[Application of acellular dermal matrix in prevention of laryngeal stenosis in glottic carcinoma].

Objective:To investigate the effect of acellular dermal matrix in preventing laryngeal stenosis in glottic carcinoma patients. Methods:Fifty-five patients with glottic carcinoma（T2, T3） from February 2018 to December 2022 were divided into experimental group（28 cases） and control group（27 cases） according to their wishes. Acellular dermal matrix was placed in the operation cavity in the experimental group after laryngofission, while control group 12 cases were sutured by pulling the upper and lower edges, 15 cases were repaired with sternohyoid muscle fascia flap. Results:In the experimental group, 1 case had laryngeal stenosis caused by laryngeal mucosa swelling after operation, and extubated successfully after symptomatic treatment. In the control group, 7 cases had laryngeal stenosis after operation, of which 3 cases were caused by granulation tissue hyperplasia in laryngeal cavity, and extubated after symptomatic treatment. 2 cases extubated after operation suffered from progressive dyspnea during radiotherapy, and underwent tracheotomy again, extubation successful after treatment. 2 cases caused by laryngeal mucosa swelling, after symptomatic treatment, one case was successfully extubated, and one case had long-term intubation. The laryngeal stenosis rate of the experimental group was 3.6%（1/28） , which was lower than control group 25.9%（7/27）, and the therapeutic effect of the experimental group was significantly better than control group （χ²=5.526, P=0.019）. Conclusion:Implanting acellular dermal matrix in the operation cavity of glottic carcinoma can reduce the occurrence of laryngeal stenosis and have satisfactory preventive effect on laryngeal stenosis.

Preparation of healing-promoting and fibrosis-inhibiting asymmetric poly(ethylene glycol-b-L-phenylalanine)/cRGD-modified hyaluronate sponges and their applications in hemorrhage and nasal mucosa repair.

Acute or chromic bleeding, such as epistaxis, requires hemostatic materials to assist hemostasis. Even in complex cases, hemostatic materials must have other functions, including the promotion of healing and prevention of adhesion. Herein, a series of fibrosis-suppressive functional cRGD-modified crosslinking hyaluronic acid sponges were prepared. The in vitro hemostatic efficiency and mechanism were determined using blood clotting time, blood coagulation index, lactate dehydrogenase (LDH) and thromboxane B2 (TX-B2) ELISA, and proteomics. Among the prepared sponges, both poly(ethylene-b-L-Phe) (PEBP)-and cRGD contained SPN4 and exhibited the highest platelet concentration and activation efficiency as well as the most effective coagulative effect. In addition, no significant cytotoxicity was observed for the sponges in rat airway epithelial cells. The in vivo hemostatic and adhesion-preventive effects of the sponges were evaluated using rat models of liver injury and sidewall defect-cecum abrasion. PEBP-containing sponges effectively prevented postoperative adhesion and cRGD-modified sponges exhibited excellent hemostatic effects. Finally, the comprehensive repair effects of the sponges were evaluated using a rabbit maxillary sinus mucosal injury model, based on CT, MRI examination, and pathological staining. SPN4 exhibited the best comprehensive reparative effects, including the promotion of mucosal repair and infection inhibition. Thus, SPN4 is a promising multifunctional hemostatic material.

Bacteriostatic effect of Ag@TiO2-Poly(p-dioxanone)-coated gauzes in vitro and in vivo on otitis media pathogens.

The application of packing agents affects the final surgical outcomes in treating otitis media (OM) and introduces the risk of infection. To decrease the infectious risks of packing agents and even introduce positive bacteriostatic functions, a kind of PPDO-grafted Ag-incorporated TiO2 nanoparticles (Ag@TiO2-PPDO NP)-coated gauzes were prepared by a solution immersion method. Morphologies and in vitro Ag+ releasing of Ag@TiO2-PPDO NP coated gauzes were determined by scanning electron microscope (SEM) and inductively coupled plasma-mass spectrum (ICP-Ms). Ag@TiO2-PPDO NP could respond to visible light, which might make Ag@TiO2-PPDO NP inhibit the proliferation of bacteria continually and positively with irradiation of visible light. Then the bacteriostatic effects of these gauzes on OM pathogens were investigated in vitro and in vivo. These gauzes could inhibit the proliferation of pathogenic Staphylococcus aureus (S. aureus) and Streptococcus pneumoniae (S. pneumoniae) in vitro and rat subcutaneous infection models. Specifically, the bacteriostatic effect of these gauzes on S. aureus and S. pneumoniae could be enhanced with irradiation by visible light in vitro. Further, the rat external auditory canal infection model verified the enhanced bacteriostatic effect of Ag@TiO2-PPDO-coated gauzes on S. aureus with irradiation by visible light. The Ag@TiO2-PPDO-coated gauzes are promising for packing materials after OM surgery and could reduce postoperative antibiotic requirements.

Recent advances in biofunctional guided bone regeneration materials for repairing defective alveolar and maxillofacial bone: A review.

