Tissue-engineered grafts from human decellularized extracellular matrices: A systematic review and future perspectives

Tissue engineering and regenerative medicine involve many different artificial and biologic materials, frequently integrated in composite scaffolds, which can be repopulated with various cell types. One of the most promising scaffolds is decellularized allogeneic extracellular matrix (ECM) then recellularized by autologous or stem cells, in order to develop fully personalized clinical approaches. Decellularization protocols have to efficiently remove immunogenic cellular materials, maintaining the nonimmunogenic ECM, which is endowed with specific inductive/differentiating actions due to its architecture and bioactive factors. In the present paper, we review the available literature about the development of grafts from decellularized human tissues/organs. Human tissues may be obtained not only from surgery but also from cadavers, suggesting possible development of Human Tissue BioBanks from body donation programs. Many human tissues/organs have been decellularized for tissue engineering purposes, such as cartilage, bone, skeletal muscle, tendons, adipose tissue, heart, vessels, lung, dental pulp, intestine, liver, pancreas, kidney, gonads, uterus, childbirth products, cornea, and peripheral nerves. In vitro recellularizations have been reported with various cell types and procedures (seeding, injection, and perfusion). Conversely, studies about in vivo behaviour are poorly represented. Actually, the future challenge will be the development of human grafts to be implanted fully restored in all their structural/functional aspects

The Detectability of Pair-Production Supernovae at z < 6

Nonrotating, zero metallicity stars with initial masses 140 < M < 260 solar masses are expected to end their lives as pair-production supernovae (PPSNe), in which an electron-positron pair-production instability triggers explosive nuclear burning. Interest in such stars has been rekindled by recent theoretical studies that suggest primordial molecular clouds preferentially form stars with these masses. Since metal enrichment is a local process, the resulting PPSNe could occur over a broad range of redshifts, in pockets of metal-free gas. Using the implicit hydrodynamics code KEPLER, we have calculated a set of PPSN light curves that addresses the theoretical uncertainties and allows us to assess observational strategies for finding these objects at intermediate redshifts. The peak luminosities of typical PPSNe are only slightly greater than those of Type Ia, but they remain bright much longer (~ 1 year) and have hydrogen lines. Ongoing supernova searches may soon be able to limit the contribution of these very massive stars to < 1% of the total star formation rate density out to z=2 which already provides useful constraints for theoretical models. The planned Joint Dark Energy Mission satellite will be able to extend these limits out to z=6.Comment: 12 pages, 6 figures, ApJ in press; slightly revised version, a few typos correcte

First-in-human Use of a Microsurgical Robotic System for Central Lymphatic Reconstruction

Advances in the development of robotic systems have recently enabled the use of robotic technology in reconstructive lymphatic surgery. Although the advantages of microsurgical robots must be weighed carefully against the costs, their use may allow for smaller surgical approaches and easier access to anatomically deeper structures or even smaller vessels. We report on a case of a patient with central lymphatic dilation causing abdominal pain and severely reduced physical capacity. Sonography-assisted intranodal injection of indocyanine green allowed for localization of the lymphatic cyst and anastomosis with the left ovarian vein, applying robotic-assisted microsurgery for the first time on the central lymphatic system. Following the successful reconstruction of lymphatic drainage and decompression of the cyst, the patient reported a complete regression of her preoperative symptoms. From a surgical point of view, the Symani Surgical System improved precision and allowed significantly smaller surgical access. Considering the high morbidity and rarity of pathologies of the central lymphatic system, central lymphatic surgery is to date rarely performed. With improved precision and significantly smaller surgical access, robotic-assisted microsurgery has great potential to expand the treatment options for central lymphatic lesions

Running Inflation in the Standard Model

An interacting scalar field with largish coupling to curvature can support a distinctive inflationary universe scenario. Previously this has been discussed for the Standard Model Higgs field, treated classically or in a leading log approximation. Here we investigate the quantum theory using renormalization group methods. In this model the running of both the effective Planck mass and the couplings is important. The cosmological predictions are consistent with existing WMAP5 data, with 0.967 < n_s < 0.98 (for N_e = 60) and negligible gravity waves. We find a relationship between the spectral index and the Higgs mass that is sharply varying for m_h ~ 120-135 GeV (depending on the top mass); in the future, that relationship could be tested against data from PLANCK and LHC. We also comment briefly on how similar dynamics might arise in more general settings, and discuss our assumptions from the effective field theory point of view.Comment: 17 pages in Phys Lett B format, 5 figures; v3: updated to match published version, includes new Appendix B on EF

