PLLA Scaffolds Research Articles

Cu-S-Mo Interfacial Sites in CuO2@MoS2/PLLA Scaffolds for Robust Synergistic Antibacterial Efficacy via CDT and PTT

Bacterial infections considerably limit the success of scaffold transplantation. CuO2 may generate hydroxyl radicals through a self-cascade catalytic process, which is effective for sterilization. However, reducing CuO2-derived Cu+ ions to Cu° can lead to a decline in catalytic activity. To overcome these limitations, we anchored CuO2 onto MoS2 to establish stable Cu-S-Mo interfacial sites. The CuO2/MoS2 nanozyme was fabricated using a low-temperature co-precipitation technique and introduced into poly-L-lactic acid scaffolds using selective laser sintering. The Cu-S-Mo interfacial sites showed a triad of functions that synergistically enhanced catalytic performance. These sites stabilized the Cu atoms, augmented catalytic activity by facilitating efficient electron transfer through the Mo4+/Mo6+ redox couple, and improved the conduction of heat derived from the photothermal response of MoS2 to the Cu catalyst. The synergistic action of chemodynamic and photothermal therapy, mediated by the Cu-S-Mo sites, resulted in remarkable antibacterial efficacy, with 92.3% and 93.5% inhibition rates against Staphylococcus aureus and Escherichia coli, respectively. Experimental evidence and simulations demonstrated that Cu-S-Mo structure stabilized the Cu atoms and improved electron transfer via interatomic charge transfer. These results highlight the potential of the CuO2@MoS2/PLLA scaffold in eliminating bacterial infections.

Biocompatibility and Bone Regeneration by Shape Memory Polymer Scaffolds.

Biodegradable, shape memory polymer (SMP) scaffolds based on poly(ε-caprolactone) (PCL) offer unique advantages as a regenerative treatment strategy for critical-sized bone defects. In particular, a conformal fit may be achieved following exposure to warm saline, thereby improving osseointegration and regeneration. Advancing the clinical translation of these SMP scaffolds requires establishment of efficacy not only in non-loading models, but also load-bearing or load-sharing models. Thus, the present study evaluated the biocompatibility and bone regeneration potential of SMP scaffolds in a rabbit distal femoral condyle model. Two distinct SMP scaffold compositions were evaluated, a "PCL-only" scaffold formed from PCL-diacrylate (PCL-DA) and a semi-interpenetrating network (semi-IPN) formed from PCL-DA and poly(L-lactic acid) (PCL:PLLA). Semi-IPN PCL:PLLA scaffolds possess greater rigidity and faster rates of degradation versus PCL scaffolds. In vivo biocompatibility was assessed with a rat subcutaneous implantation model, whereas osseointegration was assessed with a 4 mm × 8 mm rabbit distal femoral condyle defect model. Both types of SMP scaffolds exhibited excellent biocompatibility marked by infiltration with fibrous tissue and a minimal inflammatory response. When implanted in the rabbit distal femur, both SMP scaffolds supported bone ingrowth. Collectively, these results demonstrate that the SMP scaffolds are biocompatible and integrate with adjacent host osseous tissues when implanted in vivo in a load-sharing environment. This study provides key proof-of-concept data necessary to proceed with large animal translational studies and clinical trials in human subjects.

Enhancing bone tissue engineering with nanocomposites based on NiO nanoparticles/graphene oxide

Through the creation and characterization of novel poly (L-lactic acid) (PLLA)-based nanocomposites containing graphene oxide (GO), nanocrystalline hydroxyapatite (nano-HAP), and nickel oxide (NiO) nanoparticles, this study seeks to improve the performance of bone tissue scaffolds. Utilizing a casting procedure to create nanocomposites, wet chemical methods were used to synthesize nano-HAP. X-ray diffraction, transmission electron microscopy, and Fourier transform infrared spectroscopy were used to characterize the materials. The nanocomposite comprising 5 % GO + 5 % NiO + 10 % nano-HAP showed a 110 % increase in tensile modulus, a 38 % increase in extension, and a 29 % increase in load-bearing capacity compared to plain PLLA. The results showed a considerable increase in mechanical strength. On the surfaces of the nanocomposite, osteoblast adhesion and proliferation increased by 185 %, according to biological tests. Studies on degradation revealed regulated rates that matched bones' natural mending process while preserving a pH environment that was steady. According to these results, adding nanostructures to PLLA scaffolds improves their mechanical and biological properties considerably, which may lead to therapeutic uses in bone tissue engineering in the future.

