Application of the Stanford Biodesign Framework in Healthcare Innovation Training and Commercialization of Market Appropriate Products: A Scoping Review.

The Stanford Biodesign needs-centric framework can guide healthcare innovators to successfully adopt the 'Identify, Invent and Implement' framework and develop new healthcare innovations products to address patients' needs. This scoping review explored the application of the Stanford Biodesign framework for healthcare innovation training and the development of novel healthcare innovative products. Seven electronic databases were searched from their respective inception dates till April 2023: PubMed, Embase, CINAHL, PsycINFO, Web of Science, Scopus, ProQuest Dissertations, and Theses Global. This review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews and was guided by the Arksey and O'Malley's scoping review framework. Findings were analyzed using Braun and Clarke's thematic analysis framework. Three themes and eight subthemes were identified from the 26 included articles. The main themes are: (1) Making a mark on healthcare innovation, (2) Secrets behind success, and (3) The next steps. The Stanford Biodesign framework guided healthcare innovation teams to develop new medical products and achieve better patient health outcomes through the induction of training programs and the development of novel products. Training programs adopting the Stanford Biodesign approach were found to be successful in improving trainees' entrepreneurship, innovation, and leadership skills and should continue to be promoted. To aid innovators in commercializing their newly developed medical products, additional support such as securing funds for early start-up companies, involving clinicians and users in product testing and validation, and establishing new guidelines and protocols for the new healthcare products would be needed.

Early osteogenic differentiation of mouse preosteoblasts induced by collagen-derived DGEA-peptide on nanofibrous phage tissue matrices.

Specific biochemical and physical cues in tissue extracellular matrices play a critical role in regulating cellular growth processes and their fate. We report initial responses of bone stem cells induced by collagen-derived DGEA-peptides on nanofibrous M13 phage tissue matrices. We constructed genetically engineered M13 phage with DGEA-peptide displayed in high density on the major coat proteins and biomimetic nanofibrous tissue-like matrices in two and three dimensions. We investigated the effects of biochemical cues, specifically DGEA-peptides on preosteoblast (MC3T3) morphologies. The preosteoblasts grown on the top of the DGEA-incorporated phage matrices exhibited significant outgrown morphology with early bone cell marker protein expression. Through soluble peptide competition assays and control experiments, we verified that the observed cellular morphologies and osteogenic protein marker expression were specifically caused by the DGEA-peptides. We confirmed that the outgrown morphologies are linked with the early phase of osteogenic protein expression through mRNA quantification and bone cell protein marker expression. Additionally, we demonstrated that the phage-based tissue matrix systems could work as a good cell culture platform to investigate the specific effect of biochemical cues, which can be tuned precisely at a single amino acid level with little change in other physical and chemical properties of the environment. Our study advances the understanding of osteogenic differentiation and our phage-based tissue matrices have the potential for future bone regeneration therapy and systemic investigation of specific cellular responses to biochemical ligand stimulation.

Unidirectional and sustained delivery of the proresolving lipid mediator resolvin D1 from a biodegradable thin film device.

Resolvin D1 (RvD1) belongs to a family of endogenously derived proresolving lipid mediators that have been shown to attenuate inflammation, activate proresolution signaling, and promote homeostasis and recovery from tissue injury. In this study we present a poly(lactic-co-glycolic acid) (PLGA) based thin-film device composed of layers of varying ratios of lactic and glycolic acid that elutes RvD1 unidirectionally to target tissues. The device demonstrated sustained release in vitro for 56 days with an initial burst of release over 14 days. The asymmetric design of the device released 98% of RvD1 through the layer with the lowest molar ratio of lactic acid to glycolic acid, and the remainder through the opposite side. We validated structural integrity of RvD1 released from the device by mass spectrometry and investigated its bioactivity on human vascular endothelial (EC) and smooth muscle cells (VSMC). RvD1 released from the device attenuated VSMC migration, proliferation, and TNF-α induced NF-κB activation, without evidence of cytotoxicity. Delivery of RvD1 to blood vessels was demonstrated ex vivo in a flow chamber system using perfused rabbit aortas and in vivo in a rat carotid artery model, with the devices applied as an adventitial wrap. Our results demonstrate a novel approach for sustained, local delivery of Resolvin D1 to vascular tissue at therapeutically relevant levels. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 31-41, 2017.

PEGylated silicon nanowire coated silica microparticles for drug delivery across intestinal epithelium.

