Ultra-thin electrospun nanocomposite scaffold of poly (3-hydroxybutyrate)-chitosan/magnetic mesoporous bioactive glasses for bone tissue engineering applications.

Bioglass is widely used in skeletal tissue engineering due to its outstanding bioactive properties. In the present study, magnetic mesoporous bioglass (MMBG) synthesized through the sol-gel method was incorporated into poly(3-hydroxybutyrate)-chitosan (PHB-Cs) solution and the resulting electrospun nanocomposite scaffolds were investigated and compared with MMBG free scaffold. The addition of 10 wt% MMBG has an outstanding effect on producing ultra-thin electrospun nanocomposite fibers due to its magnetic content (diameter of ≃128 nm). This improvement led to better mechanical properties, including an increase in both tensile modulus (up to ≃229 MPa) and tensile strength (to ≃4.95 MPa). Although the inclusion of MMBG slightly decreased the surface roughness of the nanofibrous scaffold (RMS from ≃197 to 154 nm), it could improve the wettability (WCA from ≃54 to 44°). This achievement has the potential to bring an enhancement in biomineralization and biological response. These outputs, combined with the observed increase in human osteoblast MG-63 cell viability (≃53 % improvement) as measured by MTT assay, DAPI, and SEM indicate prefer cell behavior of this nanocomposite structure. Additionally, the qualitative improvement in Alizarin Red staining and the quantitative enhancement of ALP secretion, serve as further evidence of the PHB-Cs/MMBG ultrathin nanofibers potential in bone tissue engineering.

Immunobiology of foreign body response to composite PLACL/gelatin electrospun nanofiber meshes with mesenchymal stem/stromal cells in a mouse model: Implications in pelvic floor tissue engineering and regeneration.

Pelvic Organ Prolapse (POP) is a common gynaecological disorder where pelvic organs protrude into the vagina. While transvaginal mesh surgery using non-degradable polymers was a commonly accepted treatment for POP, it has been associated with high rates of adverse events such as mesh erosion, exposure and inflammation due to serious foreign body response and therefore banned from clinical use after regulatory mandates. This study proposes a tissue engineering strategy using uterine endometrium-derived mesenchymal stem/stromal cells (eMSC) delivered with degradable poly L-lactic acid-co-poly ε-caprolactone (PLACL) and gelatin (G) in form of a composite electrospun nanofibrous mesh (P + G nanomesh) and evaluates the immunomodulatory mechanism at the material interfaces. The study highlights the critical acute and chronic inflammatory markers along with remodelling factors that determine the mesh surgery outcome. We hypothesise that such a bioengineered construct enhances mesh integration and mitigates the Foreign Body Response (FBR) at the host interface associated with mesh complications. Our results show that eMSC-based nanomesh significantly increased 7 genes associated with ECM synthesis and cell adhesion including, Itgb1, Itgb2, Vcam1, Cd44, Cdh2, Tgfb1, Tgfbr1, 6 genes related to angiogenesis including Ang1, Ang2, Vegfa, Pdgfa, Serpin1, Cxcl12, and 5 genes associated with collagen remodelling Col1a1, Col3a1, Col6a1, Col6a2, Col4a5 at six weeks post-implantation. Our findings suggest that cell-based tissue-engineered constructs potentially mitigate the FBR response elicited by biomaterial implants. From a clinical perspective, this construct provides an alternative to current inadequacies in surgical outcomes by modulating the immune response, inducing angiogenesis and ECM synthesis during the acute and chronic phases of the FBR.

6-Shogaol Exhibits Anti-viral and Anti-inflammatory Activity in COVID-19-Associated Inflammation by Regulating NLRP3 Inflammasomes.

Recent global health concern motivated the exploration of natural medicinal plant resources as an alternative target for treating COVID-19 infection and associated inflammation. In the current study, a phytochemical, 6-shogaol [1-(4-hydroxy-3-methoxyphenyl)dec-4-en-3-one; 6-SHO] was investigated as a potential anti-inflammatory and anti-COVID-19 agent. In virus release assay, 6-SHO efficiently (94.5%) inhibited SARS-CoV2 replication. When tested in the inflammasome activation model, 6-SHO displayed mechanistic action by regulating the expression of the inflammasome pathway molecules. In comparison to the existing drugs, remdesivir and hydroxy-chloroquine, 6-SHO was not only found to be as effective as the standard anti-viral drugs but also much superior and safe in terms of predicted physicochemical properties and clinical toxicity. Comparative molecular dynamics simulation demonstrated a stable interaction of 6-SHO with NLRP3 (the key inflammasome regulator) in the explicit water environment. Overall, this study provides important cues for further development of 6-SHO as potential anti-inflammatory and anti-viral therapeutic agents.