Micro-Nanostructured Polymeric Scaffolds for Bone Tissue Engineering

While bone tissue allograft and autograft are commonly used in bone healing, their application is limited by factors such as availability, donor site morbidity, and immune response to the grafted tissue. Tissue-engineered implants, such as acellular or cellular polymeric structures, offer a promising alternative, and are a current trend in tissue engineering. Leveraging recent advancements in bone tissue engineering (BTE), we utilize 3D printing to develop biodegradable scaffolds that combine mechanical strength and bioactivity to facilitate bone repair and regeneration. This study focuses on the design and fabrication of mechanically competent 3D printed poly (L-lactic acid) (PLLA) micro-structured scaffolds. These scaffolds are enhanced with collagen type I nanofibrils to create bioactive scaffolds that promote tissue regeneration. The performance of these mechanically competent, micro-nanostructured polymeric matrices, in combination with bone marrow stromal cells (BMSCs), is evaluated in PLLA and PLLA-collagen scaffolds. The resulting micro-nanostructured PLLA-Collagen scaffolds mimic trabecular bone architecture, mechanical strength, and the extracellular matrix environment found in native bone tissue. The composite PLLA-collagen scaffolds exhibit mechanical properties in the mid-range of human trabecular bone. Both PLLA and PLLA-Collagen scaffolds support human BMSCs adhesion, proliferation, and osteogenic differentiation. A significantly higher number of implanted host cells are distributed in the PLLA-Collagen scaffolds with greater bone density, more uniform cell distribution, and attachment compared to the PLLA microstructure. Additionally, the biomimetic collagen nanostructure potently induces osteogenic transcription evidenced by increased alkaline phosphatase activity and upregulation of bone markers such as sialoprotein and collagen type I, ultimately guiding stem cell-mediated formation of a mature, mineralized bone matrix throughout the interconnected scaffold pores. This study underscores the benefits of micro-nanostructured scaffolds in successfully generating the inductive microenvironment of native bone extracellular matrix, triggering the cascade of cellular events required for functional bone regeneration, repairing critical-sized bone defects, and ultimately serving as an alternative material platform for bone regeneration, thereby instilling confidence in the potential of our research.

Amino‐functionalized nano‐hydroxyapatite boosts the grafting efficiency of poly (l‐lactic acid) to enhance interfacial bonding in composite bone scaffold

AbstractNano‐hydroxyapatite (nano‐HAP)/poly (l‐lactic acid) (PLLA) bone scaffold is expected to overcome the deficiencies and achieve the complementary advantages of individual constituents, but the weak interfacial bonding due to their thermodynamic incompatibility is detrimental to the mechanical properties. Herein, the PLLA chains were grafted onto nano‐HAP with 3‐aminopropyltriethoxysilane (KH550) as a coupling reagent to enhance the interfacial bonding with PLLA. Specifically, the silicon hydroxyl group produced by KH550 hydrolysis could form covalent bonding with the hydroxyl group of nano‐HAP, and the amino group of KH550 initiated the ring‐opening polymerization of l‐lactide monomers to graft PLLA chains onto nano‐HAP more effectively, leading to a higher grafting ratio of 16.7% compared with 7.2% in direct grafting without KH550 modification. Consequently, the tensile and compressive strength of the modified nano‐HAP/PLLA scaffold were improved by 40.8% and 59.5% enhancement due to the enhanced interfacial bonding in the composite scaffold, respectively, compared to the original nano‐HAP/PLLA scaffold. Additionally, the bone scaffold was conducive to cell adhesion and proliferation, making it an ideal candidate for bone defect repair.Highlights Amino‐functionalized nano‐HAP boosted the grafting efficiency of PLLA chains. Interfacial bonding between nano‐HAP and matrix was enhanced. Bone scaffold showed better mechanical properties and benign cytocompatibility.

