Synthesis and characterization of PCL-DA:PEG-DA based polymeric blends grafted with SMA hydrogel as bio-degradable intrauterine contraceptive implant.

Presently available long-acting reversible female contraceptive implants are said to be an effective way of preventing unintended pregnancy. Unacceptable side effects attributed by these contraceptive implants act as a major drawback for the practitioners. These problems pave the way for the development of a new form of long-acting non-hormonal female contraceptive implant, especially in the developing countries. PCL-DA: PEG-DA polymeric scaffold is grafted with Styrene Maleic Anhydride (SMA) based hydrogel, and their physicochemical, thermal and biological parameters are being explored for developing a bio-degradable form of the non-hormonal intrauterine contraceptive implant. With the fixed ratio of PEG-DA: PCL-DA polymer, SMA hydrogel was added at four different concentrations to determine the optimum concentration of SMA hydrogel for the development of a promising long-acting biodegradable intrauterine contraceptive implant. Structural elucidation of the polymers was confirmed using 1H and 13C NMR spectroscopic analyses. The physiochemical characterization report suggests that SMA hydrogel interacts with the PCL-DA: PEG-DA polymeric scaffold through intermolecular hydrogen bonding interaction. The in-vitro spermicidal activity of the polymeric scaffold increases when the concentration of SMA based hydrogel in the polymer samples is increased without showing any significant toxicological effects. From the study results, it may be concluded that SMA hydrogel grafted PCL-DA: PEG-DA scaffold can be developed as intra-uterine biodegradable non-hormonal female contraceptive implant due to its excellent bio-compatibility and spermicidal activity.

Biocompatible polyvinyl alcohol and RISUG® blend polymeric films with spermicidal potential.

Majority of the commercially available vaginal contraceptives encompasses cervicovaginal membrane disrupting detergent molecules as pharmacologically active ingredients. Development of a tissue-compatible vaginal contraceptive agent is necessary to circumvent the existing demand for female contraception in the reproductive healthcare sector. With this objective, the present study delineates the use of RISUG® based non-hormonal female contraceptive films. RISUG® was blended with polyvinyl alcohol (PVOH) to formulate biodegradable intra-vaginal contraceptive films. The formulated films were characterized for their thermal, physiochemical and biological features. The results showed that both RISUG® and PVOH were miscible and interacted at the intermolecular level. Variations in the concentration of RISUG® resulted in the changes in physicochemical, thermal and rheological characteristics of the formulated blends. In vitro toxicological assay of the polymeric formulations did not show any significant toxicity. However, the blend films retained spermicidal potential of RISUG®. Furthermore, in vivo toxicological evaluation of the polymeric blend in the rat model revealed about their biocompatibility with no significant organ toxicity, hematological and biochemical alterations. These results together confirm the potential applicability of the PVOH:RISUG® blend films as a vaginal contraceptive.

RISUG® based improved intrauterine contraceptive device (IIUCD) could impart protective effects against development of endometrial cancer.

Intrauterine Contraceptive Devices with multifaceted application potential is a need of an hour. Although, copper-based IUDs exert an effective contraceptive as well as anticancer effects in a long-term basis, but also results in multiple complications. In this regard, RISUG® a polymer based contraceptive device has been introduced as a suitable alternative. However, its potential to impart protective effects against development of endometrial cancer still remains unexplored. This article presents the hypothesis on this unexplored domain and provides scientific facts to support the hypothesis. The mechanism of anticancerous activity is hypothesized that RISUG® involves its lipid membrane destabilizing activity. This activity is modulated by both, the cellular microenvironment and lipid bilayer composition. Acidic environment along with the significantly higher fluidic nature of lipid bilayer of the cancerous cells make them more prone to lipid solubilisation effect of RISUG®. We here present an in-depth insight into the factors that would favour faster solubilisation of cancer cell membrane, thereby exerting an anticancer effect.

Promoted Osteoconduction of Polyurethane-Urea Based 3D Nanohybrid Scaffold through Nanohydroxyapatite Adorned Hierarchical Titanium Phosphate.

