Silk Fiber-Reinforced Hyaluronic Acid-Based Hydrogel for Cartilage Tissue Engineering.

A continuing challenge in cartilage tissue engineering for cartilage regeneration is the creation of a suitable synthetic microenvironment for chondrocytes and tissue regeneration. The aim of this study was to develop a highly tunable hybrid scaffold based on a silk fibroin matrix (SM) and a hyaluronic acid (HA) hydrogel. Human articular chondrocytes were embedded in a porous 3-dimensional SM, before infiltration with tyramine modified HA hydrogel. Scaffolds were cultured in chondropermissive medium with and without TGF-ß1. Cell viability and cell distribution were assessed using CellTiter-Blue assay and Live/Dead staining. Chondrogenic marker expression was detected using qPCR. Biosynthesis of matrix compounds was analyzed by dimethylmethylene blue assay and immuno-histology. Differences in biomaterial stiffness and stress relaxation were characterized using a one-step unconfined compression test. Cell morphology was investigated by scanning electron microscopy. Hybrid scaffold revealed superior chondro-inductive and biomechanical properties compared to sole SM. The presence of HA and TGF-ß1 increased chondrogenic marker gene expression and matrix deposition. Hybrid scaffolds offer cytocompatible and highly tunable properties as cell-carrier systems, as well as favorable biomechanical properties.

Joint academic and industrial efforts towards innovative and efficient solutions for clinical needs.

The 4th Translational Research Symposium (TRS) was organised at the annual meeting of the European Society for Biomaterials (ESB) 2017, Athens, Greece, with a focus on 'Academia-Industry Clusters of Research for Innovation Catalysis'. Collaborations between research institutes and industry can be sustained in several ways such as: European Union (EU) funded consortiums; syndicates of academic institutes, clinicians and industries; funding from national governments; and private collaborations between universities and companies. Invited speakers from industry and research institutions presented examples of these collaborations in the translation of research ideas or concepts into marketable products. The aim of the present article is to summarize the key messages conveyed during these lectures. In particular, emphasis is put on the challenges to appropriately identify and select unmet clinical needs and their translation by ultimately implementing innovative and efficient solutions achieved through joint academic and industrial efforts.

Improved Chondrogenic Differentiation of rAAV SOX9-Modified Human MSCs Seeded in Fibrin-Polyurethane Scaffolds in a Hydrodynamic Environment.

The repair of focal articular cartilage defects remains a problem. Combining gene therapy with tissue engineering approaches using bone marrow-derived mesenchymal stem cells (MSCs) may allow the development of improved options for cartilage repair. Here, we examined whether a three-dimensional fibrin-polyurethane scaffold provides a favorable environment for the effective chondrogenic differentiation of human MSCs (hMSCs) overexpressing the cartilage-specific SOX9 transcription factor via recombinant adeno-associated virus (rAAV) -mediated gene transfer cultured in a hydrodynamic environment in vitro. Sustained SOX9 expression was noted in the constructs for at least 21 days, the longest time point evaluated. Such spatially defined SOX9 overexpression enhanced proliferative, metabolic, and chondrogenic activities compared with control (reporter lacZ gene transfer) treatment. Of further note, administration of the SOX9 vector was also capable of delaying premature hypertrophic and osteogenic differentiation in the constructs. This enhancement of chondrogenesis by spatially defined overexpression of human SOX9 demonstrate the potential benefits of using rAAV-modified hMSCs seeded in fibrin-polyurethane scaffolds as a promising approach for implantation in focal cartilage lesions to improve cartilage repair.

Cross-Linking Chemistry of Tyramine-Modified Hyaluronan Hydrogels Alters Mesenchymal Stem Cell Early Attachment and Behavior.

