Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications.

This review brings up to date the state of the art of strontium and zinc based regenerative therapies, both having a promoting effect on tissue formation and a role inhibiting resorption in musculoskeletal disorders.

The development of bone replacement materials is an important healthcare objective due to the drawbacks of treating defects with bone autografts. In this work we propose a bone tissue engineering approach in which arginine-glycine-aspartic acid (RGD)-modified alginate hydrogels are crosslinked with bioactive strontium and zinc ions as well as calcium. Strontium was chosen for its ability to stimulate bone formation, and zinc is essential for alkaline phosphatase (ALP) activity. Calcium and strontium gels had similar stiffnesses but different stabilities over time. Strontium gels made with alginate with a high percentage of guluronic acid residues (high G) were slow to degrade, whereas those made with alginate rich in mannuronic acid (high M) degraded more quickly, and supported proliferation of Saos-2 osteoblast-like cells. After an initial burst, strontium release from alginate gels was steady and sustained, and the magnitude of release from high M gels was biologically relevant. Saos-2 cultured within alginate gels upregulated the osteoblast phenotypic marker genes RUNX2, collagen I (COL1A1) and bone sialoprotein (BSP), and ALP protein activity was highest in alginate gels cast with strontium ions. This strategy has the potential to be combined with other alginate-based systems for bone tissue engineering, or adapted to other tissue engineering applications.

The current study has investigated the use of decellularised, demineralised bone extracellular matrix (ECM) hydrogel constructs for in vivo tissue mineralisation and bone formation. Stro-1-enriched human bone marrow stromal cells were incorporated together with select growth factors including VEGF, TGF-β3, BMP-2, PTHrP and VitD3, to augment bone formation, and mixed with alginate for structural support. Growth factors were delivered through fast (non-osteogenic factors) and slow (osteogenic factors) release PLGA microparticles. Constructs of 5 mm length were implanted in vivo for 28 days within mice. Dense tissue assessed by micro-CT correlated with histologically assessed mineralised bone formation in all constructs. Exogenous growth factor addition did not enhance bone formation further compared to alginate/bone ECM (ALG/ECM) hydrogels alone. UV irradiation reduced bone formation through degradation of intrinsic growth factors within the bone ECM component and possibly also ECM cross-linking. BMP-2 and VitD3 rescued osteogenic induction. ALG/ECM hydrogels appeared highly osteoinductive and delivery of angiogenic or chondrogenic growth factors led to altered bone formation. All constructs demonstrated extensive host tissue invasion and vascularisation aiding integration and implant longevity. The proposed hydrogel system functioned without the need for growth factor incorporation or an exogenous inducible cell source. Optimal growth factor concentrations and spatiotemporal release profiles require further assessment, as the bone ECM component may suffer batch variability between donor materials. In summary, ALG/ECM hydrogels provide a versatile biomaterial scaffold for utilisation within regenerative medicine which may be tailored, ultimately, to form the tissue of choice through incorporation of select growth factors.