Improved osteoblast function on titanium implant surfaces coated with nanocomposite Apatite-Wollastonite-Chitosan- an experimental in-vitro study.

BACKGROUND: There is a continuous research in the area of biomimetic coatings on the titanium (Ti) implant surfaces for improved survival and long-term successful outcomes in the field of dentistry and orthopedics. In-vitro approaches are ideal systems for studying cell-material interactions without complexity and interference observed in in-vivo models. PURPOSE: The present study was undertaken to evaluate the osteoblast characteristics and function on Ti substrates coated with the novel composite coating of ceramic apatite-wollastonite (AW) and polymer chitosan. MATERIALS AND METHODS: Ti substrate coated with composite AW-Chitosan was synthesized, using electrophoretic deposition. MG-63 cells were seeded onto the coated substrates and cellular morphology and growth was assessed using Scanning Electron Microscopy (SEM) and Laser Scanning Microscopy (LSM). Osteocalcin expression of the seeded cells was assessed by FITC tagging and LSM analysis. Alizarin Red S staining and Confocal LSM (CSLM) analysis was used to study the in-vitro mineralization on the titanium samples. RESULTS: The AW-Chitosan coating on Ti samples by electrophoretic deposition exerted significant positive influence on cell proliferation, growth and mineralization as compared to uncoated titanium samples. Scanning electron microscopy and laser confocal microscopy experiments revealed that the coating was non-toxic to cells, enhanced adhesion and proliferation of MG-63 cells. Increased functional activity was observed by increased production of bone-specific protein osteocalcin and mineralized calcium through day 7 and 14. CONCLUSIONS: The present study underscores that optimal inorganic-organic phase nanocomposite crack-free coating created on Ti by simple, cost-effective electrophoretic deposition technique may have osteoconductive potential and may have wide application in the field of implantology. Graphical abstract.

Vaginal pressure sensor measurement during maximal voluntary pelvic floor contraction correlates with vaginal birth and pelvic organ prolapse-A pilot study.

AIMS: To measure the force applied along the anterior and posterior vaginal walls in a cohort of 46 patients measured by a fiber-optic pressure sensor and determine if this correlates with vaginal parity and pelvic organ prolapse (POP). METHODS: An intravaginal fiber-optic sensor measured pressure at nine locations along the anterior and posterior vaginal walls during a maximal voluntary pelvic floor muscle contraction (MVC). An automated probe dilation cycle measured the tissue resistance incorporating the vagina and surrounding anatomy. MVC and resting tissue resistance (RTR) were assessed between subjects grouped by the number of vaginal births and prolapse stage. RESULTS: A previous vaginal birth was associated with a significant threefold decrease in the overall anterior pressure measurement during MVC. Decreased anterior pressure measurements were observed at Sensors 1 and 3 (distal vagina) and, posteriorly at Sensors 4-6 (midvagina). Women with Stage 2 posterior prolapse exhibited a decreased MVC pressure in the midvagina than those with Stage 0/1. In this pilot study, there was no difference in the vaginal wall RTR according to previous vaginal birth or stage of prolapse. CONCLUSION: This pilot study found that a decrease in vaginal pressure measured during MVC is associated with vaginal birth and with posterior POP. Greater sample size is required to assess the role of resting tissue pressure measurement.

Endometrial SUSD2+ Mesenchymal Stem/Stromal Cells in Tissue Engineering: Advances in Novel Cellular Constructs for Pelvic Organ Prolapse.

Cellular therapy is an emerging field in clinical and personalised medicine. Many adult mesenchymal stem/progenitor cells (MSC) or pluripotent derivatives are being assessed simultaneously in preclinical trials for their potential treatment applications in chronic and degenerative human diseases. Endometrial mesenchymal stem/progenitor cells (eMSC) have been identified as clonogenic cells that exist in unique perivascular niches within the uterine endometrium. Compared with MSC isolated from other tissue sources, such as bone marrow and adipose tissue, eMSC can be extracted through less invasive methods of tissue sampling, and they exhibit improvements in potency, proliferative capacity, and control of culture-induced differentiation. In this review, we summarize the potential cell therapy and tissue engineering applications of eMSC in pelvic organ prolapse (POP), emphasising their ability to exert angiogenic and strong immunomodulatory responses that improve tissue integration of novel surgical constructs for POP and promote vaginal tissue healing.