Given the significance of hydrogels as cell-instructive materials, it is important to understand how differences in their chemical and physical properties are able to direct cell fate. For example, it remains unclear how different hydrogel cross-linking chemistries and gelation mechanisms influence cell behavior. Here, we report on hyaluronan-tyramine (HA-Tyr) hydrogels prepared either with enzymatic cross-linking using horseradish peroxidase and H2O2 or with visible light (500 nm) triggered gelation. We demonstrate that when hydrogels are polymerized to equivalent Young's moduli, the specific cross-linking chemistry of HA-Tyr hydrogels can have a substantial impact on mesenchymal stem cell (MSC) behavior. MSCs cultured on HA-Tyr hydrogels exhibit increased cell spread areas on enzymatically formed substrates relative to photo-cross-linked matrices. While enzymatically formed hydrogels led to MSCs exhibiting greater cell focal adhesion length, MSCs cultured on the photo-cross-linked matrices exhibited smaller cell spread area and shorter focal adhesion length but generated increased traction stress. These findings highlight the importance of understanding hydrogel cross-linking chemistries when the role of biophysical cues in regulating stem cell fate is investigated.

Structural and Chemical Modification to Improve Adhesive and Material Properties of Fibrin-Genipin for Repair of Annulus Fibrosus Defects in Intervertebral Disks.

Annulus fibrosus (AF) defects from intervertebral disk (IVD) herniation and degeneration are commonly associated with back pain. Genipin-crosslinked fibrin hydrogel (FibGen) is an injectable, space-filling AF sealant that was optimized to match AF shear properties and partially restored IVD biomechanics. This study aimed to enhance mechanical behaviors of FibGen to more closely match AF compressive, tensile, and shear properties by adjusting genipin crosslink density and by creating a composite formulation by adding Poly(D,L-lactide-co-glycolide) (PDLGA). This study also evaluated effects of thrombin concentration and injection technique on gelation kinetics and adhesive strength. Increasing FibGen genipin concentration from 1 to 36 mg/mL significantly increased adhesive strength (∼5 to 35 kPa), shear moduli (∼10 to 110 kPa), and compressive moduli (∼25 to 150 kPa) with concentration-dependent effects, and spanning native AF properties. Adding PDLGA to FibGen altered the material microstructure on electron microscopy and nearly tripled adhesive strength, but did not increase tensile moduli, which remained nearly 5× below native AF, and had a small increase in shear moduli and significantly decreased compressive moduli. Increased thrombin concentration decreased gelation rate to < 5 min and injection methods providing a structural FibGen cap increased pushout strength by ∼40%. We conclude that FibGen is highly modifiable with tunable mechanical properties that can be formulated to be compatible with human AF compressive and shear properties and gelation kinetics and injection techniques compatible with clinical discectomy procedures. However, further innovations, perhaps with more efficient fiber reinforcement, will be required to enable FibGen to match AF tensile properties.

Evaluation of a press-fit osteochondral poly(ester-urethane) scaffold in a rabbit defect model.

The purpose of this study was to evaluate the impact on osteochondral healing of press-fitted multiphasic osteochondral scaffolds consisting of poly(ester-urethane) (PUR) and hydroxyapatite into a cylindric osteochondral defect in the distal non-weight bearing femoral trochlear ridge of the rabbit. Two scaffolds were investigated, one with and one without an intermediate microporous membrane between the cartilage and the bone compartment of the scaffold. A control group without a scaffold placed into the defect was included. After 12 weeks macroscopic and histomorphological analyses were performed. The scaffold was easily press-fitted and provided a stable matrix for tissue repair. The membrane did not demonstrate a detrimental effect on tissue healing compared with the scaffold without membrane. However, the control group had statistically superior healing as reflected by histological differences in the cartilage and subchondral bone compartment between control group and each scaffold group. A more detailed analysis revealed that the difference was localized in the bone compartment healing. The present study demonstrates that an elastomeric PUR scaffold can easily be press-fitted into an osteochondral defect and provides a stable matrix for tissue repair. However, the multi-phasic scaffold did not provide a clear advantage for tissue healing. Future investigations should refine especially the bone phase of the implant to increase its stiffness, biocompatibility and osteoconductive activity. A more precise fabrication technique would be necessary for the matching of tissue organisation.

Tissue engineering for articular cartilage repair--the state of the art.