Inter and intra-population variability of the migratory behaviour of a short-distance partial migrant, the Eurasian Stone-curlew Burhinus oedicnemus (Charadriiformes, Burhinidae)

Migratory behaviour in birds shows a remarkable variability at species, population and individual levels. Short-distance migrants often adopt a partial migratory strategy and tend to have a flexible migration schedule that allows a more effective response to extreme environmental variations. Weather seasonality and environmental heterogeneity have been reported as significant factors in the diversification of migratory behaviour for Mediterranean migrants, but relatively few studies investigated the migration patterns of non-passerine birds migrating within the Mediterranean basin. In this study, we investigated the migratory strategy of 40 Eurasian Stone-curlews Burhinus oedicnemus tagged with geolocators and GPS-GSM tags and belonging to continental and Mediterranean populations of the Italian peninsula. The proportion of migrants was higher in continental populations, but we observed a significant variability also within Mediterranean populations. All birds spent the winter within the Mediterranean basin. Continental Stone-curlews departed earlier in spring and later in autumn and covered longer distances than those from Mediterranean areas. The speed of migration did not change between seasons for continental birds, while Mediterranean individuals migrated faster in spring. The likelihood of departure for autumn migration of GPS-tagged birds increased when temperatures were near or below 0 °C suggesting that Stone-curlews tend to delay departure until weather conditions worsen abruptly. As a consequence of global warming in the Mediterranean, the frequency of migratory birds in the considered populations might decrease in the near future. This could affect the distribution of species throughout the year and should be taken into account when targeting conservation measures

In vitro assessment of a novel composite scaffold for articular cartilage restoration

Articular cartilage (AC) lesions are a particular challenge for regenerative medicine due to cartilage low self-ability repair in case of damage. Hence, a significant goal of musculoskeletal tissue engineering is the development of suitable structures in virtue of their matrix composition and biomechanical properties [1]. The objective of our study was to design in vitro a supporting structure for cartilage chondrocytes to treat focal articular joint defects. We realized a bio-hybrid composite scaffold combining decellularized Wharton’s jelly (W’s J) with the biomechanical properties of the synthetic hydrogel polyvinyl alcohol (PVA). The hydrogel itself and the more specific decellularized cartilage matrix were used as controls. Immunohistochemical analysis highlighted a similar histomorphology for W’s J and AC matrices. Human chondrocytes were isolated from articular cartilage by collagenase II digestion and then characterized by flow-cytometry and RT-PCR to assess the expression of specific markers. CD44+/CD73+/CD151+ chondrocytes were seeded on PVA, PVA/AC and PVA/W’s J scaffolds to test their ability to support cell colonization. According to SEM micrographs and MTT proliferation assay, PVA/W’s J revealed a singular attitude to sustain cell proliferation despite its aspecific origin. Our preliminary evidences highlighted the chance of using Wharton’s jelly in combination with PVA hydrogels as an innovative and easily available scaffold for cartilage restoration

Mutable Collagenous Tissue Isolated from Echinoderms Leads to the Production of a Dermal Template That Is Biocompatible and Effective for Wound Healing in Rats

The mutable collagenous tissue (MCT) of echinoderms possesses biological peculiarities that facilitate native collagen extraction and employment for biomedical applications such as regenerative purposes for the treatment of skin wounds. Strategies for skin regeneration have been developed and dermal substitutes have been used to cover the lesion to facilitate cell proliferation, although very little is known about the application of novel matrix obtained from marine collagen. From food waste we isolated eco-friendly collagen, naturally enriched with glycosaminoglycans, to produce an innovative marine-derived biomaterial assembled as a novel bi-layered skin substitute (Marine Collagen Dermal Template or MCDT). The present work carried out a preliminary experimental in vivo comparative analysis between the MCDT and Integra, one of the most widely used dermal templates for wound management, in a rat model of full-thickness skin wounds. Clinical, histological, and molecular evaluations showed that the MCDT might be a valuable tool in promoting and supporting skin wound healing: it is biocompatible, as no adverse reactions were observed, along with stimulating angiogenesis and the deposition of mature collagen. Therefore, the two dermal templates used in this study displayed similar biocompatibility and outcome with focus on full-thickness skin wounds, although a peculiar cellular behavior involving the angiogenesis process was observed for the MCDT

Alpha-synuclein/synapsin III pathological interplay boosts the motor response to methylphenidate