Identification and characterisation of maternal perivascular SUSD2+ placental mesenchymal stem/stromal cells.

Mesenchymal stem cells (MSCs) that meet the International Society for Cellular Therapy (ISCT) criteria are obtained from placental tissue by plastic adherence. Historically, no known single marker was available for isolating placental MSCs (pMSCs) from the decidua basalis. As the decidua basalis is derived from the regenerative endometrium, we hypothesised that SUSD2, an endometrial perivascular MSC marker, would purify maternal perivascular pMSC. Perivascular pMSCs were isolated from the maternal placenta using SUSD2 magnetic bead sorting and assessed for the colony-forming unit-fibroblasts (CFU-F), surface markers, and in vitro differentiation into mesodermal lineages. Multi-colour immunofluorescence was used to colocalise SUSD2 and α-SMA, a perivascular marker in the decidua basalis. Placental stromal cell suspensions comprised 5.1%SUSD2+ cells. SUSD2 magnetic bead sorting of the placental stromal cells increased their purity approximately two-fold. SUSD2+ pMSCs displayed greater CFU-F activity than SUSD2- stromal fibroblasts (pSFs). However, both SUSD2+ pMSC and SUSD2- pSF underwent mesodermal differentiation in vitro, and both expressed the ISCT surface markers. Higher percentages of cultured SUSD2+ pMSCs expressed the perivascular markers CD146, CD140b, and SUSD2 than SUSD2- pSFs. These findings suggest that SUSD2 is a single marker that enriches maternal pMSCs, suggesting they may originate from eMSC. Placental decidua basalis can be used as an alternative source of MSC for clinical translation in situations where there is no access to endometrial tissue.

Immunobiology and Application of Aloe Vera-Based Scaffolds in Tissue Engineering.

Aloe vera (AV), a succulent plant belonging to the Liliaceae family, has been widely used for biomedical and pharmaceutical application. Its popularity stems from several of its bioactive components that have anti-oxidant, anti-microbial, anti-inflammatory and even immunomodulatory effects. Given such unique multi-modal biological impact, AV has been considered as a biomaterial for regenerative medicine and tissue engineering applications, where tissue repair and neo-angiogenesis are vital. This review outlines the growing scientific evidence that demonstrates the advantage of AV as tissue engineering scaffolds. We particularly highlight the recent advances in the application of AV-based scaffolds. From a tissue engineering perspective, it is pivotal that the implanted scaffolds strike an appropriate foreign body response to be well-accepted in the body without complications. Herein, we highlight the key cellular processes that regulate the foreign body response to implanted scaffolds and underline the immunomodulatory effects incurred by AV on the innate and adaptive system. Given that AV has several beneficial components, we discuss the importance of delving deeper into uncovering its action mechanism and thereby improving material design strategies for better tissue engineering constructs for biomedical applications.

Chemokine SDF1 Mediated Bone Regeneration Using Biodegradable Poly(D,L-lactide-co-glycolide) 3D Scaffolds and Bone Marrow-Derived Mesenchymal Stem Cells: Implication for the Development of an "Off-the-Shelf" Pharmacologically Active Construct.

There is an increasing need for bone substitutes for reconstructive orthopedic surgery following removal of bone tumors. Despite the advances in bone regeneration, the use of autologous mesenchymal stem cells (MSC) presents a significant challenge, particularly for the treatment of large bone defects in cancer patients. This study aims at developing new chemokine-based technology to generate biodegradable scaffolds that bind pharmacologically active proteins for regeneration/repair of target injured tissues in patients. Primary MSC were cultured from the uninvolved bone marrow (BM) of cancer patients and further characterized for "stemness". Their ability to differentiate into an osteogenic lineage was studied in 2D cultures as well as on 3D macroporous PLGA scaffolds incorporated with biomacromolecules bFGF and homing factor chemokine stromal-cell derived factor-1 (SDF1). MSC from the uninvolved BM of cancer patients exhibited properties similar to that reported for MSC from BM of healthy individuals. Macroporous PLGA discs were prepared and characterized for pore size, architecture, functional groups, thermostability, and cytocompatibility by ESEM, FTIR, DSC, and CCK-8 dye proliferation assay, respectively. It was observed that the MSC+PLGA+bFGF+SDF1 construct cultured for 14 days supported significant cell growth, osteo-lineage differentiation with increased osteocalcin expression, alkaline phosphatase secretion, calcium mineralization, bone volume, and soluble IL6 compared to unseeded PLGA and PLGA+MSC, as analyzed by confocal microscopy, biochemistry, ESEM, microCT imaging, flow cytometry, and EDS. Thus, chemotactic biomacromolecule SDF1-guided tissue repair/regeneration ability of MSC from cancer patients opens up the avenues for development of "off-the-shelf" pharmacologically active construct for optimal repair of the target injured tissue in postsurgery cancer patients, bone defects, damaged bladder tissue, and radiation-induced skin/mucosal lesions.

