Tissue engineering aims to repair, restore, and regenerate lost or damaged tissues by using biomaterials, cells, mechanical forces and factors (chemical and biological) alone or in combination. Growth factors are routinely used in the tissue engineering approach to expedite the process of regeneration. The growth factor approach has been hampered by several complications including high dose requirements, lower half-life, protein instability, higher costs and undesired side effects. Recently a variety of alternative small molecules of both natural and synthetic origin have been explored as alternatives to growth factors for tissue regeneration applications. Small molecules are simple biochemical components that elicit certain cellular responses through signaling cascades. Small molecules present a viable alternative to biological factors. Small molecule strategies can reduce various side effects, maintain bioactivity in a biological environment and minimize cost issues associated with complex biological growth factors. This manuscript focuses on three-osteoinductive small molecules, namely melatonin, resveratrol (from natural sources) and purmorphamine (synthetically designed) as inducers of bone formation and osteogenic differentiation of stem cells. Efforts have been made to summarize possible biological pathways involved in the action of each of these drugs. Melatonin is known to affect Mitogen Activated Protein (MAP) kinase, Bone morphogenic protein (BMP) and canonical wnt signaling. Resveratrol is known to activate cascades involving Wnt and NAD-dependent deacetylase sirtuin-1 (Sirt1). Purmorphamine is a Hedgehog (Hh) pathway agonist as it acts on Smoothened (Smo) receptors. These mechanisms and the way they are affected by the respective small molecules will also be discussed in the manuscript.

Purpose African Americans experience greater prostate cancer risk and mortality than do Caucasians. An analysis of pooled phase III data suggested differences in overall survival (OS) between African American and Caucasian men receiving sipuleucel-T. We explored this in PROCEED (NCT01306890), an FDA-requested registry in over 1900 patients with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T. Patients and methods OS for patients who received ≥1 sipuleucel-T infusion was compared between African American and Caucasian men using an all patient set and a baseline prostate-specific antigen (PSA)-matched set (two Caucasians to every one African American with baseline PSAs within 10% of each other). Univariable and multivariable analyses were conducted. Survival data were examined using Kaplan-Meier and Cox proportional hazard methodologies. Results Median follow-up was 46.6 months. Overall survival differed between African American and Caucasian men with hazard ratios (HR) of 0.81 (95% confidence interval [CI]: 0.68-0.97, P = 0.03) in the all patient set and 0.70 (95% CI: 0.57-0.86, P < 0.001) in the PSA-matched set. Median OS was longer in African Americans than in Caucasian men for both analysis sets, e.g., 35.3 and 25.8 months, respectively, in the PSA-matched set. Similar results were observed in the all patient set. Differences were larger when treatment began at lower baseline PSA; curves were more similar among patients with higher baseline PSA. In patients with baseline PSA below the median, the HR was 0.52 (95% CI: 0.37-0.72, P < 0.001), with median OS of 54.3 versus 33.4 months. Known prognostic factors and African American race (multivariable analyses; HR: 0.60, 95% CI: 0.48-0.74, P < 0.001) were independently associated with OS. Use of post-sipuleucel-T anticancer interventions was balanced between races. Conclusion In this exploratory analysis of a registry including nearly 12% African American men with mCRPC, OS was significantly different between African Americans and Caucasians, indicating further research is warranted.

Scaffold based bone tissue engineering (BTE) has made great progress in regenerating lost bone tissue. Materials of natural and synthetic origin have been used for scaffold fabrication. Scaffolds derived from natural polymers offer greater bioactivity and biocompatibility with mammalian tissues to favor tissue healing, due to their similarity to native extracellular matrix (ECM) components. Often it is a challenge to fabricate natural polymer based scaffolds for BTE applications without compromising their bioactivity, while maintaining adequate mechanical properties. In this work, we report the fabrication and characterization of cellulose and collagen based micro-nano structured scaffolds using human osteoblasts (HOB) for BTE applications. These porous micro-nano structured scaffolds (average pore diameter 190 +/- 10 microm) exhibited mechanical properties in the mid range of human trabecular bone (compressive modulus 266.75 +/- 33.22 MPa and strength 12.15 3 +/- 2.23 MPa). These scaffolds supported the greater adhesion and phenotype maintenance of cultured HOB as reflected by higher levels of osteogenic enzyme alkaline phosphatase and mineral deposition compared to control polyester micro-nano structured scaffolds of identical pore properties. These natural polymer based micro-nano structured scaffolds may serve as alternatives to polyester based scaffolds for BTE applications.

The success of the scaffold-based bone regeneration approach critically depends on the biomaterial's mechanical and biological properties. Cellulose and its derivatives are inherently associated with exceptional strength and biocompatibility due to their β-glycosidic linkage and extensive hydrogen bonding. This polymer class has a long medical history as a dialysis membrane, wound care system and pharmaceutical excipient. Recently cellulose-based scaffolds have been developed and evaluated for a variety of tissue engineering applications. In general porous polysaccharide scaffolds in spite of many merits lack the necessary mechanical competence needed for load-bearing applications. The present study reports the fabrication and characterization of three-dimensional (3D) porous sintered microsphere scaffolds based on cellulose derivatives using a solvent/non-solvent sintering approach for load-bearing applications. These 3D scaffolds exhibited a compressive modulus and strength in the mid-range of human trabecular bone and underwent degradation resulting in a weight loss of 10-15% after 24 weeks. A typical stress-strain curve for these scaffolds showed an initial elastic region and a less-stiff post-yield region similar to that of native bone. Human osteoblasts cultured on these scaffolds showed progressive growth with time and maintained expression of osteoblast phenotype markers. Further, the elevated expression of alkaline phosphatase and mineralization at early time points as compared to heat-sintered poly(lactic acid-glycolic acid) control scaffolds with identical pore properties affirmed the advantages of polysaccharides and their potential for scaffold-based bone regeneration.