The lack of optimal physiological properties, bacterial colonization, and auto-osteoinduction, are the foremost issues of orthopedic implantations. In terms of bone healing, many researchers have reported the release of additional growth factors of the implanted biomaterials to accelerate the bone regeneration process. However, the additional growth factor may cause side effects such as contagion, nerve pain, and the formation of ectopic bone. Thus, the design of an osteoconductive scaffold having excellent biocompatibility, appropriate physicomechanical properties, and promoted auto osteoinductivity with antibacterial activity is greatly desired. In this study, 2D rodlike nanohydroxyapatite (nHA) adorned titanium phosphate (TP) with a flowerlike morphology was synthesized by a hydrothermal precipitation reaction. The nanohybrid material (nHA-TP) was incorporated into the synthesized polycaprolactone diol and spermine based thermoplastic polyurethane-urea (PUU) via in situ technique followed by salt leaching to fabricate the macroporous 3D polymer nanohybrid scaffold (PUU/nHA-TP). Structure explication of PUU was performed by NMR spectroscopy. The synthesized nanohybrid scaffold with 1% nHA-TP showed 67% increase of tensile strength and 18% improved modulus compared to the pristine PUU via formation of H-bonding or dative bonds between the metal and the amide linkage of the polyurethane or polyurea. In vitro study showing improved cell viability and proliferation of the seeded cell revealed the superior osteoconductivity of the nanohybrid scaffold. Most importantly, the in vivo experiments revealed a significant amount of bone regeneration in the nanohybrid scaffold implanted tibial site compared to the pristine scaffold without any toxic effect. Introduction of the minute amount of titanium phosphate within the adorned nHA promotes the osteoconductivity significantly by the capability of forming coordinate bonds of the titanium ion. Depending on the mechanical, physicochemical, in vitro characteristics, and in vivo osteoconductivity, the PUU/nHA-TP nanohybrid scaffold has great potential as an alternative biomaterial in bone tissue regeneration application.

Liver Tissue Engineering: Challenges and Opportunities.

Liver tissue engineering aims at the possibility of reproducing a fully functional organ for the treatment of acute and chronic liver disorders. Approaches in this field endeavor to replace organ transplantation (gold standard treatment for liver diseases in a clinical setting) with in vitro developed liver tissue constructs. However, the complexity of the liver microarchitecture and functionality along with the limited supply of cellular components of the liver pose numerous challenges. This review provides a comprehensive outlook onto how the physicochemical, mechanobiological, and spatiotemporal aspects of the substrates could be tuned to address current challenges in the field. We also highlight the strategic advancements made in the field so far for the development of artificial liver tissue. We further showcase the currently available prototypes in research and clinical trials, which shows the hope for the future of liver tissue engineering.

Impact of styrene maleic anhydride (SMA) based hydrogel on rat fallopian tube as contraceptive implant with selective antimicrobial property.

Development of non-hormonal female contraception is a need to combat against increasing population growth. The presently available short term or long term female contraceptives and sterilization methods have their own restrictions and side effects. With this objective, herein, we describe an innovative insight about the use of hydrogel formulation consisting of Styrene Maleic Anhydride (SMA) dissolved in Dimethyl Sulfoxide (DMSO) as non-hormonal fallopian tube contraceptive implant. Firstly, in vitro behavior of SMA hydrogel was evaluated by in vitro swelling and rheological properties to comprehend the polymeric hydrogel property post implantation inside the fallopian tube. Simulated Uterine Fluid (SUF) was used to simulate female reproductive tract environment in this study. Mechanical strength of the hydrogel when subjected to dynamic environment post implantation in the fallopian tube was estimated by the G' values demonstrated. SMA hydrogel expressed selective antimicrobial activity against opportunistic pathogens (Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus) while having limited consequence over the growth of Lactobacillus spp. After confirmation of cytocompatibility against primary rat endometrial cell lines, the polymeric hydrogel was implanted inside the uterine horns of Sprague-Dawley rats. In vivo biocompatibility of the hydrogel was confirmed by histological and immunohistochemical evaluation of uterine tissue sections. Hematology, blood biochemistry and organ toxicity (kidney, liver, spleen, lungs and heart) also revealed biocompatibility of SMA hydrogel. The results of the current study indicated that the SMA copolymer dissolved in DMSO to form hydrogel has excellent biocompatibility for application as female contraceptive gel which can be implanted in the fallopian tube.

Mycobacterial heat shock protein 65 mediated metabolic shift in decidualization of human endometrial stromal cells.

Successful implantation is dependent on the appropriate decidualization of endometrial stromal cells for the establishment of pregnancy in women. Mycobacterial heat shock protein 65 (HSP65) is involved in pathogenesis of the genital tuberculosis (GTB), one of the common causes of infertility in emerging countries. Though implantation failure appears to be the major cause, understanding the status of decidualizaiton process in women diagnosed with GTB has not been thoroughly addressed. We, therefore, explored the effect of HSP65 protein on the endometrial cell metabolism during in vitro decidualization. In order to identify the cellular metabolism of decidual cells with and without HSP65 treatment, proton NMR based characterization of metabolites extracted from cells and culture media were performed. In presence of HSP65, significant reduction in the decidual phenotype of endometrial stromal cells and prolactin expression is suggestive of impairment in decidualization. The intracellular and extracellular metabolic changes in HSP65 treated endometrial stromal cells produced a distinct pattern, reflecting the interaction between the protein and cellular metabolism. HSP65 mediated dysregulation in cellular metabolism is associated with poor decidualization. Besides enriching the present knowledge on metabolic changes underlying stromal cells decidualization, these findings assist in identifying potential molecular causes for decidualization failure in GTB women.

On-Demand Guided Bone Regeneration with Microbial Protection of Ornamented SPU Scaffold with Bismuth-Doped Single Crystalline Hydroxyapatite: Augmentation and Cartilage Formation.