Emerging Nano/Micro-Structured Degradable Polymeric Meshes for Pelvic Floor Reconstruction.

Pelvic organ prolapse (POP) is a hidden women's health disorder that impacts 1 in 4 women across all age groups. Surgical intervention has been the only treatment option, often involving non-degradable meshes, with variable results. However, recent reports have highlighted the adverse effects of meshes in the long term, which involve unacceptable rates of erosion, chronic infection and severe pain related to mesh shrinkage. Therefore, there is an urgent unmet need to fabricate of new class of biocompatible meshes for the treatment of POP. This review focuses on the causes for the downfall of commercial meshes, and discusses the use of emerging technologies such as electrospinning and 3D printing to design new meshes. Furthermore, we discuss the impact and advantage of nano-/microstructured alternative meshes over commercial meshes with respect to their tissue integration performance. Considering the key challenges of current meshes, we discuss the potential of cell-based tissue engineering strategies to augment the new class of meshes to improve biocompatibility and immunomodulation. Finally, this review highlights the future direction in designing the new class of mesh to overcome the hurdles of foreign body rejection faced by the traditional meshes, in order to have safe and effective treatment for women in the long term.

Design of Novel Perovskite-Based Polymeric Poly(l-Lactide-Co-Glycolide) Nanofibers with Anti-Microbial Properties for Tissue Engineering.

: There is a growing need for anti-microbial materials in several biomedical application areas, such are hernia, skin grafts as well as gynecological products, owing to the complications caused by infection due to surgical biomaterials. The anti-microbial effects of silver in the form of nanoparticles, although effective, can be toxic to surrounding cells. In this study, we report, for the first time, a novel biomedical application of Ag0.3Na1.7La2Ti3O10-layered perovskite particles, blended with poly(L-lactide-co-glycolide) (PLGA), aimed at designing anti-microbial and tissue engineering scaffolds. The perovskite was incorporated in three concentrations of 1, 5, 10 and 15 w/w% and electrospun using dimethylformamide (DMF) and chloroform. The morphology of the resultant nanofibers revealed fiber diameters in the range of 408 to 610 nm by scanning electron microscopy. Mechanical properties of perovskite-based nanofibers also matched similar mechanical properties to human skin. We observed impressive anti-microbial activity, against Gram-negative, Gram-positive bacteria and even fungi, to Ag0.3Na1.7La2Ti3O10 in powder as well as nanofiber-incorporated forms. Furthermore, cytotoxicity assay and immunocytochemistry revealed that perovskite-based nanofibers promoted the proliferation of human dermal fibroblasts whist maintaining normal cellular protein expression. Our study shows that perovskite-nanofibers have potential as scaffolds for biomedical applications with anti-microbial needs.

Electrospun Nanofiber Meshes With Endometrial MSCs Modulate Foreign Body Response by Increased Angiogenesis, Matrix Synthesis, and Anti-Inflammatory Gene Expression in Mice: Implication in Pelvic Floor.