Harnessing IL-10 induced anti-inflammatory response in maturing macrophages in presence of electrospun dexamethasone-loaded PLLA scaffold.

The ultimate goal of tissue engineering is to repair and regenerate damaged tissue or organ. Achieving this goal requires blood vessel networks to supply oxygen and nutrients to new forming tissues. Macrophages are part of the immune system whose behavior plays a significant role in angiogenesis and blood vessel formation. On the other hand, macrophages are versatile cells that change their behavior in response to environmental stimuli. Given that implantation of a biomaterial is followed by inflammation; therefore, we reasoned that this inflammatory condition in tissue spaces modulates the final phenotype of macrophages. Also, we hypothesized that anti-inflammatory glucocorticoid dexamethasone improves modulating macrophages behavior. To check these concepts, we investigated the macrophages that had matured in an inflammatory media. Furthermore, we examined macrophages' behavior after maturation on a dexamethasone-containing scaffold and analyzed how the behavioral change of maturing macrophages stimulates other macrophages in the same environment. In this study, the expression of pro-inflammatory markers TNFa and NFκB1 along with pro-healing markers IL-10 and CD163 were investigated to study the behavior of macrophages. Our results showed that macrophages that were matured in the inflammatory media in vitro increase expression of IL-10, which in turn decreased the expression of pro-inflammatory markers TNFa and NFκB in maturing macrophages. Also, macrophages that were matured on dexamethasone-containing scaffolds decreased the expression of IL-10, TNFa, and NFκB and increase the expression of CD163 compared to the control group. Moreover, the modulation of anti-inflammatory response in maturing macrophages on dexamethasone-containing scaffold resulted in increased expression of TNFa and CD163 by other macrophages in the same media. The results obtained in this study, proposing strategies to improve healing through controlling the behavior of maturing macrophages and present a promising perspective for inflammation control using tissue engineering scaffolds.

PLLA scaffolds functionalized with ketoprofen via rotary jet spinning for biomedical applications

Biopolymer-based biomaterials, such as poly (l-lactic acid) (PLLA), have long been recognized as scaffolds for drug delivery applications due to their advantages, including biodegradability and biocompatibility. Ketoprofen (KET) is a non-steroidal anti-inflammatory drug known for its analgesic properties. Despite its potential, more research is needed on the effective production of scaffolds functionalized with KET for biomedical applications. This study, therefore, aimed to develop PLLA-based carriers to transport KET obtained using Rotary Jet Spinning (RJS) and evaluate the influence of KET at different concentrations. RJS allowed PLLA-KET scaffold production with high productivity and uniform fiber morphology. KET particles dispersed in the PLLA fibers were observed through scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Furthermore, the Fourier Transform Infrared Spectroscopy (FTIR) and X-ray diffraction (XRD) confirmed the presence of KET in the PLLA and that the crystalline structure of PLLA remained unchanged with the incorporation of KET, ensuring the material's structural integrity. Likewise, the thermogravimetric analysis showed the presence of KET affected the thermal stability of PLLA. Cell viability and confocal microscopy with preosteoblast cells demonstrated that PLLA-KET fibers maintained cell viability over time, indicating their compatibility with cell cultures, and revealed cell adhesion and distribution in the fibers varied with KET concentration. These results have significant implications, highlighting the potential use of PLLA-KET carriers in practical biomedical applications, such as drug delivery systems, bone implant devices, and dental applications, thereby advancing the field of biomaterials.

Photothermal effect of graphene oxide accelerate singlet oxygen release from artesunate to endow the scaffold with antibacterial properties

