Extracellular vesicle (EV)- based therapies have been successfully tested in preclinical models for several biomedical applications, including tissue engineering, drug delivery and cancer therapy. ...However, EVs are most commonly delivered via local or systemic injection, which results in rapid clearance. In order to prolong the retention of EVs at target site and improve their therapeutic efficacy, biomaterial-based delivery systems are being investigated. This review discusses the various biomaterial-based systems that have been used to deliver EVs for therapeutic applications, specifically highlighting any strategies for controlled release. Further, challenges to clinical translation of biomaterial-based EV delivery systems are also discussed.
Display omitted
Mesenchymal stem cell (MSC)-based therapies have demonstrated tissue repair and regeneration capacity in various preclinical models. These therapeutic effects have recently been largely attributed to ...the paracrine effects of the MSC secretome, including proteins and extracellular vesicles (EVs). EVs are cell-secreted nano-sized vesicles with lipid bilayer membranes that facilitate cell-cell signaling. Treatments based on MSC-derived EVs are beginning to be explored as an alternative to MSC transplantation-based therapies. However, it remains to be determined which MSC source produces EVs with the greatest therapeutic potential. This review compares the tissue regeneration capacity of EVs isolated from the two most common clinical sources of adult MSCs, bone marrow and adipose tissue, with a particular focus on their angiogenic, osteogenic, and immunomodulatory potentials. Other important issues in the development of MSC-derived EV based therapies are also discussed.
Cloned 20 years ago, stem cell antigen‐1 (Sca‐1) is used extensively to enrich for murine hematopoietic stem cells. The realization that many different stem cell types share conserved biochemical ...pathways has led to a flood of recent research using Sca‐1 as a candidate marker in the search for tissue‐resident and cancer stem cells. Although surprisingly little is still known about its biochemical function, the generation and analysis of knockout mice has begun to shed light on the functions of Sca‐1 in stem and progenitor cells, demonstrating that it is more than a convenient marker for stem cell biologists. This review summarizes the plethora of recent findings utilizing Sca‐1 as a parenchymal stem cell marker and detailing its functional role in stem and progenitor cells and also attempts to explain the lingering mysteries surrounding its biochemical function and human ortholog.
Disclosure of potential conflicts of interest is found at the end of this article.
Substrate-mediated transfection is one of the key strategies for localized gene delivery. Layer-by-layer (LbL) polyelectrolyte deposition is a promising technique which enables controlled delivery of ...a number of biofactors, including nucleic acids. Here, we embed lipoplexes containing plasmid DNA within polyelectrolyte multilayers composed of glycol-chitosan (Glyc-CHI) and hyaluronic acid (HA) in order to produce a film system that enables localized, surface-based transfection. The topography and morphology of the resulting multilayers were characterized after lipoplex absorption and during subsequent film build-up via atomic force microscopy (AFM) and scanning electron microscopy (SEM), respectively. DNA embedding efficiency and release were then examined. Lipoplex-containing Glyc-CHI/HA films were found to successfully transfect NIH3T3 fibroblasts and HEK293 kidney cells in vitro, maintaining transfection levels of approximately 20% for a period of at least 7 days.
To analyze preclinical bone regeneration studies employing mesenchymal stromal cell (MSC)- derived extracellular vesicles (EVs) and highlight any commonalities in EV biomarker expression, miRNA ...cargo(s) or pathway activation that will aid in understanding the underlying therapeutic mechanisms.
Articles employing EVs derived from either MSCs or MSC-like osteogenic stromal cells in preclinical bone regeneration studies are included in this review.
EVs derived from a variety of MSC types were able to successfully induce bone formation in preclinical models. Many studies failed to perform in-depth EV characterization. The studies with detailed EV characterization data report very different miRNA cargos, even in EVs isolated from the same species and cell types. Few preclinical studies have analyzed the underlying mechanisms of MSC-EV therapeutic action.