Articular cartilage exhibits little capacity for intrinsic repair, and thus even minor injuries or lesions may lead to progressive damage and osteoarthritic joint degeneration, resulting in significant pain and disability. While there have been numerous attempts to develop tissue-engineered grafts or patches to repair focal chondral and osteochondral defects, there remain significant challenges in the clinical application of cell-based therapies for cartilage repair. This paper reviews the current state of cartilage tissue engineering with respect to different cell sources and their potential genetic modification, biomaterial scaffolds and growth factors, as well as preclinical testing in various animal models. This is not intended as a systematic review, rather an opinion of where the field is moving in light of current literature. While significant advances have been made in recent years, the complexity of this problem suggests that a multidisciplinary approach - combining a clinical perspective with expertise in cell biology, biomechanics, biomaterials science and high-throughput analysis will likely be necessary to address the challenge of developing functional cartilage replacements. With this approach we are more likely to realise the clinical goal of treating both focal defects and even large-scale osteoarthritic degenerative changes in the joint.

Micro-porous PLGA/ß-TCP/TPU scaffolds prepared by solvent-based 3D printing for bone tissue engineering purposes.

The 3D printing process of fused deposition modelling is an attractive fabrication approach to create tissue-engineered bone substitutes to regenerate large mandibular bone defects, but often lacks desired surface porosity for enhanced protein adsorption and cell adhesion. Solvent-based printing leads to the spontaneous formation of micropores on the scaffold's surface upon solvent removal, without the need for further post processing. Our aim is to create and characterize porous scaffolds using a new formulation composed of mechanically stable poly(lactic-co-glycol acid) and osteoconductive ß-tricalcium phosphate with and without the addition of elastic thermoplastic polyurethane prepared by solvent-based 3D-printing technique. Large-scale regenerative scaffolds can be 3D-printed with adequate fidelity and show porosity at multiple levels analysed via micro-computer tomography, scanning electron microscopy and N2 sorption. Superior mechanical properties compared to a commercially available calcium phosphate ink are demonstrated in compression and screw pull out tests. Biological assessments including cell activity assay and live-dead staining prove the scaffold's cytocompatibility. Osteoconductive properties are demonstrated by performing an osteogenic differentiation assay with primary human bone marrow mesenchymal stromal cells. We propose a versatile fabrication process to create porous 3D-printed scaffolds with adequate mechanical stability and osteoconductivity, both important characteristics for segmental mandibular bone reconstruction.

Standard in vitro evaluations of engineered bone substitutes are not sufficient to predict in vivo preclinical model outcomes.

Understanding the optimal conditions required for bone healing can have a substantial impact to target the problem of non-unions and large bone defects. The combination of bioactive factors, regenerative progenitor cells and biomaterials to form a tissue engineered (TE) complex is a promising solution but translation to the clinic has been slow. We hypothesized the typical material testing algorithm used is insufficient and leads to materials being mischaracterized as promising. In the first part of this study, human bone marrow - derived mesenchymal stromal cells (hBM-MSCs) were embedded in three commonly used biomaterials (hyaluronic acid methacrylate, gelatin methacrylate and fibrin) and combined with relevant bioactive osteogenesis factors (dexamethasone microparticles and polyphosphate nanoparticles) to form a TE construct that underwent in vitro osteogenic differentiation for 28 days. Gene expression of relevant transcription factors and osteogenic markers, and von Kossa staining were performed. In the second and third part of this study, the same combination of TE constructs were implanted subcutaneously (cell containing) in T cell-deficient athymic Crl:NIH-Foxn1rnu rats for 8 weeks or cell free in an immunocompetent New Zealand white rabbit calvarial model for 6 weeks, respectively. Osteogenic performance was investigated via MicroCT imaging and histology staining. The in vitro study showed enhanced upregulation of relevant genes and significant mineral deposition within the three biomaterials, generally considered as a positive result. Subcutaneous implantation indicates none to minor ectopic bone formation. No enhanced calvarial bone healing was detected in implanted biomaterials compared to the empty defect. The reasons for the poor correlation of in vitro and in vivo outcomes are unclear and needs further investigation. This study highlights the discrepancy between in vitro and in vivo outcomes, demonstrating that in vitro data should be interpreted with extreme caution. In vitro models with higher complexity are necessary to increase value for translational studies. STATEMENT OF SIGNIFICANCE: Preclinical testing of newly developed biomaterials is a crucial element of the development cycle. Despite this, there is still significant discrepancy between in vitro and in vivo test results. Within this study we investigate multiple combinations of materials and osteogenic stimulants and demonstrate a poor correlation between the in vitro and in vivo data. We propose rationale for why this may be the case and suggest a modified testing algorithm.

