Injuries to the meniscus of the knee commonly lead to osteoarthritis. Current therapies for meniscus regeneration, including meniscectomies and scaffold implantation, fail to achieve complete functional regeneration of the tissue. This has led to increased interest in cell and gene therapies and tissue engineering approaches to meniscus regeneration. The implantation of a biomimetic implant, incorporating cells, growth factors, and extracellular matrix (ECM)-derived proteins, represents a promising approach to functional meniscus regeneration. The objective of this study was to develop a range of ECM-functionalised bioinks suitable for 3D bioprinting of meniscal tissue. To this end, alginate hydrogels were functionalised with ECM derived from the inner and outer regions of the meniscus and loaded with infrapatellar fat pad-derived stem cells. In the absence of exogenously supplied growth factors, inner meniscus ECM promoted chondrogenesis of fat pad-derived stem cells, whereas outer meniscus ECM promoted a more elongated cell morphology and the development of a more fibroblastic phenotype. With exogenous growth factors supplementation, a more fibrogenic phenotype was observed in outer ECM-functionalised hydrogels supplemented with connective tissue growth factor, whereas inner ECM-functionalised hydrogels supplemented with TGFβ3 supported the highest levels of Sox-9 and type II collagen gene expression and sulfated glycosaminoglycans (sGAG) deposition. The final phase of the study demonstrated the printability of these ECM-functionalised hydrogels, demonstrating that their codeposition with polycaprolactone microfibres dramatically improved the mechanical properties of the 3D bioprinted constructs with no noticeable loss in cell viability. These bioprinted constructs represent an exciting new approach to tissue engineering of functional meniscal grafts.
Minimally invasive delivery of "living cell factories" consisting of cells and therapeutic agents has gained wide attention for next generation biomaterial device systems for multiple applications including musculoskeletal tissue regeneration, diabetes and cancer. Cellularbased microcapsules and microcarrier systems offer several attractive features for this particular purpose. One such technology capable of generating these types of systems is electrohydrodynamic (EHD) spraying. Depending on various parameters including applied voltage, biomaterial properties (viscosity, conductivity) and needle geometry, complex structures and arrangements can be fabricated for therapeutic strategies. In this paper, we outline the advances in the use of EHD technology specifically in the manipulation of bioactive and dynamic material systems to control size, composition and configuration in the development of minimally invasive micro-scaled biopolymeric systems. The exciting therapeutic applications of this technology, future perspectives and associated challenges are also presented.
Lower back pain from degenerative disc disease represents a global health burden, and presents a prominent opportunity for regenerative therapeutics. While current regenerative therapies such as autologous disc chondrocyte transplantation (ADCT), allogeneic juvenile chondrocyte implantation (NuQu 1 ), and immunoselected allogeneic adipose derived precursor cells (Mesoblast) show exciting clinical potential, limitations remain. The heterogeneity of preclinical approaches and the paucity of clinical guidance have limited translational outcomes in disc repair, lagging almost a decade behind cartilage repair. Advances in cartilage repair have evolved to single step approaches with improved orthopedic repair and regeneration. Elements from cartilage regeneration endeavors could be adopted and applied to harness translatable approaches and deliver a clinically and economically feasible regenerative surgery for back pain. In this article, we trace the developments behind the translational success of cartilage repair, examine elements to consider in achieving disc regeneration, and the need for surgical redesign. We further discuss clinical parameters, objectives, and coordination required to deliver improved regenerative surgery. Cell source, processing, and delivery modalities are key issues to be addressed in considering surgical redesign. Advances in biomanufacturing, tissue cryobanking, and point of care cell processing technology may enable intraoperative solutions for single step procedures. To maximize translational success a triad partnership between clinicians, industry, and researchers will be critical in providing instructive clinical guidelines for design as well as practical and economic considerations. This will allow a consensus in research ventures and add regenerative surgery into the algorithm in managing and treating a debilitating condition such as back pain. ß
Laboratory based processing and expansion to yield adequate cell numbers had been the standard in Autologous Disc Chondrocyte Transplantation (ADCT), Allogeneic Juvenile Chondrocyte Implantation (NuQu®), and Matrix-Induced Autologous Chondrocyte Implantation (MACI). Optimizing cell isolation is a key challenge in terms of obtaining adequate cell numbers while maintaining a vibrant cell population capable of subsequent proliferation and matrix elaboration. However, typical cell yields from a cartilage digest are highly variable between donors and based on user competency. The overall objective of this study was to optimize chondrocyte isolation from cartilaginous nasal tissue through modulation of enzyme concentration exposure (750 and 3000 U/ml) and incubation time (1 and 12 h), combined with physical agitation cycles, and to assess subsequent cell viability and matrix forming capacity. Overall, increasing enzyme exposure time was found to be more detrimental than collagenase concentration for subsequent viability, proliferation, and matrix forming capacity (sGAG and collagen) of these cells resulting in nonuniform cartilaginous matrix deposition. Taken together, consolidating a 3000 U/ml collagenase digest of 1 h at a ratio of 10 ml/g of cartilage tissue with physical agitation cycles can improve efficiency of chondrocyte isolation, yielding robust, more uniform matrix formation.
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