There is a critical need for mechanistic preclinical studies with thorough EV characterization to determine the best therapeutic MSC-EV source for bone regeneration therapies. Issues including controlled EV delivery, large scale production, and proper storage also need to be addressed before EV-based bone regeneration therapies can be translated for clinical bone repair.
•EVs from different MSC sources successfully regenerate bone in preclinical models.•Studies were reviewed to find commonalities in EV cargo(s)/pathways activated in MSC-EV-based bone regeneration therapies.•Issues that need to be overcome to enable clinical translation of EV-based therapies were addressed.
Abstract Use of polyelectrolyte multi-layers as biomaterials for cell attachment has been limited due to their gel-like characteristics. Herein, we attempt to improve the cellular adhesion properties ...of multi-layer films, reduce their gel-like nature and rigidify them through chemical cross-linking with genipin; a natural and non-cytotoxic compound. Chitosan (CH), hyaluronan (HA) and alginate (Alg) were used to assemble CH–HAn CH and CH–Algn CH films, and the effects of genipin cross-linking on the cell adhesion properties of these multi-layers were investigated. Atomic force microscopy (AFM) confirmed that cross-linking affected each of the films differently. Quartz crystal microbalance with dissipation (QCM-D) revealed that CH–HA10 CH films were very viscoelastic, with thicknesses in the range 350–450 nm, while CH–Alg10 CH films only grew to thicknesses of ∼100 nm. These differences were a result of the different growth regimes of these two polyelectrolyte systems. Cell adhesion studies using MC3T3 pre-osteoblasts and rat fibroblastic skin cells, carried out on both films demonstrated vast differences in cell adhesion. CH–HAn CH cross-linked films proved to be highly non-adhesive for pre-osteoblasts and fibroblastic skin cells. Conversely, cross-linking CH–Algn CH films was shown to dramatically improve pre-osteoblast and rat fibroblastic skin cell adhesion, especially for high bi-layer numbers and using higher concentrations of cross-linker.
Growth factors are essential orchestrators of the normal bone fracture healing response. For non-union defects, delivery of exogenous growth factors to the injured site significantly improves healing ...outcomes. However, current clinical methods for scaffold-based growth factor delivery are fairly rudimentary, and there is a need for greater spatial and temporal regulation to increase their in vivo efficacy. Various approaches used to provide spatiotemporal control of growth factor delivery from bone tissue engineering scaffolds include physical entrapment, chemical binding, surface modifications, biomineralization, micro- and nanoparticle encapsulation, and genetically engineered cells. Here, we provide a brief review of these technologies, describing the fundamental mechanisms used to regulate release kinetics. Examples of their use in pre-clinical studies are discussed, and their capacities to provide tunable, growth factor delivery are compared. These advanced scaffold systems have the potential to provide safer, more effective therapies for bone regeneration than the systems currently employed in the clinic.
Tissue-engineered approaches to regenerate bone in the craniomaxillofacial region utilize biomaterial scaffolds to provide structural and biological cues to stem cells to stimulate osteogenic ...differentiation. Bioactive scaffolds are typically comprised of natural components but often lack the manufacturability of synthetic materials. To circumvent this trade-off, we 3D printed materials comprised of decellularized bone (DCB) matrix particles combined with polycaprolactone (PCL) to create novel hybrid DCB:PCL scaffolds for bone regeneration. Hybrid scaffolds were readily printable at compositions of up to 70% bone by mass and displayed robust mechanical properties. Assessments of surface features revealed both collagenous and mineral components of bone were present. Qualitative and quantitative assessments showed increased surface roughness relative to that of pure PCL scaffolds. These findings correlated with enhanced cell adhesion on hybrid surfaces relative to that on pure surfaces. Human adipose-derived stem cells (hASCs) cultured in DCB:PCL scaffolds without soluble osteogenic cues exhibited significant upregulation of osteogenic genes in hybrid scaffolds relative to pure PCL scaffolds. In the presence of soluble phosphate, hybrid scaffolds resulted in increased calcification. The hASC-seeded scaffolds were implanted into critical-sized murine calvarial defects and yielded greater bone regeneration in DCB:PCL scaffolds compared to that in PCL-only at 1 and 3 months post-transplantation. Taken together, these results demonstrate that 3D printed DCB:PCL scaffolds might be effective for stimulating bone regeneration.