Hyaluronic acid-based interpenetrating network hydrogel as a cell carrier for nucleus pulposus repair.

Hyaluronic acid (HA) is a key component of the intervertebral disc (IVD) that is widely investigated as an IVD biomaterial. One persisting challenge is introducing materials capable of supporting cell encapsulation and function, yet with sufficient mechanical stability. In this study, a hybrid interpenetrating polymer network (IPN) was produced as a non-covalent hydrogel, based on a covalently cross-linked HA (HA-BDDE) and HA-poly(N-isopropylacrylamide) (HA-pNIPAM). The hybrid IPN was investigated for its physicochemical properties, with histology and gene expression analysis to determine matrix deposition in vitro and in an ex vivo model. The IPN hydrogel displayed cohesiveness for at least one week and rheological properties resembling native nucleus pulposus (NP) tissue. When implanted in an ex vivo IVD organ culture model, the IPN supported cell viability, phenotype expression of encapsulated NP cells and IVD matrix production over four weeks under physiological loading. Overall, our results indicate the therapeutic potential of this HA-based IPN hydrogel for IVD regeneration.

An anisotropic nanocomposite hydrogel guides aligned orientation and enhances tenogenesis of human tendon stem/progenitor cells.

The uniform and aligned arrangement of tendon cells is a marker of tendon tissue morphology and the embodiment of its biological anisotropy. However, most of the hydrogels used for tendon tissue engineering do not present anisotropic structures. In this work, a magnetically-responsive nanocomposite hydrogel composed of collagen type I (COL I) and aligned iron oxide nanoparticles (IOPs) was investigated for potential application in tendon tissue engineering. COL I with a mixture of remotely aligned IOPs (A/IOPs) and human tendon stem/progenitor cells (COL I-A/IOPs-hTSPCs) was prepared and the alignment of IOPs was induced under a remote magnetic field. Following the gelation of COL I, a stable and anisotropic nanocomposite COL I-A/IOPs hydrogel was formed. In addition, hTSPCs embedded in COL I with random IOPs (COL I-R/IOPs-hTSPCs) and in pure COL I (COL I-hTSPCs) were used as control groups. Cell viability, proliferation, morphology, cell row formation, and alignment of IOPs and hTSPCs were evaluated over time. In addition, a comprehensive gene expression profile of 48 different genes, including tendon-related genes and lineage/cross-linking genes, was obtained by implementing designer quantitative RT-PCR plates. The hTSPCs morphology followed the orientation of the anisotropic COL I-A/IOPs hydrogel with increased row formation in comparison to pristine COL I and COL-R/IOPs. Moreover, higher proliferation rate and significant upregulation of tendon gene markers were measured in comparison to hTSPCs cultivated in the COL I-R/IOPs and COL I. Thus, we suggest that providing the cells with aligned focal contact points, namely the aligned IOPs, is sufficient to provoke an immense effect on the formation of aligned cell rows. Taken together, we report a novel strategy for directing stem cell behavior without the use of exogenous growth factors or pre-aligned COL I fibers, and propose that anisotropic nanocomposite hydrogels hold great potential for tendon tissue engineering applications.

Single-stage revision of MRSA orthopedic device-related infection in sheep with an antibiotic-loaded hydrogel.