PURPOSE: Transvaginal meshes for the treatment of Pelvic Organ Prolapse (POP) have been associated with severe adverse events and have been banned for clinical use in many countries. We recently reported the design of degradable poly L-lactic acid-co-poly ε-caprolactone nanofibrous mesh (P nanomesh) bioengineered with endometrial mesenchymal stem/stromal cells (eMSC) for POP repair. We showed that such bioengineered meshes had high tissue integration as well as immunomodulatory effects in vivo. This study aimed to determine the key molecular players enabling eMSC-based foreign body response modulation. METHODS: SUSD2+ eMSC were purified from single cell suspensions obtained from endometrial biopsies from cycling women by magnetic bead sorting. Electrospun P nanomeshes with and without eMSC were implanted in a NSG mouse skin wound repair model for 1 and 6 weeks. Quantitative PCR was used to assess the expression of extracellular matrix (ECM), cell adhesion, angiogenesis and inflammation genes as log2 fold changes compared to sham controls. Histology and immunostaining were used to visualize the ECM, blood vessels, and multinucleated foreign body giant cells around implants. RESULTS: Bioengineered P nanomesh/eMSC constructs explanted after 6 weeks showed significant increase in 35 genes associated with ECM, ECM regulation, cell adhesion angiogenesis, and immune response in comparison to P nanomesh alone. In the absence of eMSC, acute inflammatory genes were significantly elevated at 1 week. However, in the presence of eMSC, there was an increased expression of anti-inflammatory genes including Mrc1 and Arg1 by 6 weeks. There was formation of multinucleated foreign body giant cells around both implants at 6 weeks that expressed CD206, a M2 macrophage marker. CONCLUSION: This study reveals that eMSC modulate the foreign body response to degradable P nanomeshes in vivo by altering the expression profile of mouse genes. eMSC reduce acute inflammatory and increase ECM synthesis, angiogenesis and anti-inflammatory gene expression at 6 weeks while forming newly synthesized collagen within the nanomeshes and neo-vasculature in close proximity. From a tissue engineering perspective, this is a hallmark of a highly successful implant, suggesting significant potential as alternative surgical constructs for the treatment of POP.

Coatings Releasing the Relaxin Peptide Analogue B7-33 Reduce Fibrotic Encapsulation.

The development of antifibrotic materials and coatings that can resist the foreign body response (FBR) continues to present a major hurdle in the advancement of current and next-generation implantable medical devices, biosensors, and cell therapies. From an implant perspective, the most important issue associated with the FBR is the prolonged inflammatory response leading to a collagenous capsule that ultimately blocks mass transport and communication between the implant and the surrounding tissue. Up to now, most attempts to reduce the capsule thickness have focused on providing surface coatings that reduce protein fouling and cell attachment. Here, we present an approach that is based on the sustained release of a peptide drug interfering with the FBR. In this study, the biodegradable polymer poly(lactic-co-glycolic) acid (PLGA) was used as a coating releasing the relaxin peptide analogue B7-33, which has been demonstrated to reduce organ fibrosis in animal models. While in vitro protein quantification was used to demonstrate controlled release of the antifibrotic peptide B7-33 from PLGA coatings, an in vitro reporter cell assay was used to demonstrate that B7-33 retains activity against the relaxin family peptide receptor 1 (RXFP1). Subcutaneous implantation of PLGA-coated polypropylene samples in mice with and without the peptide demonstrated a marked reduction in capsule thickness (49.2%) over a 6 week period. It is expected that this novel approach will open the door to a range of new and improved implantable medical devices.

A fiber-optic sensor-based device for the measurement of vaginal integrity in women.

AIMS: Pelvic floor disorders (PFDs) in women are a major public health concern. Current clinical methods for assessing PFDs are either subjective or confounded by interference from intra-abdominal pressure (IAP). This study introduces an intravaginal probe that can determine distributed vaginal pressure during voluntary exercises and measures the degree of vaginal tissue support independent of IAP fluctuations. METHODS: An intravaginal probe was fabricated with 18 independent fiber-optic pressure transducers positioned along its upper and lower blades. Continuous pressure measurement along the anterior and posterior vaginal walls during the automated expansion of the probe enabled the resistance of the tissue to be evaluated as a function of displacement, in a manner reflecting the elastic modulus of the tissue. After validation in a simulated vaginal phantom, in vivo measurements were conducted in the relaxed state and during a series of voluntary exercises to gauge the utility of the device in women. RESULTS: The probe reliably detected variations in the composition of sub-surface material in the vaginal phantom. During in-vivo measurements the probe detected distributed tissue elasticity in the absence of IAP change. In addition, the distribution of pressure along both anterior and posterior vaginal walls during cough, Valsalva and pelvic floor contraction was clearly resolved with a large variation observed between subjects. CONCLUSIONS: Our data highlight the potential for the probe to assess the integrity of the vagina wall and support structures as an integrated functional unit. Further in vivo trials are needed to correlate data with clinical findings to assist in the assessment of PFDs.