Abstract Background context A persistent challenge in spine surgery is improving screw fixation in patients with poor bone quality. Augmenting pedicle screw fixation with cement appears to be a ...promising approach. Purpose The purpose of this study was to survey the literature and assess the previous biomechanical studies on pedicle screw augmentation with cement to provide in-depth discussions of the biomechanical benefits of multiple parameters in screw augmentation. Study design/Setting This is a systematic literature review. Methods A search of Medline was performed, combining search terms of pedicle screw, augmentation, vertebroplasty, kyphoplasty, polymethylmethacrylate, calcium phosphate, or calcium sulfate. The retrieved articles and their references were reviewed, and articles dealing with biomechanical testing were included in this article. Results Polymethylmethacrylate is an effective material for enhancing pedicle screw fixation in both osteoporosis and revision spine surgery models. Several other calcium ceramics also appear promising, although further work is needed in material development. Although fenestrated screw delivery appears to have some benefits, it results in similar screw fixation to prefilling the cement with a solid screw. Some differences in screw biomechanics were noted with varying cement volume and curing time, and some benefits from a kyphoplasty approach over a vertebroplasty approach have been noted. Additionally, in cadaveric models, cemented-augmented screws were able to be removed, albeit at higher extraction torques, without catastrophic damage to the vertebral body. However, there is a risk of cement extravasation leading to potentially neurological or cardiovascular complications with cement use. A major limitation of these reviewed studies is that biomechanical tests were generally performed at screw implantation or after a limited cyclic loading cycle; thus, the results may not be entirely clinically applicable. This is particularly true in the case of the bioactive calcium ceramics, as these biomechanical studies would not have measured the effects of osseointegration. Conclusions Polymethylmethacrylate and various calcium ceramics appear promising for the augmentation of pedicle screw fixation biomechanically in both osteoporosis and revision spine surgery models. Further translational studies should be performed, and the results summarized in this review will need to be correlated with the clinical outcomes.
Since the wiki page was categorized Women's/Gender/Queer Studies, we also included sexuality studies jobs whether they were housed within GWFS departments/programs or in stand-alone departments and ...programs such as LGBT studies, queer studies, and sexuality studies (of which there are few).14 We excluded positions that wanted a gender and/or sexuality specialist in another department (for example, a political science department recruiting a feminist scholar). ...in addition to knowing more about how search committees regard the GWFS PhD, we wonder to what degree GWFS searches are tasked with hiring marginalized scholars to increase the diversity profile of the institution.32 To the extent that this is the case, it not only puts pressure on GWFS to do the diversity work of the institution, thereby letting other programs off the hook for their continued hiring of faculty with identity-based privilege, but it also puts tremendous pressure on the faculty member who secures the position to take on undue burdens of committee and mentorship work.33 We wonder how this phenomenon marks some GWFS PhDs as more attractive to hiring committees or influences a hiring committee's decision to turn to non-GWFS PhD applicants to fill available positions. For those who wish to stay in academia, what are the dominant narratives about finding a tenure-track job in GWFS, how do they circulate, and why do they persist? Since our inquiry was prompted by a desire to test our theories - our stories - about the job market, it would be valuable to return to these stories in the future. ...we see ourselves in conversation with the New Faculty Majority and the NWSA Contingent Faculty Interest Group (incidentally coestablished by Gwendolyn Beetham, who has a PhD in GWFS).35 Like these initiatives, our findings call into question the expansion of PhD programs meant to prepare graduates for jobs that do not exist.
PDF
