomposite systems to benefit the sustained release of hydrophilic drugs with hydrophobic polymers. In particular, electrospun hybrid materials consisting of polylactic acid (PLA):poly(ε-caprolactone) (PCL) blends, as well as PLA:PCL/halloysite nanotubes-3-aminopropyltriethoxysilane (HNT-ASP) nanocomposites were developed in order to achieve sustained release of hydrophilic drug tetracycline hydrochloride (TCH) using hydrophobic PLA:PCL nanocomposite membranes as a drug carrier. The impact of interaction between two commonly used drugs, namely TCH and indomethacin (IMC) and PLA:PCL blends on the drug release was examined. The drug release kinetics by fitting the experimental release data with five mathematical models for drug delivery were clearly demonstrated. The average nanofiber diameters were found to be significantly reduced when increasing the TCH concentration due to increasing solution electrical conductivity in contrast to the presence of IMC. The addition of both TCH and IMC drugs to PLA:PCL blends reduced the crystallinity level, glass transition temperature (Tg) and melting temperature (Tm) of PCL within the blends. The decrease in drug release and the impairment elimination for the interaction between polymer blends and drugs was accomplished by mobilising TCH into HNT-ASP for their embedding effect into PLA:PCL nanofibres. The typical characteristic was clearly identified with excellent agreement between our experimental data obtained and Ritger-Peppas model and Zeng model in drug release kinetics. The biodegradation behaviour of nanofibre membranes indicated the effective incorporation of TCH onto HNT-ASP.

Fabrication and in vitro evaluation of PCL/gelatin hierarchical scaffolds based on melt electrospinning writing and solution electrospinning for bone regeneration.

As an emerging 3D printing technique, melt electrospinning writing (MEW) has been used to fabricate scaffolds with controllable structure and good mechanical strength for bone regeneration. However, how to further improve MEW scaffolds with nanoscale extracellular matrix (ECM) mimic structure and bioactivity is still challenging. In this study, we proposed a simple composite process by combining MEW and solution electrospinning (SE) to fabricate a micro/nano hierarchical scaffold for bone tissue engineering. The morphological results confirmed the hierarchical structure with both well-defined MEW microfibrous grid structure and SE random nanofiber morphology. The addition of gelatin nanofibers turned the scaffolds to be hydrophilic, and led to a slight enhancement of mechanical strength. Compared with PCL MEW scaffolds, higher cell adhesion efficiency, improved cell proliferation and higher osteoinductive ability were achieved for the MEW/SE composite scaffolds. Finally, multilayer composite scaffolds were fabricated by alternately stacking of MEW layer and SE layer and used to assess the effect on cell ingrowth in the scaffolds. The results showed that gelatin nanofibers did not inhibit cell penetration, but promoted the three-dimensional growth of bone cells. Thus, the strategy of the combined use of MEW and SE is a potential method to fabricate micro/nano hierarchical scaffolds to improve bone regeneration.

Surface Crystal Nucleation and Growth in Poly (ε-caprolactone): Atomic Force Microscopy Combined with Fast Scanning Chip Calorimetry.

By using an atomic force microscope (AFM) coupled to a fast scanning chip calorimeter (FSC), AFM-tip induced crystal nucleation/crystallization in poly (ε-caprolactone) (PCL) has been studied at low melt-supercooling, that is, at a temperature typically not assessable for melt-crystallization studies. Nanogram-sized PCL was placed on the active/heatable area of the FSC chip, melted, and then rapidly cooled to 330 K, which is 13 K below the equilibrium melting temperature. Subsequent isothermal crystallization at this temperature was initiated by a soft-tapping AFM-tip nucleation event. Crystallization starting at such surface nucleus led to formation of a single spherulite within the FSC sample, as concluded from the radial symmetry of the observed morphology. The observed growth rate in the sub-micron thin FSC sample, nucleated at its surface, was found being much higher than in the case of bulk crystallization, emphasizing a different growth mechanism. Moreover, distinct banding/ring-like structures are observed, with the band period being less than 1 µm. After crystallization, the sample was melted for gaining information about the achieved crystallinity and the temperature range of melting, both being similar compared to much slower bulk crystallization at the same temperature but for a much longer time.

Effects of Polymer Blending on the Performance of a Subcutaneous Biodegradable Implant for HIV Pre-Exposure Prophylaxis (PrEP).