3D bioprinted endometrial stem cells on melt electrospun poly ε-caprolactone mesh for pelvic floor application promote anti-inflammatory responses in mice.

Endometrial mesenchymal stem/stromal cells (eMSCs) exhibit excellent regenerative capacity in the endometrial lining of the uterus following menstruation and high proliferative capacity in vitro. Bioprinting eMSCs onto a mesh could be a potential therapy for Pelvic Organ Prolapse (POP). This study reports an alternative treatment strategy targeting vaginal wall repair using bioprinting of eMSCs encapsulated in a hydrogel and 3D melt electrospun mesh to generate a tissue engineering construct. Following a CAD, 3D printed poly ε-caprolactone (PCL) meshes were fabricated using melt electrospinning (MES) at different temperatures using a GMP clinical grade GESIM Bioscaffolder. Electron and atomic force microscopies revealed that MES meshes fabricated at 100 °C and with a speed 20 mm/s had the largest open pore diameter (47.2 ±â€¯11.4 µm) and the lowest strand thickness (121.4 ±â€¯46 µm) that promoted optimal eMSC attachment. An Aloe Vera-Sodium Alginate (AV-ALG) composite based hydrogel was optimised to a 1:1 mixture (1%AV-1%ALG) and eMSCs, purified from human endometrial biopsies, were then bioprinted in this hydrogel onto the MES printed meshes. Acute in vivo foreign body response assessment in NSG mice revealed that eMSC printed on MES constructs promoted tissue integration, eMSC retention and an anti-inflammatory M2 macrophage phenotype characterised by F4/80+CD206+ colocalization. Our results address an unmet medical need highlighting the potential of 3D bioprinted eMSC-MES meshes as an alternative approach to overcome the current challenges with non-degradable knitted meshes in POP treatment. STATEMENT OF SIGNIFICANCE: This study presents the first report of bioprinting mesenchymal stem cells derived from woman endometrium (eMSCs) to boost Pelvic Organ Prolapse (POP) treatment. It impacts over 50% of elderly women with no optimal treatment at present. The overall study is conducted in three stages as fabricating a melt electrospun (MES) mesh, bioprinting eMSCs into a Ca2+ free Aloe Vera-Alginate (AV-Alg) based hydrogel and in vivo study. Our data showed that AV-ALG hydrogel potentially suppresses the foreign body response and further addition of eMSCs triggered a high influx of anti-inflammatory CD206+ M2 macrophages. Our final construct demonstrates a favourable foreign body response to predict expected tissue integration, therefore, provides a potential for developing an alternative treatment for POP.

Mesenchymal stem cell-based bioengineered constructs: foreign body response, cross-talk with macrophages and impact of biomaterial design strategies for pelvic floor disorders.

An excessive foreign body response (FBR) has contributed to the adverse events associated with polypropylene mesh usage for augmenting pelvic organ prolapse surgery. Consequently, current biomaterial research considers the critical role of the FBR and now focuses on developing better biocompatible biomaterials rather than using inert implants to improve the clinical outcomes of their use. Tissue engineering approaches using mesenchymal stem cells (MSCs) have improved outcomes over traditional implants in other biological systems through their interaction with macrophages, the main cellular player in the FBR. The unique angiogenic, immunomodulatory and regenerative properties of MSCs have a direct impact on the FBR following biomaterial implantation. In this review, we focus on key aspects of the FBR to tissue-engineered MSC-based implants for supporting pelvic organs and beyond. We also discuss the immunomodulatory effects of the recently discovered endometrial MSCs on the macrophage response to new biomaterials designed for use in pelvic floor reconstructive surgery. We conclude with a focus on considerations in biomaterial design that take into account the FBR and will likely influence the development of the next generation of biomaterials for gynaecological applications.

Tissue engineering approaches for treating pelvic organ prolapse using a novel source of stem/stromal cells and new materials.

