Tissue engineering combines cell and molecular biology with materials and mechanical engineering to replace damaged or diseased organs and tissues. Fibrin is a critical blood component responsible for hemostasis, which has been used extensively as a biopolymer scaffold in tissue engineering. In this review we summarize the latest developments in organ and tissue regeneration using fibrin as the scaffold material. Commercially available fibrinogen and thrombin are combined to form a fibrin hydrogel. The incorporation of bioactive peptides and growth factors via a heparin-binding delivery system improves the functionality of fibrin as a scaffold. New technologies such as inkjet printing and magnetically influenced self-assembly can alter the geometry of the fibrin structure into appropriate and predictable forms. Fibrin can be prepared from autologous plasma, and is available as glue or as engineered microbeads. Fibrin alone or in combination with other materials has been used as a biological scaffold for stem or primary cells to regenerate adipose tissue, bone, cardiac tissue, cartilage, liver, nervous tissue, ocular tissue, skin, tendons, and ligaments. Thus, fibrin is a versatile biopolymer, which shows a great potential in tissue regeneration and wound healing.

Injury of articular cartilage due to trauma or pathological conditions is the major cause of disability worldwide, especially in North America. The increasing number of patients suffering from joint-related conditions leads to a concomitant increase in the economic burden. In this review article, we focus on strategies to repair and replace knee joint cartilage, since knee-associated disabilities are more prevalent than any other joint. Because of inadequacies associated with widely used approaches, the orthopedic community has an increasing tendency to develop biological strategies, which include transplantation of autologous (i.e., mosaicplasty) or allogeneic osteochondral grafts, autologous chondrocytes (autologous chondrocyte transplantation), or tissue-engineered cartilage substitutes. Tissue-engineered cartilage constructs represent a highly promising treatment option for knee injury as they mimic the biomechanical environment of the native cartilage and have superior integration capabilities. Currently, a wide range of tissue-engineering-based strategies are established and investigated clinically as an alternative to the routinely used techniques (i.e., knee replacement and autologous chondrocyte transplantation). Tissue-engineering-based strategies include implantation of autologous chondrocytes in combination with collagen I, collagen I/III (matrix-induced autologous chondrocyte implantation), HYAFF 11 (Hyalograft C), and fibrin glue (Tissucol) or implantation of minced cartilage in combination with copolymers of polyglycolic acid along with polycaprolactone (cartilage autograft implantation system), and fibrin glue (DeNovo NT graft). Tissue-engineered cartilage replacements show better clinical outcomes in the short term, and with advances that have been made in orthopedics they can be introduced arthroscopically in a minimally invasive fashion. Thus, the future is bright for this innovative approach to restore function.

SUMMARY The complex biochemical effects of RAF inhibitors account for both the effectiveness and mechanisms of resistance to these drugs, but a unified mechanistic model has been lacking. Here we show that RAF inhibitors exert their effects via two distinct allosteric mechanisms. Drug resistance due to dimerization is determined by the position of the αC-helix stabilized by inhibitor, whereas inhibitor-induced RAF priming and dimerization are the result of inhibitor-induced formation of the RAF/RAS-GTP complex. The biochemical effect of RAF inhibitor in cells is the combined outcome of the two mechanisms. Therapeutic strategies including αC-helix-IN inhibitors are more effective in multiple mutant BRAF-driven tumor models, including colorectal and thyroid BRAFV600E cancers, in which first generation RAF inhibitors have been ineffective.

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SUMMARY Pharmacologic targeting of components of ERK signaling in ERK-dependent tumors is often limited by adaptive resistance, frequently mediated by feedback-activation of RTK signaling and rebound of ERK activity. Here, we show that combinatorial pharmacologic targeting of ERK signaling and the SHP2 phosphatase prevents adaptive resistance in defined subsets of ERK-dependent tumors. In each tumor that was sensitive to combined treatment, p(Y542) SHP2 induction was observed in response to ERK signaling inhibition. The strategy was broadly effective in TNBC models and tumors with RAS mutations at G12, whereas tumors with RAS(G13D) or RAS(Q61X) mutations were resistant. In addition, we identified a subset of BRAF(V600E) tumors that were resistant to the combined treatment, in which FGFR was found to drive feedback-induced RAS activation, independently of SHP2. Thus, we identify molecular determinants of response to combined ERK signaling and SHP2 inhibition in ERK-dependent tumors.