Artesunate, as a semi-synthetic artemisinin derivative, exhibits a broad-spectrum bactericidal effect via the release of singlet oxygen. However, its release is slow due to the difficulty breaking the endoperoxide bridge bond. Ammoniated graphene oxide could be electrostatic adsorbed with artesunate and efficiently transfer thermal energy to artesunate by interfacial heat transfer, thereby facilitating the breaking of the endoperoxide bridge bond. In detail, artesunate was anchored on graphene oxide by a one-pot hydrothermal synthesis method and introduced to the PLLA scaffold fabricated by selective laser sintering. Under near-infrared light irradiation, graphene oxide could convert light to heat through photothermal conversion. Then the heat energy was transferred to artesunate by interfacial heat transfer, accelerating the release of singlet oxygen. Meanwhile, graphene oxide could achieve the purpose of thermal ablation for bacterial infection by increasing the local temperature. Based on the combination of singlet oxygen and thermal ablation therapy, the scaffold possesses a high bactericidal ability triggered by near-infrared light. Under the near-infrared light irradiation, the singlet oxygen production from artesunate increased by 39 %, and the antibacterial ratio against S. aureus and E. coli reached 91.6 % and 93.3 %, respectively. Additionally, the scaffold was favorable cytocompatibility with mBMSCs. All the results highlight the great potential of artesunate-mediated graphene oxide scaffold in eliminating bacterial infections.

(158) Comparison Implants for Penile Girth Enlargement: PPLA Shaft vs Silicone Implant

Abstract Introduction Male dissatisfaction with the penis size is the most common manifestation of penile dysmorphophobia. Despite the diversity of penis enlargement methods a single safe technique that fully satisfies patients has not yet been developed. Objective The aim of this work is to compare the results of a combined operation on installation of a silicone implant or a porous polylactic acid (PPLA) scaffold impregnated with autologous stem cells with simultaneous ligamenotaxis to increase the length and circumference of the penis. Methods In 2017–2023 there were performed penis enlargement surgeries in 3 centers. In Ukraine and Poland 38 patients from were operated with implantation of a porous Max Pol PLLA scaffold, and in Mexico implantation of silicone implants Peniflex in 36 patients was performed. The results of penis enlargement were evaluated in the early (2 months) and long-term (36 months) periods. Results While implanting a silicone implant the majority of the patients - 31 (86.1%) are satisfied with the result, 27 (75%) patients mention an improvement in sexual life, 31 (86.1%) also mention an increase in their own self-sufficiency. At the same time, some patients mentioned the following complications: 2 (5.6%) patients mentioned displacement of the silicone matrix, 1 (2.8%) patient mentioned prolapse of the implant, 1 (2.8%) patient mentioned a decrease in erection (which did not improve after removal of the implant), in 1 (2.8%) case the silicone implant had to be removed due to the fact that the patient did not liked the appearance. While using a collagen-like matrix made of polymerized polylactic acid impregnated with autological stem cells in 38 patients, we have seen one significant complication - prolapse that caused the removal of the matrix (in men that had denied circumcision before implantation). However, 5 (13.2%) patients required additional polylactic acid gel injections between 6 and 36 months to optimize the shape or volume of the penis. 34 (89.5%) patients mentioned an improvement in the sexual function and sexual sensations of their partner, harmonization of relationships in a couple, and 36 (97.4%) men - an increase in a sense of self-sufficiency. In 3 years most of the patients 26 (68,4%) have been satisfied with particularly resolved implant but 13 (34.2) patients want to add some PLA gel as injection for penile girth recovery. Conclusions Thus, modern implants can improve the size and appearance of the penis, improve the quality of sexual life and the feeling of self-sufficiency in operated men. The use of silicone implants is simpler, it require only long drain 3–5 days. Most of operated patients were satisfied results of silicone implant. The use of a polymer matrix impregnated with autologuous stem cells requires a special biostem cell laboratory, more time for preoperative rehabilitation, but can be considered as more philological. Both methods can be considered as permanent and quite safe for penis enlargement. Disclosure No.

Osteo-inductive effect of piezoelectric stimulation from the poly(l-lactic acid) scaffolds.

Piezoelectric biomaterials can generate piezoelectrical charges in response to mechanical activation. These generated charges can directly stimulate bone regeneration by triggering signaling pathway that is important for regulating osteogenesis of cells seeded on the materials. On the other hand, mechanical forces applied to the biomaterials play an important role in bone regeneration through the process called mechanotransduction. While mechanical force and electrical charges are both important contributing factors to bone tissue regeneration, they operate through different underlying mechanisms. The utilizations of piezoelectric biomaterials have been explored to serve as self-charged scaffolds which can promote stem cell differentiation and the formation of functional bone tissues. However, it is still not clear how mechanical activation and electrical charge act together on such a scaffold and which factors play more important role in the piezoelectric stimulation to induce osteogenesis. In our study, we found Poly(l-lactic acid) (PLLA)-based piezoelectric scaffolds with higher piezoelectric charges had a more pronounced osteoinductive effect than those with lower charges. This provided a new mechanistic insight that the observed osteoinductive effect of the piezoelectric PLLA scaffolds is likely due to the piezoelectric stimulation they provide, rather than mechanical stimulation alone. Our findings provide a crucial guide for the optimization of piezoelectric material design and usage.

