Tissue engineered vascular grafts transform into autologous neovessels capable of native function and growth

Background Tissue-engineered vascular grafts (TEVGs) have the potential to advance the surgical management of infants and children requiring congenital heart surgery by creating functional vascular conduits with growth capacity. Methods Herein, we used an integrative computational-experimental approach to elucidate the natural history of neovessel formation in a large animal preclinical model; combining an in vitro accelerated degradation study with mechanical testing, large animal implantation studies with in vivo imaging and histology, and data-informed computational growth and remodeling models. Results Our findings demonstrate that the structural integrity of the polymeric scaffold is lost over the first 26 weeks in vivo, while polymeric fragments persist for up to 52 weeks. Our models predict that early neotissue accumulation is driven primarily by inflammatory processes in response to the implanted polymeric scaffold, but that turnover becomes progressively mechano-mediated as the scaffold degrades. Using a lamb model, we confirm that early neotissue formation results primarily from the foreign body reaction induced by the scaffold, resulting in an early period of dynamic remodeling characterized by transient TEVG narrowing. As the scaffold degrades, mechano-mediated neotissue remodeling becomes dominant around 26 weeks. After the scaffold degrades completely, the resulting neovessel undergoes growth and remodeling that mimicks native vessel behavior, including biological growth capacity, further supported by fluid–structure interaction simulations providing detailed hemodynamic and wall stress information. Conclusions These findings provide insights into TEVG remodeling, and have important implications for clinical use and future development of TEVGs for children with congenital heart disease.

Polymeric Scaffolds for Dental, Oral, and Craniofacial Regenerative Medicine

Dental, oral, and craniofacial (DOC) regenerative medicine aims to repair or regenerate DOC tissues including teeth, dental pulp, periodontal tissues, salivary gland, temporomandibular joint (TMJ), hard (bone, cartilage), and soft (muscle, nerve, skin) tissues of the craniofacial complex. Polymeric materials have a broad range of applications in biomedical engineering and regenerative medicine functioning as tissue engineering scaffolds, carriers for cell-based therapies, and biomedical devices for delivery of drugs and biologics. The focus of this review is to discuss the properties and clinical indications of polymeric scaffold materials and extracellular matrix technologies for DOC regenerative medicine. More specifically, this review outlines the key properties, advantages and drawbacks of natural polymers including alginate, cellulose, chitosan, silk, collagen, gelatin, fibrin, laminin, decellularized extracellular matrix, and hyaluronic acid, as well as synthetic polymers including polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), poly (ethylene glycol) (PEG), and Zwitterionic polymers. This review highlights key clinical applications of polymeric scaffolding materials to repair and/or regenerate various DOC tissues. Particularly, polymeric materials used in clinical procedures are discussed including alveolar ridge preservation, vertical and horizontal ridge augmentation, maxillary sinus augmentation, TMJ reconstruction, periodontal regeneration, periodontal/peri-implant plastic surgery, regenerative endodontics. In addition, polymeric scaffolds application in whole tooth and salivary gland regeneration are discussed.

Development and Utilization of Multifunctional Polymeric Scaffolds for the Regulation of Physical Cellular Microenvironments

Polymeric biomaterials exhibit excellent physicochemical characteristics as a scaffold for cell and tissue engineering applications. Chemical modification of the polymers has been the primary mode of functionalization to enhance biocompatibility and regulate cellular behaviors such as cell adhesion, proliferation, differentiation, and maturation. Due to the complexity of the in vivo cellular microenvironments, however, chemical functionalization alone is usually insufficient to develop functionally mature cells/tissues. Therefore, the multifunctional polymeric scaffolds that enable electrical, mechanical, and/or magnetic stimulation to the cells, have gained research interest in the past decade. Such multifunctional scaffolds are often combined with exogenous stimuli to further enhance the tissue and cell behaviors by dynamically controlling the microenvironments of the cells. Significantly improved cell proliferation and differentiation, as well as tissue functionalities, are frequently observed by applying extrinsic physical stimuli on functional polymeric scaffold systems. In this regard, the present paper discusses the current state-of-the-art functionalized polymeric scaffolds, with an emphasis on electrospun fibers, that modulate the physical cell niche to direct cellular behaviors and subsequent functional tissue development. We will also highlight the incorporation of the extrinsic stimuli to augment or activate the functionalized polymeric scaffold system to dynamically stimulate the cells.

Glycosaminoglycan-Based Cryogels as Scaffolds for Cell Cultivation and Tissue Regeneration

Cryogels are a class of macroporous, interconnective hydrogels polymerized at sub-zero temperatures forming mechanically robust, elastic networks. In this review, latest advances of cryogels containing mainly glycosaminoglycans (GAGs) or composites of GAGs and other natural or synthetic polymers are presented. Cryogels produced in this way correspond to the native extracellular matrix (ECM) in terms of both composition and molecular structure. Due to their specific structural feature and in addition to an excellent biocompatibility, GAG-based cryogels have several advantages over traditional GAG-hydrogels. This includes macroporous, interconnective pore structure, robust, elastic, and shape-memory-like mechanical behavior, as well as injectability for many GAG-based cryogels. After addressing the cryogelation process, the fabrication of GAG-based cryogels and known principles of GAG monomer crosslinking are discussed. Finally, an overview of specific GAG-based cryogels in biomedicine, mainly as polymeric scaffold material in tissue regeneration and tissue engineering-related controlled release of bioactive molecules and cells, is provided.