Composite particles made by growing nanoscopic silicon wires from the surface of monodispersed, microsized silica beads were tested in this study for their ability to affect the integrity and permeability of an epithelial cell layer. Polyethylene glycol (PEG) is known to sterically stabilize particles and prevent protein binding; as such, it is a routine way to impart in vivo longevity to drug carriers. The effect of the silica beads, both with and without silicon nanowires and PEG, on the disruption of the tight junctions in Caco-2 cells was evaluated by means of: (a) analysis of the localization of zonula occludens-1 (ZO-1), claudin-1 and f-actin; (b) measurements of trans-epithelial electrical resistance (TEER); (c) real-time quantitative RT-PCR analysis of the expression of PKC-α and PKC-z, which regulate the fluidity of cell membranes, and RhoA and Rac1, which are mainly involved in mechanotransduction processes; and (d) drug permeability experiments with fluorescein-sodium. The results have shown that Si-nanowire-coated silica microparticles added to Caco-2 cells in culture lead to alterations in tight junction permeability and the localization of ZO-1 and f-actin, as well as to decreased width of ZO-1 and claudin-1 at the tight junction and increased expression of PKC transcripts. Si-nanowire-coated silica microparticles increased the permeability of Caco-2 cell monolayers to fluorescein-sodium in proportion to their amount. Effects indicative of loosening the Caco-2 cell monolayers and increasing their permeability were less pronounced for PEGylated particles, owing to their greater supposed inertness in comparison with the non-functionalized beads and nanowires. The analyzed Si-nanowire-coated silica microparticles have thus been shown to affect membrane barrier integrity in vitro, suggesting the possibility of using nanostructured microparticles to enhance drug permeability through the intestinal epithelium in vivo.

Shape effect in the design of nanowire-coated microparticles as transepithelial drug delivery devices.

While the oral drug delivery route has traditionally been the most popular among patients, it is estimated that 90% of therapeutic compounds possess oral bioavailability limitations. Thus, the development of novel drug carriers for more effective oral delivery of therapeutics is an important goal. Composite particles made by growing nanoscopic silicon wires from the surface of narrowly dispersed, microsized silica beads were previously shown to be able to (a) adhere well onto the epithelium by interdigitating their nanowires with the apical microvilli and (b) increase the permeability of Caco-2 cell monolayers with respect to small organic molecules in direct proportion to their concentration. A comparison between the effects of spherical and planar particle morphologies on the permeability of the epithelial cell layer in vitro and in vivo presented the subject of this study. Owing to their larger surface area, the planar particles exhibited a higher drug-loading efficiency than their spherical counterparts, while simultaneously increasing the transepithelial permeation of a moderately sized model drug, insulin. The insulin elution profile for planar nanowire-coated particles displayed a continual increase in the cumulative amount of the released drug, approaching a constant release rate for a 1-4 h period of the elution time. An immunohistochemical study confirmed the ability of planar silica particles coated with nanowires to loosen the tight junction of the epithelial cells to a greater extent than the spherical particles did, thus, enabling a more facile transport of the drug across the epithelium. Transepithelial permeability tests conducted for model drugs ranging in size from 0.4 to 150 kDa yielded three categories of molecules depending on their permeation propensities. Insulin belonged to the category of molecules deliverable across the epithelium only with the assistance of nanowire-coated particles. Other groups of drugs, smaller and bigger, respectively, either did not need the carrier to permeate the epithelium or were not able to cross it even with the support from the nanowire-coated particles. Bioavailability of insulin orally administered to rabbits was also found to be increased when delivered in conjunction with the nanowire-coated planar particles.

Nanotextured titanium surfaces for enhancing skin growth on transcutaneous osseointegrated devices.

A major problem with transcutaneous osseointegrated implants is infection, mainly due to improper closure of the implant-skin interface. Therefore, the design of transcutaneous osseointegrated devices that better promote skin growth around these exit sites needs to be examined and, if successful, would clearly limit infection. Due to the success already demonstrated for orthopedic implants, developing surfaces with biologically inspired nanometer features is a design criterion that needs to be investigated for transcutaneous devices. This study therefore examined the influence of nanotextured titanium (Ti) created through electron beam evaporation and anodization on keratinocyte (skin-forming cell) function. Electron beam evaporation created Ti surfaces with nanometer features while anodization created Ti surfaces with nanotubes. Conventional Ti surfaces were largely micron rough, with few nanometer surface features. Results revealed increased keratinocyte adhesion in addition to increased keratinocyte spreading and differences in keratinocyte filopodia extension on the nanotextured Ti surfaces prepared by either electron beam evaporation or anodization compared to their conventional, unmodified counterparts after 4h. Results further revealed increased keratinocyte proliferation and cell spreading over 3 and 5days only on the nanorough Ti surfaces prepared by electron beam evaporation compared to both the anodized nanotubular and unmodified Ti surfaces. Therefore, the results from this in vitro study provided the first evidence that nano-modification techniques should be further researched as a means to possibly improve skin growth, thereby improving transcutaneous osseointegrated orthopedic implant longevity.