Local antimicrobial therapy is an integral aspect of treating orthopedic device-related infection (ODRI), which is conventionally administered via polymethyl-methacrylate (PMMA) bone cement. PMMA, however, is limited by a suboptimal antibiotic release profile and a lack of biodegradability. In this study, we compare the efficacy of PMMA versus an antibiotic-loaded hydrogel in a single-stage revision for chronic methicillin-resistant Staphylococcus aureus (MRSA) ODRI in sheep. Antibiofilm activity of the antibiotic combination (gentamicin and vancomycin) was determined in vitro. Swiss alpine sheep underwent a single-stage revision of a tibial intramedullary nail with MRSA infection. Local gentamicin and vancomycin therapy was delivered via hydrogel or PMMA (n = 5 per group), in conjunction with systemic antibiotic therapy. In vivo observations included: local antibiotic tissue concentration, renal and liver function tests, and quantitative microbiology on tissues and hardware post-mortem. There was a nonsignificant reduction in biofilm with an increasing antibiotic concentration in vitro (p = 0.12), confirming the antibiotic tolerance of the MRSA biofilm. In the in vivo study, four out of five sheep from each treatment group were culture-negative. Antibiotic delivery via hydrogel resulted in 10-100 times greater local concentrations for the first 2-3 days compared with PMMA and were comparable thereafter. Systemic concentrations of gentamicin were minimal or undetectable in both groups, while renal and liver function tests were within normal limits. This study shows that a single-stage revision with hydrogel or PMMA is equally effective, although the hydrogel offers certain practical benefits over PMMA, which make it an attractive proposition for clinical use.

Tailoring thermoreversible hyaluronan hydrogels by "click" chemistry and RAFT polymerization for cell and drug therapy.

Thermoreversible hydrogels are promising matrices for tissue-engineered cartilage and spine constructs. They require specific properties during all the stages of a cell therapy (e.g., cell expansion, recovery, injection, delivery). Thermoreversible hyaluronan-poly(N-isopropylacrylamide) (HA-PNIPAM) hydrogels with well-defined molecular architecture and properties were synthesized through RAFT polymerization and "click" chemistry. The effect of PNIPAM grafting length and density on HA-PNIPAM properties was evaluated by methods relevant for a cell therapy. It was found that reversibility of the PNIPAM gelling process was improved in the presence of HA. Increasing M(n) of PNIPAM decreased the viscosity at 20 degrees C and led to high G' at T > 30 degrees C; however, higher grafting density led to lower mechanical properties. Water uptake of the hydrogels was mainly dependent on PNIPAM M(n). All of the hydrogels and their degradation products were cytocompatible to hTERT-BJ1 fibroblasts. A composition with properties ideal for cell encapsulation was identified and characterized by a low viscosity at 20 degrees C, rapid gelling at 37 degrees C, absence of volume change upon gelling, and G' of 140 Pa at 37 degrees C.

Synergistic anti-fouling and bactericidal poly(ether ether ketone) surfaces via a one-step photomodification.

Implants of poly(ether ether ketone) (PEEK) are gaining importance in surgical bone reconstruction of the skull. As with any implant material, PEEK is susceptible to bacterial contamination and occasionally PEEK implants were removed from patients because of infection. To address this problem, a combination of anti-fouling and bactericidal polymers is grafted onto PEEK. The originality is that anti-fouling (modified poly(ethylene glycol)) and bactericidal (quaternized poly(dimethylaminoethyl acrylate)) moieties are simultaneously and covalently grafted onto PEEK via UV photoinsertion. The functionalized PEEK surfaces are evaluated by water contact angle measurements, FTIR, XPS and AFM. Grafting of anti-fouling and bactericidal polymers significantly reduces Staphylococcus aureus adhesion on PEEK surfaces without exhibiting cytotoxicity in vitro. This study demonstrates that grafting combinations of anti-fouling and bactericidal polymers synergistically prevents bacterial adhesion on PEEK implants. This approach shows clinical relevance as grafting is rapid, does not modify PEEK properties and can be conducted on pre-formed implants.

Design of tunable gelatin-dopamine based bioadhesives.

Bioadhesives have a potential to modulate the wound closure process with significant biological outcomes. However, none of the currently commercialized adhesives are satisfactory in their performance. It is a challenging task to develop an adhesive system that can work on wet surface and enhances tissue repair and closure. In this study, we have fabricated a series of gelatin-dopamine (Gel-dop) conjugates and studied their adhesive properties after being chemically crosslinked using sodium periodate. The designed material was assessed for its adhesive properties including tensile, lap shear and peeling study by varying the degree of dopamine substitution. It was observed that the adhesive property has a direct correlation with increase in dopamine content until reaching a maximum and then a subsequent decrease. We tested the adhesive strength of the different formulations by varying the degree of substitution and compared against fibrin glue, which is considered as the gold standard of adhesives. The formulation with a moderate substitution degree demonstrated the optimal adhesive property than those formulations with lower and larger substitution degree. Further, the in vitro cytotoxicity study showed that this tunable Gel-dop adhesives are to non-cytotoxic, indicating a potential use in clinic applications. This study illustrates that adhesiveness can be regulated by changing the degree of dopamine substitution.

