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BACKGROUND: Cells, growth factors (GFs), and scaffold are three essential factors for tissue engineering. Our previous studies suggested that multiple applications of human amnion growth factors (AGF) into osseous defects could “mimic in-utero” growth. However, micro-gaps still exist between the scaffold and recipient tissue. We hypothesized that hyaluronic acid (HA) could act an accessory scaffold and gradually release active components of AGF and improve bone healing. MATERIALS AND METHODS: Calvaria from 50 7–9-day old CD1 neonatal mice were harvested, and a 2 mm defect punch made in each one. A type I collagen membrane with AGF alone or with HA at different concentrations applied over the defect. The culture medium was changed every 2-3 days and collected for alkaline phosphatase (ALP) and protein analysis. RESULTS: A single dose of AGF combined with 0.125% HA increased cellular infiltration into the defect area more than AGF with no HA or a lower concentration of HA (0.0625%). A single dose of AGF with HA can improve bone healing. CONCLUSION: A single dose of AGF with HA as an extra scaffold and a carrier can achieve bone formation like multiple dosages of AGF and reduce the number of clinical applications needed.

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Yes / Insulin resistance is associated with impaired endothelial regeneration in response to mechanical injury. We recently demonstrated that insulinlike growth factor–binding protein-1 (IGFBP1) ameliorated insulin resistance and increased nitric oxide generation in the endothelium. In this study, we hypothesized that IGFBP1 would improve endothelial regeneration and restore endothelial reparative functions in the setting of insulin resistance. In male mice heterozygous for deletion of insulin receptors, endothelial regeneration after femoral artery wire injury was enhanced by transgenic expression of human IGFBP1 (hIGFBP1). This was not explained by altered abundance of circulating myeloid angiogenic cells. Incubation of human endothelial cells with hIGFBP1 increased integrin expression and enhanced their ability to adhere to and repopulate denuded human saphenous vein ex vivo. In vitro, induction of insulin resistance by tumor necrosis factor α (TNFα) significantly inhibited endothelial cell migration and proliferation. Coincubation with hIGFBP1 restored endothelial migratory and proliferative capacity. At the molecular level, hIGFBP1 induced phosphorylation of focal adhesion kinase, activated RhoA and modulated TNFα-induced actin fiber anisotropy. Collectively, the effects of hIGFBP1 on endothelial cell responses and acceleration of endothelial regeneration in mice indicate that manipulating IGFBP1 could be exploited as a putative strategy to improve endothelial repair in the setting of insulin resistance. / Funded by a British Heart Foundation Clinical Research Training Fellowship for A.A. R.M.C. holds a British Heart Foundation Intermediate Clinical Research Fellowship. M.T.K. holds a British Heart Foundation Chair in Cardiology. S.B.W. holds a European Research Council Starting Grant.

Yes / Background: Platelet rich plasma (PRP), processed from autologous peripheral blood, is used to treat androgenetic alopecia (AGA). Objective: To determine the efficacy of PRP for hair growth promotion in AGA patients in a randomized, blinded, placebo controlled, pilot clinical trial (NCT02074943). Methods: The efficacy of an 8 week, 5 session, PRP treatment course was determined by measuring hair density and hair caliber changes in 10 AGA affected patients. For each PRP sample, the concentrations of selected growth factors were determined using a multiplex assay system. The clinical results were then correlated to the growth factor concentrations in PRP. Results: At 16 weeks, 8 weeks after the last PRP injection, treated areas exhibited increased mean hair density (+12.76%) over baseline compared to placebo (+0.99%). Mean hair caliber decreased in both treated and placebo regions (-16.22% and -19.46% respectively). Serial analysis of PRP significant variability in concentrations between patients. Overall, there was a positive correlation between GDNF concentration and hair density (p= 0.004). Trends, though not statistically significant, were also observed for FGF2 and VEGF. Limitations: Small sample size and lack of comparative cohorts receiving protocol variations limit confidence in the study data. Conclusions: This small pilot clinical trial suggests PRP treatment may be beneficial for AGA. However, the variable hair growth responses between patients indicate there is a significant opportunity to improve PRP therapy protocols for hair growth promotion. The variability in growth factor concentration in PRP suggests standardization of growth factors post-processing might improve hair growth responses. / RepliCel Life Sciences Inc. (Canada)