Long-acting (LA) HIV pre-exposure prophylaxis (PrEP) can mitigate challenges of adhering to daily or on-demand regimens of antiretrovirals (ARVs). We are developing a subcutaneous implant comprising polycaprolactone (PCL) for sustained delivery of ARVs for PrEP. Here we use tenofovir alafenamide (TAF) as a model drug. Previously, we demonstrated that the release rates of drugs are controlled by the implant surface area and wall thickness, and the molecular weight (MW) of PCL. Here, we further advance the implant design and tailor the release rates of TAF and the mechanical integrity of the implant through unique polymer blend formulations. In vitro release of TAF from the implant exhibited zero-order release kinetics for ~120 days. TAF release rates were readily controlled via the MW of the polymer blend, with PCL formulations of higher MW releasing the drug faster than implants with lower MW PCL. Use of polymer MW to tune drug release rates is partly explained by PCL crystallinity, as higher PCL crystalline material is often associated with a slower release rate. Moreover, results showed the ability to tailor mechanical properties via PCL blends. Blending PCL offers an effective approach for tuning the ARV release rates, implant duration, and integrity, and ultimately the biodegradation profiles of the implant.

Electrospun PCL-Based Vascular Grafts: In Vitro Tests.

BACKGROUND: Electrospun fibers have attracted a lot of attention from researchers due to their several characteristics, such as a very thin diameter, three-dimensional topography, large surface area, flexible surface, good mechanical characteristics, suitable for widespread applications. Indeed, electro-spinning offers many benefits, such as great surface-to-volume ratio, adjustable porosity, and the ability of imitating the tissue extra-cellular matrix. METHODS: we processed Poly ε-caprolactone (PCL) via electrospinning for the production of bilayered tubular scaffolds for vascular tissue engineering application. Endothelial cells and fibroblasts were seeded into the two side of the scaffolds: endothelial cells onto the inner side composed of PCL/Gelatin fibers able to mimic the inner surface of the vessels, and fibroblasts onto the outer side only exposing PCL fibers. Extracellular matrix production and organization has been performed by means of classical immunofluorescence against collagen type I fibers, Scanning Electron-Microscopy (SEM) has been performed in order to evaluated ultrastructural morphology, gene expression by means gene expression has been performed to evaluate the phenotype of endothelial cells and fibroblasts. RESULTS AND CONCLUSION: results confirmed that both cells population are able to conserve their phenotype colonizing the surface supporting the hypothesis that PCL scaffolds based on electrospun fibers should be a good candidate for vascular surgery.

Controlling the Poly(ε-caprolactone) Degradation to Maintain the Stemness and Function of Adipose-Derived Mesenchymal Stem Cells in Vascular Regeneration Application.

Biodegradable poly(ε-caprolactone) (PCL) scaffolds with adipose-derived mesenchymal stem cells (ADSCs) have been used in vascular regeneration studies. An evaluation method of the effect of PCL degradation products (DP) on the viability, stemness, and differentiation capacities of ADSCs is established. ADSCs are cultured in medium containing different concentrations of PCL DP before evaluating the effect of PCL DP on the cell apoptosis and proliferation, cell surface antigens, adipogenic and osteogenic differentiation capacities, and capacities to differentiate into endothelial cells and smooth muscle cells. The results demonstrate that PCL DP exceed 0.05 mg mL-1 may change the stemness and differentiation capacities of ADSCs. Therefore, to control the proper concentration of PCL DP is essential for ADSCs in vascular regeneration application.

Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP).

A critical need exists to develop diverse biomedical strategies for the widespread use of HIV Pre-Exposure Prophylaxis (HIV PrEP). This manuscript describes a subcutaneous reservoir-style implant for long-acting delivery of tenofovir alafenamide (TAF) for HIV PrEP. We detail key parameters of the TAF formulation that affect implant performance, including TAF ionization form, the selection of excipient and the exposure to aqueous conditions. Both in-vitro studies and shelf stability tests demonstrate enhanced performance for TAF freebase (TAFFB) in this long-acting implant platform, as TAFFB maintains higher chemical stability than the TAF hemifumarate salt (TAFHF). We also examined the hydrolytic degradation profiles of various formulations of TAF and identified inflection points for the onset of the accelerated drug hydrolysis within the implant using a two-line model. The compositions of unstable formulations are characterized by liquid chromatography-mass spectrometry (LC-MS) and are correlated to predominant products of the TAF hydrolytic pathways. The hydrolysis rate of TAF is affected by pH and water content in the implant microenvironment. We further demonstrate the ability to substantially delay the degradation of TAF by reducing the rates of drug release and thus lowering the water ingress rate. Using this approach, we achieved sustained release of TAFFB formulations over 240 days and maintained > 93% TAF purity under simulated physiological conditions. The opportunities for optimization of TAF formulations in this biodegradable implant supports further advancement of strategies to address long-acting HIV PrEP.