An Ex Vivo Bone Defect Model to Evaluate Bone Substitutes and Associated Bone Regeneration Processes.

The increased incidence of bone defects, especially in cases of comminuted fractures or bone tumor resections demands suitable bone grafts and substitutes. The aim of this study was to establish an ex vivo bone defect model to evaluate new bone substitutes and associated repair processes under controlled conditions. Femoral heads derived from patients undergoing total hip replacement were cut into cylinders (20 mm diameter, 7 mm height). A central bone defect (6 mm diameter, 5 mm depth) was inserted centrally. The bone slides were cultured for 28 days and viability was evaluated by lactate dehydrogenase and alkaline phosphatase assay, and Calcein-AM viability staining and DNA quantification. Data revealed the viability of the bone tissue over the tested time period of 28 days, and an increase in cell numbers implicating active cell proliferation processes in the sections. To analyze the bone regeneration potential of this model in combination with a bone replacement material, we injected a collagen-type 1 hydrogel into the central defect. Cellular ingrowth into the gel was evaluated by microscopy and DNA quantification at different time points demonstrating an increase of cells in the defect over time. Finally, gene expression of osteogenic markers indicated an osteoblastic phenotype of the cells in the defect. In summary, the ex vivo bone defect model remains viable and shows active bone repair processes over 28 days. Additional advantages include high reproducibility, manageable costs, and a native bone-implant interface supporting the evaluation of bone substitute materials and associated regeneration processes. Impact statement Testing of new implant materials and bone repair strategies up to date rely mainly on in vivo and in vitro investigation models providing different pros and cons. In this study we established a novel human ex vivo bone defect model with a proven vitality of at least 28 days. The model provides a native bone implant interface and is designed to monitor cell invasion into a critically sized defect filled with the potential implant material. Furthermore, associated repair processes can be documented on the cell and molecular level, including additional advantages such as high reproducibility and manageable costs.

Introduction of the Anspach drill as a novel surgical driller for creating calvarial defects in animal models.

Standardized and reproducible animal models are required for the assessment of bone healing mediated by biomaterials, cells, and drugs. Among the available bone-fractured models, calvarial defect is a simple and adequate option when researchers investigate intra-membranous bone formation and the influence of their regenerative solutions. However, the conventional surgical tools required to perform calvaria osteotomies (i.e., trephine bur mounted on a dental handpiece, DS) can affect the subjacent tissues of the skull, which are the dura mater and the brain. We hypothesized that the quality of the calvaria defect and the preservation of underlying tissues can be improved using a novel Anspach high-speed drill with a Codman Neuro Disposable Perforator handheld (ACP). Using a rabbit cadaveric models, we performed calvarial defects with either conventional DS or the ACP system, and showed that both techniques allowed to create standardized defects with circular geometry. We demonstrated that the ACP had clear benefices in terms of DM preservation and absence of exothermic reaction upon drilling. Even though this comparative work was conducted on cadaver, it is of substantial importance as it introduces a novel technique, easily applicable to investigate calvaria bone healing, which brings clear advantages compared to the conventional dental station. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-9, 2019.

Osteogenic magnesium incorporated into PLGA/TCP porous scaffold by 3D printing for repairing challenging bone defect.