Background: The rare ability to manage simultaneous high growth and entrepreneurship is pivotal for a thriving business. Be leveraging intention, ability and opportunity the post growth actions of Swedish high growth SMEs facilitate effective and profitable operations. Sweden, the country with the largest share of high growth SMEs in EU, offers an ideal setting for gaining a comprehensive understanding of these operations. Purpose: The study aims to examine the impact of the pre-growth factors: intention, ability and opportunity on post high growth actions taken by Swedish high growth SMEs and identify differences and similarities regarding the use of these strategies between the firms in the sample. Method: The study is a multiple case study using semi structured interviews with six Swedish high growth SMEs. The study uses an interpretivism perspective with an abductive research approach and empirical data is analyzed through a mechanisms data analysis. Conclusion: The study concludes that firms pre-growth factors significantly impact their post high growth actions. Risk-prone firms with strong growth intentions view high growth as essential for organizational improvements, while more risk-averse firms view organizational improvements as a prerequisite for high growth. Firms with strong growth intentions employ strategic exit to align their pre-growth factors, especially when lacking investment. Firms with more passive growth intentions consider strategic exit as a last resort. Developing support functions is closely tied to firm size and ability while investments into internal competency is crucial for firms in fast-changing markets where opportunity is vital. Keywords: High growth SMEs, Pre-growth factors, Entrepreneurship, Innovation, Strategic exit, Human resource management

<p dir="ltr">Tissue engineering utilizes polymers, cells, and other bioactive factors to promote regeneration within damaged tissue. The main works in this thesis employ naturally derived polymers for use in tissue engineering and explores ways to recapitulate native environments <i>in vitro</i>.</p><p dir="ltr">Collagen (col) is the most prevalent protein in the body. Col type I, II, and III are all fibril-forming collagens that provide structure to tissues. All three types polymerize <i>in vitro</i> to form hydrogels, and these hydrogels have often been studied for use in tissue engineering. Other applications include <i>in vitro </i>tissue models for studies on drug diffusion and drug delivery. Blending collagen types is of particular interest as col I is easier to source and is therefore cheaper than other collagen types. However, to confer biological signals to tissues where col II or III are more abundant (e.g., cartilage or cardiac tissue, respectively), col II or III can be added to col I to form col I/II or col I/III gels, respectively. Additionally, adding multiple types of col to hydrogel models better recapitulates the native environment and can better capture effects on drug diffusion. In this work, compared to col I alone, col I/II hydrogels polymerize more slowly, form more fibril bundles, result in softer hydrogels, and impede transport of larger macromolecules. On the other hand, col I/III gels polymerize at a similar rate to col I, create heterogenous fibril structures, are oftentimes stiffer than col I, and also impede transport of larger macromolecules. Additionally, this work explored the effect of polymerization temperature on blended gel polymerization and properties.</p><p dir="ltr">The second work evaluates col I/II hydrogels for a specific application: cartilage tissue engineering for osteoarthritic applications. Col II is the primary protein found in cartilage. Other components include: glycosaminoglycans, such as hyaluronic acid (HA) and chondroitin sulfate, chondrocytes (cartilage cells), and other small signaling molecules. Building on prior work in the group, high molecular weight hyaluronic acid (HA) was added to col I/II hydrogels, and cartilage differentiation of mesenchymal stem cells (MSCs) was assessed under ideal laboratory conditions and under pro-inflammatory, osteoarthritic conditions (i.e., cytokine-supplemented media of oncostatin M (OSM) at 10 ng/mL and tumor necrosis factor-α (TNF-α) at 20 ng/mL). The addition of HA did not dramatically impact cartilage differentiation of MSCs, however, HA did mitigate the effect of inflammation via downregulation of a degradative enzyme. HA had little impact on inflammatory cytokine production of interleukin (IL)-6 or IL-8, both of which are upregulated during osteoarthritis. However, a linear model suggests that HA and IL-8 are strongly correlated. Thus, this system should be explored further with different HA concentrations or presentations (e.g., chemically modified).</p><p dir="ltr">The last primary chapter of this thesis provides depth to the pro-inflammatory, osteoarthritic model used in the previous chapter. Different pro-inflammatory environments are studied using cytokines found in OA. MSC pellets (used in literature as controls to confirm chondrogenic potential of MSCs) were used to evaluate these inflammatory environments since MSCs are commonly used in tissue engineering. Six treatments were studied: negative control (without the chondrogenic growth factor TGF-β3), positive control (with the chondrogenic growth factor TGF-β3), and four cytokine treatments all with TGF-β3. First, IL-1β at 10 ng/mL was utilized as a comparison to literature. The other three cytokine groups used TNF-α at 20 ng/mL and OSM at 10 ng/mL individually or combined to form the main experimental group, OSM+TNF-α. All cytokine treatment groups limited cartilage production, but OSM decreased production to a statistically lesser extent than other cytokine groups. This trend was similar to observations made via immunostaining of cartilage matrix and gene expression analysis of aggrecan. Furthermore, OSM+TNF-α statistically lowered aggrecan gene expression. In terms of degradation, when compared to all other groups, OSM dramatically increased the protein expression of the degradative enzyme matrix metalloproteinase-13 (MMP-13). Evaluation of inflammatory markers (IL-6 and IL-8) revealed no signal for OSM-treated pellets. TNF-α yielded some signal after 1 week in culture but no signal after two weeks. IL-1β and OSM+TNF-α both resulted in sustained IL-6 and IL-8 expression, however, IL-1β exhibited large variance. Thus, each cytokine contributes to various pathways that are present in OA. Since the combination of OSM and TNF-α appeared to lower cartilage gene expression and resulted in sustained and reproducible IL-6 and IL-8 production, it may serve as a better model of OA than a single cytokine such as IL-1β.</p>