: Loss of dopaminergic nigrostriatal neurons and fibrillary α-synuclein (α-syn) aggregation in Lewy bodies (LB) characterize Parkinson's disease (PD). We recently found that Synapsin III (Syn III), a phosphoprotein regulating dopamine (DA) release with α-syn, is another key component of LB fibrils in the brain of PD patients and acts as a crucial mediator of α-syn aggregation and toxicity. Methylphenidate (MPH), a monoamine reuptake inhibitor (MRI) efficiently counteracting freezing of gait in advanced PD patients, can bind α-syn and controls α-syn-mediated DA overflow and presynaptic compartmentalization. Interestingly, MPH results also efficient for the treatment of attention deficits and hyperactivity disorder (ADHD), a neurodevelopmental psychiatric syndrome associated with Syn III and α-syn polymorphisms and constituting a risk factor for the development of LB disorders. Here, we studied α-syn/Syn III co-deposition and longitudinal changes of α-syn, Syn III and DA transporter (DAT) striatal levels in nigrostriatal neurons of a PD model, the human C-terminally truncated (1-120) α-syn transgenic (SYN120 tg) mouse, in comparison with C57BL/6J wild type (wt) and C57BL/6JOlaHsd α-syn null littermates. Then, we analyzed the locomotor response of these animals to an acute administration of MPH (d-threo) and other MRIs: cocaine, that we previously found to stimulate Syn III-reliant DA release in the absence of α-syn, or the selective DAT blocker GBR-12935, along aging. Finally, we assessed whether these drugs modulate α-syn/Syn III interaction by fluorescence resonance energy transfer (FRET) and performed in silico studies engendering a heuristic model of the α-syn conformations stabilized upon MPH binding. We found that only MPH was able to over-stimulate a Syn III-dependent/DAT-independent locomotor activity in the aged SYN120 tg mice showing α-syn/Syn III co-aggregates. MPH enhanced full length (fl) α-syn/Syn III and even more (1-120) α-syn/Syn III interaction in cells exhibiting α-syn/Syn III inclusions. Moreover, in silico studies confirmed that MPH may reduce α-syn fibrillation by stabilizing a protein conformation with increased lipid binding predisposition. Our observations indicate that the motor-stimulating effect of MPH can be positively fostered in the presence of α-syn/Syn III co-aggregation. This evidence holds significant implications for PD and ADHD therapeutic management

In vitro and in vivo study of a novel biodegradable synthetic conduit for injured peripheral nerves

In case of peripheral nerve injury (PNI) with wide substance-loss, surgical reconstruction is still a challenge. Bridging the gap by autologous sensory nerves as grafts is the current standard; nevertheless, the related issues have prompted the research towards the development of effective artificial synthetic/biological nerve conduits (NCs). Here, we manufactured a novel NC using oxidized polyvinyl alcohol (OxPVA) that is a biodegradable cryogel recently patented by our group [1]. Thus, its characteristics were compared with neat polyvinyl alcohol (PVA) and silk-fibroin (SF) NCs through in vitro/in vivo analysis. Considering in vitro studies, a morphological characterization was performed by Scanning Electron Microscopy (SEM). Thereafter, cell adhesion and proliferation of a Schwann-cell line (SH-SY5Y) were evaluated by SEM and MTT assay. Regarding in vivo tests, the NCs were implanted into the surgical injured sciatic nerve (gap: 5 mm) of Sprague-Dawley rats, and the functional recovery was assessed after 12-weeks. The NCs were then processed for histological, immunohistochemical (anti-CD3; -β-tubulin; -S100) and Transmission Electron Microscopy (TEM) analyses. In particular, morphometric analyses (section area, total number and density of nerve fibers) were performed at the level of proximal, central and distal portions with respect to NC. In vitro results by SEM showed that PVA and SF supports have a smoother surface than OxPVA scaffolds. Moreover, unlike SF scaffolds, PVA-based ones do not support SH-SY5Y adhesion and proliferation. Regarding the in vivo study, all animals showed a functional recovery with normal walk, even though only animals implanted with PVA and SF NCs sometimes showed spasms while walking. On the contrary, animals implanted with OxPVA NCs exhibited a normal movement. Anti-CD3 immunohistochemistry assessed the absence of severe inflammatory reactions in all the grafts. A strong positive immunoreaction for β-tubulin and S100 demonstrated the good regeneration of nervous fibers. TEM highlighted regeneration of myelinated/un-myelinated axons and Schwann cells in all the grafts. However, morphometric analysis demonstrated that OxPVA assure a better outcome in nerve regeneration in terms of total number of nerve fibers. Our results sustain the potential of OxPVA for the development of NCs useful for PNI with substance loss with the advantage of biodegradation