Bone defect repair is a challenging clinical problem in musculoskeletal system, especially in orthopaedic disorders such as steroid associated osteonecrosis (SAON). Magnesium (Mg) as a biodegradable metal with properly mechanical properties has been investigating for a long history. In this study, Mg powder, poly (lactide-co-glycolide) (PLGA), ß-tricalcium phosphate (ß-TCP) were the elements to formulate a novel porous PLGA/TCP/Mg (PTM) scaffolds using low temperature rapid prototyping (LT-RP) technology. The physical characterization of PTM scaffold and Mg ions release were analyzed in vitro. The osteogenic and angiogenic properties of PTM scaffolds, as well as the biosafety after implantation were assessed in an established SAON rabbit model. Our results showed that the PTM scaffold possessed well-designed bio-mimic structure and improved mechanical properties. Findings of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and micro-computed tomography (micro CT)-based angiography indicated that PTM scaffold could increase blood perfusion and promote new vessel ingrowth at 4 weeks after surgery, meanwhile, a plenty of newly formed vessels with well-architective structure were observed at 8 weeks. Correspondingly, at 12 weeks after surgery, micro-CT, histological and mechanical properties analysis showed that PTM could significant enhance new bone formation and strengthen newly formed bone mechanical properties. The mean bone volume in PTM group was 56.3% greater than that in PT group. Biosafety assessments from 0 to 12 weeks after implantation did not induce increase in serum Mg ions concentration, and immune response, liver and kidney function parameters were all at normal level. These findings suggested that the PTM scaffold had both osteogenic and angiogenic abilities which were synergistic effect in enhancing new bone formation and strengthen newly formed bone quality in SAON. In summary, PTM scaffolds are promising composite biomaterials for repairing challenging bone defect that would have great potential for its clinical translation.

Lessons to be learned and future directions for intervertebral disc biomaterials.

Biomaterials science has achieved significant advancements for the replacement, repair and regeneration of intervertebral disc tissues. However, the translation of this research to the clinic presents hurdles. The goal of this paper is to identify strategies to recapitulate the intrinsic complexities of the intervertebral disc, to highlight the unresolved issues in basic knowledge hindering the clinical translation, and finally to report on the emerging technologies in the biomaterials field. On this basis, we identify promising research directions, with the hope of stimulating further debate and advances for resolving clinical problems such as cervical and low back pain using biomaterial-based approaches. STATEMENT OF SIGNIFICANCE: Although not life-threatening, intervertebral disc disorders have enormous impact on life quality and disability. Disc function within the human body is mainly mechanical, and therefore the use of biomaterials to rescue disc function and alleviate pain is logical. Despite intensive research, the clinical translation of biomaterial-based therapies is hampered by the intrinsic complexity of this organ. After decades of development, artificial discs or tissue replacements are still niche applications given their issues of integration and displacement with detrimental consequences. The struggles of biological therapies and tissue engineering are therefore understandable. However, recent advances in biomaterial science give new hope. In this paper we identify the most promising new directions for intervertebral disc biomaterials.

A drug eluting poly(trimethylene carbonate)/poly(lactic acid)-reinforced nanocomposite for the functional delivery of osteogenic molecules.

BACKGROUND: Poly(trimethylene carbonate) (PTMC) has wide biomedical applications in the field of tissue engineering, due to its biocompatibility and biodegradability features. Its common manufacturing involves photofabrication, such as stereolithography (SLA), which allows the fabrication of complex and controlled structures. Despite the great potential of SLA-fabricated scaffolds, very few examples of PTMC-based drug delivery systems fabricated using photo-fabrication can be found ascribed to light-triggered therapeutics instability, degradation, side reaction, binding to the macromers, etc. These concerns severely restrict the development of SLA-fabricated PTMC structures for drug delivery purposes. METHODS: In this context, we propose here, as a proof of concept, to load a drug model (dexamethasone) into electrospun fibers of poly(lactic acid), and then to integrate these bioactive fibers into the photo-crosslinkable resin of PTMC to produce hybrid films. The hybrid films' properties and drug release profile were characterized; its biological activity was investigated via bone marrow mesenchymal stem cells culture and differentiation assays. RESULTS: The polymer/polymer hybrids exhibit improved properties compared with PTMC-only films, in terms of mechanical performance and drug protection from UV denaturation. We further validated that the dexamethasone preserved its biological activity even after photoreaction within the PTMC/poly(lactic acid) hybrid structures by investigating bone marrow mesenchymal stem cells proliferation and osteogenic differentiation. CONCLUSION: This study demonstrates the potential of polymer-polymer scaffolds to simultaneously reinforce the mechanical properties of soft matrices and to load sensitive drugs in scaffolds that can be fabricated via additive manufacturing.