PURPOSE OF REVIEW: Nondegradable transvaginal polypropylene meshes for treating pelvic organ prolapse (POP) are now generally unavailable or banned. In this review, we summarize recent developments using tissue engineering approaches combining alternate degradable scaffolds with a novel source of mesenchymal stem/stromal cells from human endometrium (eMSC). RECENT FINDINGS: Tissue engineering constructs comprising immunomodulatory, reparative eMSC and biomimetic materials with nanoarchitecture are a promising approach for vaginal repair and improving outcomes of POP surgery. Culture expansion of eMSC that maintains them (and other MSC) in the undifferentiated state has been achieved using a small molecule transforming growth factor-ß receptor inhibitor, A83-01. The mechanism of action of A83-01 has been determined and its suitability for translation into the clinic explored. Novel blends of electrospun synthetic and natural polymers combined with eMSC shows this approach promotes host cell infiltration and slows biomaterial degradation that has potential to strengthen the vaginal wall during healing. Improving the preclinical ovine transvaginal surgical model by adapting the human clinical POP-Quantification system for selection of multiparous ewes with vaginal wall weakness enables assessment of this autologous eMSC/nanobiomaterial construct. SUMMARY: A tissue engineering approach using autologous eMSC with degradable nanobiomaterials offers a new approach for treating women with POP.

Blended Nanostructured Degradable Mesh with Endometrial Mesenchymal Stem Cells Promotes Tissue Integration and Anti-Inflammatory Response in Vivo for Pelvic Floor Application.

The current urogynecological clinical meshes trigger unfavorable foreign body response which leads to graft failure in the long term. To overcome the present challenge, we applied a tissue engineering strategy using endometrial SUSD2+ mesenchymal stem cells (eMSCs) with high regenerative properties. This study delves deeper into foreign body response to SUSD2+ eMSC based degradable PLACL/gelatin nanofiber meshes using a mouse model targeted at understanding immunomodulation and mesh integration in the long term. Delivery of cells with nanofiber mesh provides a unique topography that enables entrapment of therapeutic cells for up to 6 weeks that promotes substantial cellular infiltration of host anti-inflammatory macrophages. As a result, degradation rate and tissue integration are highly impacted by eMSCs, revealing an unexpected level of implant integration over 6 weeks in vivo. From a clinical perspective, such immunomodulation may aid in overcoming the current challenges and provide an alternative to an unmet women's urogynecological health need.

Optimally Hierarchical Nanostructured Hydroxyapatite Coatings for Superior Prosthesis Biointegration.

Bone osteogenesis is a complex phenomenon dependent on numerous microenvironmental cues, with their synchrony regulating cellular functions, such as mechanical signaling, survival, proliferation, and differentiation, as well as controlled regional specification of skeletal progenitor cell fate. Therefore, obtaining a mechanistic understanding of cellular response to a microenvironment is now coming into intense focus, which will facilitate the design of programmable biomaterials for regenerative medicine. State-of-the-art nanomaterial synthesis and self-assembly processes yield complex structures that mimic surface properties, composition, and partially the morphology of the extracellular matrix. However, determining key structural properties that control cell attachment has been challenging and contradictory results are reported regarding the mechanisms and roll of nanostructured materials. Here, we significantly improve osteogenesis on bioinert substrates, demonstrating an exemplary organic-inorganic interface for superior prosthesis biointegration. We identify critical microscale hierarchical features that drastically enhance the cellular response to the same nanoscale architecture. It was observed that hierarchical morphologies, with a porosity above 80%, promote early-stage osteoinduction, as indicated by extensive coating ingrowth and nanofilopodia formation. We determined that cellular integration was mediated by two-way recognition of specific nano- and microtopographical cues between the host tissue and cellular microenvironment. This has allowed us to detail a set of determinant features for the nanofabrication of advanced prosthesis coatings that may ultimately improve implant longevity.

Tubular Tissues and Organs of Human Body--Challenges in Regenerative Medicine.

Tissue engineering of tubular organs such as the blood vessel, trachea gastrointestinal tract, urinary tract are of the great interest due to the high amount of surgeries performed annually on those organs. Development in tissue engineering in recent years and promising results, showed need to investigate more complex constructs that need to be designed in special manner. Stent technology remain the most widely used procedure to restore functions of tubular tissues after cancer treatment, or after organ removal due to traumatic accidents. Tubular structures like blood vessels, intestines, and trachea have to work in specific environment at the boundary of the liquids, solids or air and surrounding tissues and ensure suitable separation between them. This brings additional challenges in tissue engineering science in order to construct complete organs by using combinations of various cells along with the support material systems. Here we give a comprehensive review of the tubular structures of the human body, in perspective of the current methods of treatment and progress in regenerative medicine that aims to develop fully functioning organs of tubular shape. Extensive analysis of the available literature has been done focusing on materials and methods of creations of such organs. This work describes the attempts to incorporate growth factors and drugs within the scaffolds to ensure localized drug release and enhance vascularization of the organ by attracting blood vessels to the site of implantation.