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Graphene is a novel material whose application in the biomedical sciences has only begun to be realized. In the present study, we have employed three-dimensional graphene foams as culture substrates for human mesenchymal stem cells and provide evidence that these materials can maintain stem cell viability and promote osteogenic differentiation.

Abstract-Angiogenesis, an essential component of a variety of physiological and pathological processes, offers attractive opportunities for therapeutic regulation. We hypothesized that matrix metalloproteinase-9 genetic deficiency (MMP-9 Ϫ/Ϫ ) will impair angiogenesis triggered by tissue ischemia, induced experimentally by femoral artery ligation in mice.To investigate the role of MMP-9, we performed a series of biochemical and histological analyses, including zymography, simultaneous detection of perfused capillaries, MMP-9 promoter activity, MMP-9 protein, and macrophages in MMP-9 Ϫ/Ϫ and wild-type (WT) mice. We found that ischemia resulted in doubling of capillary density in WT and no change in the MMP-9 Ϫ/Ϫ ischemic tissues, which translated into increased (39%) perfusion capacity only in the WT at 14 days after ligation. We also confirmed that capillaries in the MMP-9 Ϫ/Ϫ presented significantly (PϽ0.05) less points of capillary intersections, interpreted by us as decreased branching. The combined conclusions from simultaneous localizations of MMP-9 expression, capillaries, and macrophages suggested that macrophage MMP-9 participates in capillary branching. Transplantation of WT bone marrow into the MMP-9 Ϫ/Ϫ , restored capillary branching, further supporting the contribution of bone marrow-derived macrophages in supplying the necessary MMP-9. Our study indicates that angiogenesis triggered by tissue ischemia requires MMP-9, which may be involved in capillary branching, a potential novel role for this MMP that could be exploited to control angiogenesis. Key Words: angiography Ⅲ macrophage Ⅲ imaging Ⅲ microvessels Ⅲ bone-marrow transplantation A ngiogenesis, the growth of new capillaries from existing ones, is a process necessary for regulation and repair during wound healing and after ischemic injury of tissue. However, angiogenesis also facilitates grave pathological processes such as tumor progression and metastasis, 1 macular degeneration, 2 and atheroma progression toward plaque instability. 3 Oxygen deprivation, or tissue ischemia, is a potent stimulus of angiogenesis through both humoral and inflammatory processes. 4 Angiogenesis is a complex process that involves the activation of vascular cells through a balance of pro-and antiangiogenic factors. 4 The growth of new capillaries is thought to occur mainly through capillary splitting, also known as intussusception, or capillary budding leading to branching. 5 As growth of capillaries likely necessitates invasion of existing tissues, the potential enabling action of matrix metalloproteinases (MMPs), a family of enzymes capable of degrading the extracellular matrix components, has come under scrutiny. 6 In fact, the antiangiogenic action of nonspecific MMP inhibitors in vivo 7 and in vitro 8 is thought to be of major importance for their anticancer activity. 9 However, these chemical agents have also undesirable effects. 10 Two members of the MMP family, MMP-2 and MMP-9, known to degrade nonfibrillar collagens, a major component of the basement membrane...

Recently, significant progress has been made in developing “stimuli-sensitive” biomaterials as a new therapeutic approach to interact with dynamic physiological conditions. Reactive oxygen species (ROS) production has been implicated in important pathophysiological events, such as atherosclerosis, aging, and cancer. ROS are often overproduced locally in diseased cells and tissues, and they individually and synchronously contribute to many of the abnormalities associated with local pathogenesis. Therefore, the advantages of developing ROS-responsive materials extend beyond site-specific targeting of therapeutic delivery, and potentially include navigating, sensing, and repairing the cellular damages via programmed changes in material properties. Here we review the mechanism and development of biomaterials with ROS-induced solubility switch or degradation, as well as their performance and potential for future biomedical applications.

Background-Although multiple pathological processes have been associated with oxidative stress, the causative relation between oxidative stress and arterial lesion progression remains unclear.

Characterization of the degradation mechanism of polymeric scaffolds and delivery systems for regenerative medicine is essential to assess their clinical applicability. Key performance criteria include induction of a minimal, transient inflammatory response and controlled degradation to soluble non-cytotoxic breakdown products that are cleared from the body by physiological processes. Scaffolds fabricated from biodegradable poly(ester urethane)s (PEURs) undergo controlled degradation to non-cytotoxic breakdown products and support the ingrowth of new tissue in preclinical models of tissue regeneration. While previous studies have shown that PEUR scaffolds prepared from lysine-derived polyisocyanates degrade faster under in vivo compared to in vitro conditions, the degradation mechanism is not well understood. In this study, we have shown that PEUR scaffolds prepared from lysine triisocyanate (LTI) or a trimer of hexamethylene diisocyanate (HDIt) undergo hydrolytic, esterolytic, and oxidative degradation. Hydrolysis of ester bonds to yield α-hydroxy acids is the dominant mechanism in buffer, and esterolytic media modestly increase the degradation rate. While HDIt scaffolds show a modest (<20%) increase in degradation rate in oxidative medium, LTI scaffolds degrade six times faster in oxidative medium. Furthermore, the in vitro rate of degradation of LTI scaffolds in oxidative medium approximates the in vivo rate in rat excisional wounds, and histological sections show macrophages expressing myeloperoxidase at the material surface. While recent preclinical studies have underscored the potential of injectable PEUR scaffolds and delivery systems for tissue regeneration, this promising class of biomaterials has a limited regulatory history. Elucidation of the macrophage-mediated oxidative mechanism by which LTI scaffolds degrade in vivo provides key insights into the ultimate fate of these materials when injected into the body.

Chronic inflammation-mediated oxidative stress is a common mechanism of implant rejection and failure. Therefore, polymer scaffolds that can degrade slowly in response to this environment may provide a viable platform for implant site-specific, sustained release of immunomodulatory agents over a long time period. In this work, proline oligomers of varying lengths (Pn) were synthesized and exposed to oxidative environments, and their accelerated degradation under oxidative conditions was verified via high performance liquid chromatography and gel permeation chromatography. Next, diblock copolymers of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) were carboxylated to form 100 kDa terpolymers of 4%PEG-86%PCL-10%cPCL (cPCL = poly(carboxyl-ε-caprolactone); i% indicates molar ratio). The polymers were then crosslinked with bi-aminated PEG-Pn-PEG chains—where Pn indicates the length of the proline oligomer flanked by PEG chains. Salt-leaching of the polymeric matrices created scaffolds of macroporous and microporous architecture as observed by scanning electron microscopy. The degradation of scaffolds was accelerated under oxidative conditions, as evidenced by mass loss and differential scanning calorimetry measurements. Immortalized murine bone marrow-derived macrophages were then seeded on the scaffolds, and activated through the addition of γ-interferon and lipopolysaccharide throughout the 9-day study period. This treatment promoted the release of H2O2 by the macrophages, and the degradation of proline-containing scaffolds compared to the control scaffolds. The accelerated degradation was evidenced by increased scaffold porosity, as visualized through scanning electron microscoopy and X-ray microtomography imaging. The current study provides insight into the development of scaffolds that respond to oxidative environments through gradual degradation, for the controlled release of therapeutics targeted to diseases that feature chronic inflammation and oxidative stress.

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