Unlocking the print of poly(L-lactic acid) by melt electrowriting for medical application

Melt electrowriting (MEW) is an advanced 3D printing technology to process high-resolution scaffolds. Although MEW has printed many biodegradable polymers, most of them have low printability, including poly(L-lactic acid) (PLLA) discussed in this study. While the print of PLLA scaffolds by MEW is elementarily realized, the scaffolds' limited structural change and mechanical properties influence their application. This study aims at improving the printability and the mechanical properties of the PLLA. To this end, the printability of the PLLA regarding jet lag angle and critical translation speed is investigated; the print limitation of PLLA is discovered, and the uniaxial and cyclic tensile tests for the scaffolds in linear and nonlinear structures are carried out. The results suggest that drying the PLLA before printing can significantly restrain polymer degradation to extend the printing period to approximately one day; planar PLLA scaffolds are able to reach 25 layers, 100 µm interfiber distance, and 8 × 8 cm2 in dimension, and tubular PLLA scaffolds with 6 layers are successfully printed out; the mechanical properties of the PLLA scaffold reach the level of electrospun nonwoven fabrics. Thus, this study is a milestone work for the MEW technology to extend the printable materials.

3D Printing Drug-Free Scaffold with Triple-Effect Combination Induced by Copper-Doped Layered Double Hydroxides for the Treatment of Bone Defects.

Tissue-engineered poly(l-lactide) (PLLA) scaffolds have been widely used to treat bone defects; however, poor biological activities have always been key challenges for its further application. To address this issue, introducing bioactive drugs or factors is the most commonly used method, but there are often many problems such as high cost, uncontrollable and monotonous drug activity, and poor bioavailability. Here, a drug-free 3D printing PLLA scaffold with a triple-effect combination induced by surface-modified copper-doped layered double hydroxides (Cu-LDHs) is proposed. In the early stage of scaffold implantation, Cu-LDHs exert a photothermal therapy (PTT) effect to generate high temperature to effectively prevent bacterial infection. In the later stage, Cu-LDHs can further have a mild hyperthermia (MHT) effect to stimulate angiogenesis and osteogenic differentiation, demonstrating excellent vascularization and osteogenic activity. More importantly, with the degradation of Cu-LDHs, the released Cu2+ and Mg2+ provide an ion microenvironment effect and further synergize with the MHT effect to stimulate angiogenesis and osteogenic differentiation, thus more effectively promoting the healing of bone tissue. This triple-effect combined scaffold exhibits outstanding antibacterial, osteogenic, and angiogenic activities, as well as the advantages of low cost, convenient procedure, and long-term efficacy, and is expected to provide a promising strategy for clinical repair of bone defects.

4D Printed Poly(l‐lactide)/(FeCl3–TA/MgO) Composite Scaffolds with Near‐Infrared Light‐Induced Shape‐Memory Effect and Antibacterial Properties

Near‐infrared (NIR) light‐responsive shape‐memory polymers have drawn increasing attention because NIR light is safe and easy to perform in biological applications. Herein, a novel NIR light‐responsive shape‐memory polymer composite is developed, which comprises poly(l‐lactide) (PLLA) matrix and surface‐modified magnesium oxide (MgO) nanoparticles by ferric chloride (FeCl3) and tannic acid (TA) (FeCl3–TA/MgO). This design can fully combine the printability and shape‐memory effect of PLLA, the excellent bioactivity, and the outstanding photothermal effect of MgO nanoparticles modified by FeCl3–TA. The PLLA/(FeCl3–TA/MgO) composite scaffolds with a homogeneously porous structure are further fabricated by 4D printing. The synergetic presence of components and fabrication process can endow the prepared composite scaffolds with enhanced mechanical properties and stable NIR light‐induced shape‐memory effect, as well as antibacterial and antioxidant properties. With 5 wt% FeCl3–TA/MgO particles, the scaffold not only has a compress modulus of 0.93 MPa, which is 4 times that of a pristine PLLA scaffold, but also achieves a shape fixation ratio of 95.7% and a shape recovery ratio of 80.9% under NIR light irradiation at 2 w cm−2. The PLLA/(FeCl3–TA/MgO) composites have great potential for application in the field of bone tissue engineering scaffolds.