Guided bone regeneration (GBR) scaffolds are futile in many clinical applications due to infection problems. In this work, we fabricated GBR with an anti-infective scaffold by ornamenting 2D single crystalline bismuth-doped nanohydroxyapatite (Bi-nHA) rods onto segmented polyurethane (SPU). Bi-nHA with high aspect ratio was prepared without any templates. Subsequently, it was introduced into an unprecedented synthesized SPU matrix based on dual soft segments (PCL-b-PDMS) of poly(ε-caprolactone) (PCL) and poly(dimethylsiloxane) (PDMS), by an in situ technique followed by electrospinning to fabricate scaffolds. For comparison, undoped pristine nHA rods were also ornamented into it. The enzymatic ring-opening polymerization technique was adapted to synthesize soft segments of PCL-b-PDMS copolymers of SPU. Structure elucidation of the synthesized polymers is done by nuclear magnetic resonance spectroscopy. Sparingly, Bi-nHA ornamented scaffolds exhibit tremendous improvement (155%) in the mechanical properties with excellent antimicrobial activity against various human pathogens. After confirmation of high osteoconductivity, improved biodegradation, and excellent biocompatibility against osteoblast cells (in vitro), the scaffolds were implanted in rabbits by subcutaneous and intraosseous (tibial) sites. Various histological sections reveal the signatures of early cartilage formation, endochondral ossification, and rapid bone healing at 4 weeks of the critical defects filled with ornamented scaffold compared to SPU scaffold. This implies osteogenic potential and ability to provide an adequate biomimetic microenvironment for mineralization for GBR of the scaffolds. Organ toxicity studies further confirm that no tissue architecture abnormalities were observed in hepatic, cardiac, and renal tissue sections. This finding manifests the feasibility of fabricating a mechanically adequate nanofibrous SPU scaffold by a biomimetic strategy and the advantages of Bi-nHA ornamentation in promoting osteoblast phenotype progression with microbial protection (on-demand) for GBR applications.

Investigating the potential of human placenta-derived extracellular matrix sponges coupled with amniotic membrane-derived stem cells for osteochondral tissue engineering.

Osteochondral injuries are challenging to repair due to their complex tissue anatomy and restricted self-repairing ability associated with a limited blood supply. Osteochondral tissue engineering is an important clinical aspect of the management and treatment of cartilage and underlying bone. In the present study, we fabricated human placenta-derived extracellular matrix sponges (PEMS) for repair of osteochondral tissue through a decellularization process. There were no significant cellular components present in the PEMS; hematoxylin & eosin/DAPI staining, DNA quantification and agarose gel electrophoresis were used to evaluate the extent of decellularization. Moreover, no significant alteration to the collagen and glycosaminoglycan (native extracellular matrix) content of the PEMS was observed. PEMS in vitro provided a non-cytotoxic environment rich in bioactive cues for human amniotic membrane-derived stem cells (HAMSCs) to proliferate in and differentiate into chondrogenic and osteogenic lineages under induction. Histological analysis at 28 days after the PEMS were subcutaneously implanted demonstrated no severe immune response in the host and supported the formation of blood vessels. To assess the osteochondral tissue repair ability of PEMS, cell-free PEMS (CFP) and cell-seeded PEMS (CSP) were implanted at osteochondral defect sites in a rabbit model. Histological scores indicated that osteochondral regeneration was more successful in the defects filled with CSP compared to those filled with CFP and empty defects (ED) after 60 days of implantation. In summary, a naturally derived biocompatible scaffold composed of extracellular matrix from human placenta has been successfully developed for osteochondral tissue engineering.

Covalent cross-links in polyampholytic chitosan fibers enhances bone regeneration in a rabbit model.

Chitosan fibers were prepared in citric acid bath, pH 7.4 and NaOH solution at pH 13, to form ionotropically cross-linked and uncross-linked fibers, respectively. The fibers formed in citric acid bath were further cross-linked via carbodiimide chemistry; wherein the pendant carboxyl moieties of citric acid were used for new amide bond formation. Moreover, upon covalent cross-linking in the ionically gelled citrate-chitosan fibers, incomplete conversion of the ion pairs to amide linkages took place resulting in the formation of a dual network structure. The dual cross-linked fibers displayed improved mechanical property, higher stability against enzymatic degradation, hydrophobicity and superior bio-mineralization compared to the uncross-linked and native citrate cross-linked fibers. Additionally, upon cyclic loading, the ion pairs in the dual cross-linked fibers dissociated by dissipating energy and reformed during the relaxation period. The twin property of elasticity and energy dissipation mechanism makes the dual cross-linked fiber unique under dynamic mechanical conditions. The differences in the physico-chemical characteristics were reflected in protein adsorption, which in turn influenced the cellular activities on the fibers. Compared to the uncross-linked and ionotropically cross-linked fibers, the dual cross-linked fibers demonstrated higher proliferation and osteogenic differentiation of the MSCs in vitro as well as better osseous tissue regeneration in a rabbit model.