Manufacturing and Properties of Binary Blend from Bacterial Polyester Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) and Poly(caprolactone) with Improved Toughness.

Polyhydroxyalkanoates (PHAs) represent a promising group of bacterial polyesters for new applications. Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBH) is a very promising bacterial polyester with potential uses in the packaging industry; nevertheless, as with many (almost all) bacterial polyesters, PHBH undergoes secondary crystallization (aging) which leads to an embrittlement. To overcome or minimize this, in the present work a flexible petroleum-derived polyester, namely poly(ε-caprolactone), was used to obtain PHBH/PCL blends with different compositions (from 0 to 40 PCL wt %) using extrusion followed by injection moulding. The thermal analysis of the binary blends was studied by means of differential scanning calorimetry (DSC) and thermogravimetry (TGA). Both TGA and DSC revealed immiscibility between PHBH and PCL. Mechanical dynamic thermal analysis (DMTA) allowed a precise determination of the glass transition temperatures (Tg) as a function of the blend composition. By means of field emission scanning electron microscopy (FESEM), an internal structure formed by two phases was observed, with a PHBH-rich matrix phase and a finely dispersed PCL-rich phase. These results confirmed the immiscibility between these two biopolymers. However, the mechanical properties obtained through tensile and Charpy tests, indicated that the addition of PCL to PHBH considerably improved toughness. PHBH/PCL blends containing 40 PCL wt % offered an impact resistance double that of neat PHBH. PCL addition also contributed to a decrease in brittleness and an improvement in toughness and some other ductile properties. As expected, an increase in ductile properties resulted in a decrease in some mechanical resistant properties, e.g., the modulus and the strength (in tensile and flexural conditions) decreased with increasing wt % PCL in PHBH/PCL blends.

PCL-Blended Chitosan Substrates for Patterning the Heterotypic Cell Distribution in an Epithelial and Mesenchymal Coculture System.

Cell-cell and cell-substrate interactions in coculture systems are very important to the context of biomaterial scaffolds for tissue engineering applications. Understanding the cellular interactions and distribution of epithelial-mesenchymal microtissues on the controllable biomaterial surfaces is useful to study the organoid applications. The aim of the present study is to investigate the effects of chitosan/poly(ε-caprolactone) (PCL)-blended biomaterials on the distribution and spheroid formation of HaCaT and Hs68 cells in a coculture system. In this study, we demonstrated that the cocultured cells gradually changed their pattern from core/shell spheroid to monolayered morphology as the PCL content increased in the blended substrates. This indicates that the chitosan/PCL-blended substrates are able to regulate cell-substrate and cell-cell interactions to modify the distribution of HaCaT and Hs68 cells similar to various mesenchymal-epithelial organizations in biological tissues. Moreover, we also developed a two-dimension lattice model to elaborate the dependence of cell spheroid development on complex cell-cell interactions. This information may be helpful to develop appropriate biomaterials with appropriate properties to the applications of engineered epithelial-mesenchymal organoids.

Characterization of a Reservoir-Style Implant for Sustained Release of Tenofovir Alafenamide (TAF) for HIV Pre-Exposure Prophylaxis (PrEP).

Long-acting (LA) HIV pre-exposure prophylaxis (PrEP) offers the potential to improve adherence by lowering the burden of daily or on-demand regimens of antiretroviral (ARV) drugs. This paper details the fabrication and in vitro performance of a subcutaneous and trocar-compatible implant for the LA delivery of tenofovir alafenamide (TAF). The reservoir-style implant comprises an extruded tube of a biodegradable polymer, poly(ε-caprolactone) (PCL), filled with a formulation of TAF and castor oil excipient. Parameters that affect the daily release rates of TAF are described, including the surface area of the implant, the thickness of the PCL tube walls (between 45 and 200 µm), and the properties of the PCL (e.g., crystallinity). In vitro studies show a linear relationship between daily release rates and surface area, demonstrating a membrane-controlled release mechanism from extruded PCL tubes. Release rates of TAF from the implant are inversely proportional to the wall thickness, with release rates between approximately 0.91 and 0.15 mg/day for 45 and 200 µm, respectively. The sustained release of TAF at 0.28 ± 0.06 mg/day over the course of 180 days in vitro was achieved. Progress in the development of this implant platform addresses the need for new biomedical approaches to the LA delivery of ARV drugs.