Poly(l-lactic acid)-based double-layer composite scaffold for bone tissue repair.

Bone defect is a serious threat to human health. Osteopractic total flavone (OTF) extracted from Rhizoma Drynariae has the effects of promoting bone formation. Panax notoginseng saponin (PNS) has the function of activating blood circulation and removing blood stasis. Therefore, combining OTF and PNS with poly(l-lactic acid) (PLLA) to prepare scaffolds containing PNS in the outer layer and OTF in the inner layer is a feasible solution to rapidly remove blood stasis and continue to promote bone formation. In addition, degradation rate of the scaffold can affect the release time of two drugs. Adding Mg particles in outer layer can control the degradation rate of the scaffold and the drug release. Therefore, a double-layer drug-loaded PLLA scaffold containing OTF in the inner layer, PNS and Mg particles in the outer layer was prepared and characterized to verify its feasibility. The experimental results showed that the scaffold can realize the rapid release of PNS and the continuous release of OTF. With the increase of Mg content, the drug release rate became faster. Animal experiments showed that the scaffold containing 5% Mg particles could effectively promote the formation of new bone in the bone defect of male New Zealand white rabbits, and the area and density of new bone formed were much better than those in the control group. These results demonstrated that the double-layer drug-loaded scaffold had good ability to promote bone repair.

Temperature-responsive PCL-PLLA nanofibrous tissue engineering scaffolds with memorized porous microstructure recovery.

Biomaterial scaffolds in tissue engineering facilitate tissue regeneration and integration with the host. Poor healing outcomes arise from lack of cell and tissue infiltration, and ill-fitting interfaces between matrices or grafts, resulting in fibrous tissue formation, inflammation, and resorption. Existing tissue engineering scaffolds struggle to recover from deformation to fit irregularly shaped defects encountered in clinical settings without compromising their mechanical properties and favorable internal architecture. This study introduces a synthetic biomaterial scaffold composed of high molecular weight poly (L-lactic acid) (PLLA) and an interpenetrating network of poly (ε-caprolactone) (PCL), in a composition aiming to address the need for conformal fitting synthetic matrices which retain and recover their advantageous morphologies. The scaffold, known as thermosensitive memorized microstructure (TS-MMS), forms nanofibrous materials with memorized microstructures capable of recovery after deformation, including macropores and nanofibers. TS-MMS nanofibers, with 50-500 nm diameters, are formed via thermally induced phase separation (TIPS) of PLLA after in situ polymerization of PCL-diacrylate. A critical partial-melting temperature of TS-MMS at 52°C enables bulk deformation above this temperature, while retaining the nanofibrous and macroporous structures upon cooling to 37°C. Incorporation of drug-loaded poly (lactide-co-glycolide) (PLGA) nanoparticles directly into TS-MMS nanofibers during fabrication allows sustained release of a model drug for up to 40 days. Subcutaneous implantation in vivo using LysM-Cre;td-Tomato; Col1eGFP mice demonstrates successful cellularization and integration of deformed/recovered TS-MMS materials, surpassing the limitations of deformed PLLA scaffolds, to facilitate cell and vasculature infiltration requisite for successful bone regeneration. Additionally we demonstrated a method for embedding controlled release vehicles directly into the scaffold nanofibers; controlled release of simvastatin enhances vascularization and tissue maturation. TS-MMS scaffolds offer promising improvements in clinical handling and performance compared to existing biomaterial scaffolds.

Three-Dimensional Scaffolds for Bone Tissue Engineering.