O-102 Polymeric scaffold loaded with CD133+ BMDSCs for endometrial regeneration in Asherman’s syndrome

Study question Can CD133+ bone marrow-derived stem cells (BMDSCs) loaded in polyethylene glycol diacrylate (PEGda) and gelatin divide and decidualize? Summary answer Biocompatible porous PEGda and gelatin scaffold provides a three-dimensional environment for CD133+ cells to attach, divide, and decidualize in vitro. What is known already Intrauterine adhesions (IUA) develop due to acquired damages in the endometrium resulting in partial to complete endometrial dysfunction in the Asherman syndrome. Previous works from our group have demonstrated the engraftment of CD133+ BMDSCs and its paracrine effect on endometrial proliferation, improved endometrial thickness and clinical outcome in murine and human models of Asherman syndrome (AS). Study design, size, duration Human CD133+ BMDSCs were obtained from refractory AS patients undergoing autologous cell therapy. Two different polymers PEGda and gelatin were analysed for their ability to form porous scaffold. CD133+ BMDSCs cell adhesion and division was analysed up to 14 days, and its differentiation upon 8-Br-cAMP was evaluated in vitro on day 5. In vivo biocompatibility was evaluated until week 5. Participants/materials, setting, methods Porous PEGda and gelatin scaffolds were synthesized by cryogelation. Porosity, interconnectivity, and its distribution were characterized by scanning electron microscopy (SEM) and micro-computed tomography. Cell adhesion, growth, and morphology were analysed by SEM and fluorescence microscopy while decidualization of the adhered cells were analysed by prolactin (PRL) and IGFBP1 secretion by ELISA and the mRNA expression levels by qPCR. Biocompatibility and degradation of the scaffolds were analysed by sub-cutaneous implantation in Sprague -Dawley rats. Main results and the role of chance The average pore size was higher in the case of gelatin (100 – 250 µm) compared to PEGda which had compact structure with through pores (25 – 150 µm) and thick walls. Cross-sectional analysis revealed, well interconnected pores in both polymers. There was no significant difference between the two polymers with respect to cell adhesion, and viability (> 80% in both the cases). There was a significant increase in the expression of mRNA levels of IGFBP1 with a fold change of 3 ± 2.25 (PEGda), and 10 ± 1.3 (gelatin) whereas for PRL it was 0.08 ± 0.82 (PEGda), and 0.39 ± 1.7 (gelatin) when treated with cAMP. Secretion of IGFBP1 (7.4 ± 4.5 pg/ml for PEGda and 8.5 ± 4 pg/ml for gelatin) and PRL (4.7 ± 1.8 pg/ml for PEGda and 5.6 ± 1.2 pg/ml for gelatin) also increased with the addition of cAMP. In vivo, PEGda degraded at a faster rate (∼ 3 weeks) compared to gelatin (> 5 weeks) with no inflammatory reaction. Subcutaneous polymer degradation study was carried out to determine its degradation rate, its effect on inducing fibrosis, and to test its use as subcutaneous implant to aid in the regeneration of endometrium. Limitations, reasons for caution This is an in vitro study. Wider implications of the findings CD133+ BMDSCs loaded inflatable PEGda and gelatin scaffold could be a potential alternative to deliver the cells locally for the repair of endometrial damage provoked by the iatrogenic destruction of the endometrial niche. Trial registration number Not applicable

The Effect of Heat Treatment toward Glycerol-Based, Photocurable Polymeric Scaffold: Mechanical, Degradation and Biocompatibility

Photocurable polymers have become increasingly important for their quick prototyping and high accuracy when used in three dimensional (3D) printing. However, some of the common photocurable polymers are known to be brittle, cytotoxic and present low impact resistance, all of which limit their applications in medicine. In this study, thermal treatment was studied for its effect and potential applications on the mechanical properties, degradability and biocompatibility of glycerol-based photocurable polymers, poly(glycerol sebacate) acrylate (PGSA). In addition to the slight increase in elongation at break, a two-fold increase in both Young’s modulus and ultimate tensile strength were also observed after thermal treatment for the production of thermally treated PGSA (tPGSA). Moreover, the degradation rate of tPGSA significantly decreased due to the increase in crosslinking density in thermal treatment. The significant increase in cell viability and metabolic activity on both flat films and 3D-printed scaffolds via digital light processing-additive manufacturing (DLP-AM) demonstrated high in vitro biocompatibility of tPGSA. The histological studies and immune staining indicated that tPGSA elicited minimum immune responses. In addition, while many scaffolds suffer from instability through sterilization processes, it was proven that once glycerol-based polymers have been treated thermally, the influence of autoclaving the scaffolds were minimized. Therefore, thermal treatment is considered an effective method for the overall enhancement and stabilization of photocurable glycerol-based polymeric scaffolds in medicine-related applications.