O desmame precoce (DP) causa mudanças na mucosa gástrica, como o aumento da proliferação celular e da expressão do Fator de Crescimento Transformante (TGFa). Neste trabalho, avaliamos o papel desse peptídeo e seu receptor EGFR no controle do crescimento gástrico. Ratos com 15 dias de vida foram divididos em: amamentados (controle) e DP, no qual os filhotes foram separados da mãe e alimentados com pasta de ração. O DP aumentou o número de células marcadas para EGFR, acelerou a diferenciação de células mucosas do colo e elevou a expressão de mucina 6. A inibição do EGFR com AG1478 diminuiu a proliferação celular e o número de células mucosas do colo. Entre as proteínas envolvidas na sinalização de EGFR e ciclo celular, detectamos que o DP elevou os níveis de p-ERK1/2 e p-Src e não alterou p-Akt, p21 e p27. Nós sugerimos que o padrão alimentar influencia a proliferação e diferenciação no epitélio gástrico, e que TGFa/EGFR podem regular esses processos durante o desenvolvimento pós-natal, provavelmente por ativação das vias de sinalização de MAPK e Src. / Early weaning (EW) causes changes in the gastric mucosa, including the increase in cell proliferation and Transforming Growth Factor (TGFa). In the present study, we evaluated the role of this peptide and its receptor EGFR in the control of the gastric growth. 15-d-old rats were divided into two groups: suckling (control) and EW, in which the pups were separated from the dam and fed with powdered chow. EW increased the number of EGFR-positive cells, accelerated the differentiation of mucous neck cells and augmented the expression of mucin 6. EGFR inhibition with AG1478 decreased cell proliferation and the number of mucous neck cells. Among the proteins involved on EGFR signaling pathways and cell cycle, we found that EW increased the levels of p-ERK1/2 and p-Src, but did not change p-Akt, p21 and p27. We suggest that the diet pattern influences proliferation and differentiation in the gastric epithelium, and the TGFa/EGFR can regulate these processes throughout the postnatal development, probably by activating MAPK and Src signaling pathways.