Immobilization using external or internal splints is a standard and effective procedure to treat minor skeletal fractures. In the case of major skeletal defects caused by extreme trauma, infectious diseases or tumors, the surgical implantation of a bone graft from external sources is required for a complete cure. Practical disadvantages, such as the risk of immune rejection and infection at the implant site, are high in xenografts and allografts. Currently, an autograft from the iliac crest of a patient is considered the "gold standard" method for treating large-scale skeletal defects. However, this method is not an ideal solution due to its limited availability and significant reports of morbidity in the harvest site (30%) as well as the implanted site (5-35%). Tissue-engineered bone grafts aim to create a mechanically strong, biologically viable and degradable bone graft by combining a three-dimensional porous scaffold with osteoblast or progenitor cells. The materials used for such tissue-engineered bone grafts can be broadly divided into ceramic materials (calcium phosphates) and biocompatible/bioactive synthetic polymers. This review summarizes the types of materials used to make scaffolds for cryo-preservable tissue-engineered bone grafts as well as the distinct methods adopted to create the scaffolds, including traditional scaffold fabrication methods (solvent-casting, gas-foaming, electrospinning, thermally induced phase separation) and more recent fabrication methods (fused deposition molding, stereolithography, selective laser sintering, Inkjet 3D printing, laser-assisted bioprinting and 3D bioprinting). This is followed by a short summation of the current osteochondrogenic models along with the required scaffold mechanical properties for in vivo applications. We then present a few results of the effects of freezing and thawing on the structural and mechanical integrity of PLLA scaffolds prepared by the thermally induced phase separation method and conclude this review article by summarizing the current regulatory requirements for tissue-engineered products.

Fabrication and evaluation of 3D printed poly(l-lactide) copolymer scaffolds for bone tissue engineering

The application of poly(L-lactic acid) (PLLA) in tissue engineering is limited due to its brittleness and uncontrollable degradation rate. In this study, the flexible p-dioxanone (PDO) and highly reactive glycolide (GA) units were introduced into PLLA segments by chemical modification to prepare poly(l-lactide-ran-p-dioxanone-ran-glycolide) (PLPG) copolymers. The copolymers were then processed into the PLPG scaffold by a 3D printing technology. The physicochemical properties of the PLPG copolymers were studied by NMR, DSC, XRD, GPC, and SEM. Furthermore, the mechanical properties, degradation properties, and biocompatibility of the PLPG scaffolds were also studied. The results showed that introducing PDO and GA units disrupted the regularity of PLLA, decreasing the crystallinity of the PLPG copolymers. However, introducing PDO and GA units could effectively improve the mechanical and degradation properties of the PLLA scaffolds. In vitro cell culture experiments indicated that the PLPG scaffolds supported proliferation, growth, and differentiation of MC3T3-E1 cells. The PLPG scaffolds reported herein, with controllable degradation rates and mechanical performance, may find applications in bone tissue engineering.

Angiogenesis coupled with osteogenesis in a bone tissue engineering scaffold enhances bone repair in osteoporotic bone defects

Increased life expectancy has resulted in an increase in osteoporosis incidence worldwide. The coupling of angiogenesis and osteogenesis is indispensable for bone repair. Although traditional Chinese medicine (TCM) exerts therapeutic effects on osteoporosis, TCM-related scaffolds, which focus on the coupling of angiogenesis and osteogenesis, have not yet been used for the treatment of osteoporotic bone defects. Panax notoginseng saponin (PNS), the active ingredient of Panax notoginseng, was added to a poly (L-lactic acid) (PLLA) matrix. Osteopractic total flavone (OTF), the active ingredient of Rhizoma Drynariae, was encapsulated in nano-hydroxyapatite/collagen (nHAC) and added to the PLLA matrix. Magnesium (Mg) particles were added to the PLLA matrix to overcome the bioinert character of PLLA and neutralize the acidic byproducts generated by PLLA. In this OTF-PNS/nHAC/Mg/PLLA scaffold, PNS was released faster than OTF. The control group had an empty bone tunnel; scaffolds containing OTF:PNS = 100:0, 50:50, and 0:100 were used as the treatment groups. Scaffold groups promoted new vessel and bone formation, increased the osteoid tissue, and suppressed the osteoclast activity around osteoporotic bone defects. Scaffold groups upregulated the expression levels of angiogenic and osteogenic proteins. Among these scaffolds, the OTF-PNS (50:50) scaffold exhibited a better capacity for osteogenesis than the OTF-PNS (100:0 and 0:100) scaffolds. Activation of the bone morphogenic protein (BMP)-2/BMP receptor (BMPR)-1A/runt-related transcription factor (RUNX)-2 signaling pathway may be a possible mechanism for the promotion of osteogenesis. Our study demonstrated that the OTF-PNS/nHAC/Mg/PLLA scaffold could promote osteogenesis via the coupling of angiogenesis and osteogenesis in osteoporotic rats with bone defects, and activating the BMP-2/BMPR1A/RUNX2 signaling pathway may be an osteogenesis-related mechanism. However, further experiments are necessary to facilitate its practical application in the treatment of osteoporotic bone defects.

Towards resorbable 3D-printed scaffolds for craniofacial bone regeneration.

This review will briefly examine the development of 3D-printed scaffolds for craniofacial bone regeneration. We will, in particular, highlight our work using Poly(L-lactic acid) (PLLA) and collagen-based bio-inks. This paper is a narrative review of the materials used for scaffold fabrication by 3D printing. We have also reviewed two types of scaffolds that we designed and fabricated. Poly(L-lactic acid) (PLLA) scaffolds were printed using fused deposition modelling technology. Collagen-based scaffolds were printed using a bioprinting technique. These scaffolds were tested for their physical properties and biocompatibility. Work in the emerging field of 3D-printed scaffolds for bone repair is briefly reviewed. Our work provides an example of PLLA scaffolds that were successfully 3D-printed with optimal porosity, pore size and fibre thickness. The compressive modulus was similar to, or better than, the trabecular bone of the mandible. PLLA scaffolds generated an electric potential upon cyclic/repeated loading. The crystallinity was reduced during the 3D printing. The hydrolytic degradation was relatively slow. Osteoblast-like cells did not attach to uncoated scaffolds but attached well and proliferated after coating the scaffold with fibrinogen. Collagen-based bio-ink scaffolds were also printed successfully. Osteoclast-like cells adhered, differentiated, and survived well on the scaffold. Efforts are underway to identify means to improve the structural stability of the collagen-based scaffolds, perhaps through mineralization by the polymer-induced liquid precursor process. 3D-printing technology is promising for constructing next-generation bone regeneration scaffolds. We describe our efforts to test PLLA and collagen scaffolds produced by 3D printing. The 3D-printed PLLA scaffolds showed promising properties akin to natural bone. Collagen scaffolds need further work to improve structural integrity. Ideally, such biological scaffolds will be mineralized to produce true bone biomimetics. These scaffolds warrant further investigation for bone regeneration.

Collagen Functionalization of Polymeric Electrospun Scaffolds to Improve Integration into Full-Thickness Wounds.

Electrospun fibers are widely studied in regenerative medicine for their ability to mimic the extracellular matrix (ECM) and provide mechanical support. In vitro studies indicated that cell adhesion and migration is superior on smooth poly(L-lactic acid) (PLLA) electrospun scaffolds and porous scaffolds once biofunctionalized with collagen. The in vivo performance of PLLA scaffolds with modified topology and collagen biofunctionalization in full-thickness mouse wounds was assessed by cellular infiltration, wound closure and re-epithelialization and ECM deposition. Early indications suggested unmodified, smooth PLLA scaffolds perform poorly, with limited cellular infiltration and matrix deposition around the scaffold, the largest wound area, a significantly larger panniculus gape, and lowest re-epithelialization; however, by day 14, no significant differences were observed. Collagen biofunctionalization may improve healing, as collagen-functionalized smooth scaffolds were smallest overall, and collagen-functionalized porous scaffolds were smaller than non-functionalized porous scaffolds; the highest re-epithelialization was observed in wounds treated with collagen-functionalized scaffolds. Our results suggest that limited incorporation of smooth PLLA scaffolds into the healing wound occurs, and that altering surface topology, particularly by utilizing collagen biofunctionalization, may improve healing. The differing performance of the unmodified scaffolds in the in vitro versus in vivo studies demonstrates the importance of preclinical testing.