The anatomy of the oral and maxillofacial sites is complex, and bone defects caused by trauma, tumors, and inflammation in these zones are extremely difficult to repair. Among the most effective and reliable methods to attain osteogenesis, the guided bone regeneration (GBR) technique is extensively applied in defective oral and maxillofacial GBR. Furthermore, endowing biofunctions is crucial for GBR materials applied in repairing defective alveolar and maxillofacial bones. In this review, recent advances in designing and fabricating GBR materials applied in oral and maxillofacial sites are classified and discussed according to their biofunctions, including maintaining space for bone growth; facilitating the adhesion, migration, and proliferation of osteoblasts; facilitating the migration and differentiation of progenitor cells; promoting vascularization; providing immunoregulation to induce osteogenesis; suppressing infection; and effectively mimicking natural tissues using graded biomimetic materials. In addition, new processing strategies (e.g., 3D printing) and new design concepts (e.g., developing bone mimetic extracellular matrix niches and preparing scaffolds to suppress connective tissue to actively acquire space for bone regeneration), are particularly worthy of further study. In the future, GBR materials with richer biological functions are expected to be developed based on an in-depth understanding of the mechanism of bone-GBR-material interactions.

Preparation of healing promotive alanyl-glutamine-poly(p-dioxanone) electrospun membrane integrated with gentamycin and its application for intestinal anastomosis in rats.

Anastomosis surgery at the intestinal site is performed on millions of individuals every year. However, several persistent complications, such as anastomotic leakage, abnormal adhesion, and anastomotic stenosis, have been observed after the surgery. For promoting anastomotic healing and to overcome the challenges mentioned above, re-epithelialization at anastomotic sites is crucial. In this study, an epithelialization-promoting macromolecular prodrug Ala-Gln-PPDO was prepared and processed into fibrous membranes by electrospinning. Ala-Gln and gentamicin were sustainably released from the electrospun membranes with degradation of these membranes to promote the proliferation of rat intestinal epithelial cells and suppress the proliferation of Staphylococcus aureus and Escherichia coli. The comprehensive repair effects of Ala-Gln-PPDO membranes have been evaluated in rat models of intestinal anastomosis in this study. Application of Ala-Gln-PPDO membranes, especially the gentamicin-incorporated Ala-Gln-PPDO ones, could prevent adhesion between the injured intestine and surrounding intestinal tissues. In addition, they did not affect the healing strength of anastomotic stoma negatively and could promote re-epithelialization at the anastomotic sites. Furthermore, the gentamicin-incorporated Ala-Gln-PPDO membranes could relieve stenosis at anastomotic sites. The gentamicin-incorporated Ala-Gln-PPDO electrospun membrane is a promising, comprehensive implantable material for promoting healing after gastrointestinal anastomosis owing to its effects involving the promotion of re-epithelialization, prevention of adhesion, and relieving of anastomotic stenosis.

Preparation of Fibroblast Suppressive Poly(ethylene glycol)-b-poly(l-phenylalanine)/Poly(ethylene glycol) Hydrogel and Its Application in Intrauterine Fibrosis Prevention.

Intrauterine adhesions (IUA) often occur as a result of trauma to the basal layer after curettage, postpartum hemorrhage, or surgical miscarriage. Endometrial fibrosis is the primary pathological feature of IUA. The characteristic features of IUA include excessive deposition and reorganization of the extracellular matrix, replacing the normal endometrium. To prevent uterine fibrosis after injury, we prepared and evaluated a type of fibroblast suppressive hydrogel. Poly(ethylene glycol)-b-poly(l-phenylalanine) (PEBP) copolymers were successfully synthesized by ring opening polymerization of l-Phenylalanine N-carboxyanhydride, initiated by methoxy-poly(ethylene glycol)-amine. Injectable PEBP/PEG hydrogels were subsequently formed through π-π accumulations between PEBP macromolecules and hydrogen bonds among PEBP, PEG, and H2O molecules. PEBP/PEG hydrogel could suppress the proliferation of fibroblasts due to the action of l-Phe, released sustainably from PEBP/PEG gels. Lastly, the in vivo preventive effect of PEBP/PEG hydrogel on fibrosis was evaluated in a rat uterine curettage model. It was found that PEBP/PEG hydrogel suppressed uterine fibrosis caused by curettage and promoted embryo implantation in injured uterine by regulating the expression and interactions of transforming growth factor beta 1 (TGF-ß1) and Muc-4. PEBP/PEG hydrogels have the potential for application in uterine adhesion prevention owing to their fibrosis preventive and pregnancy promotiing effects on uterine tissue after injury.

Cecal amebiasis mimicking inflammatory bowel disease.

Amebiasis is a frequently occurring parasitic infection in South East Asia. We present a case of a 54-year-old man with right lower quadrant abdominal pain that persisted for longer than 1 year. He had been diagnosed with inflammatory bowel disease in Indonesia. His abdominal pain persisted, despite therapy, and he visited Malaysia for transnational medical advice. Abdominal ultrasound showed fatty liver, gallbladder polyps, and a small left renal stone. Colonoscopy showed multiple ulcers in the cecum and a histopathological examination confirmed amebic infection of the cecum. The colonic ulcers subsided after anti-amebic treatment. This case highlights the need to consider the differential diagnosis of amebic colitis in patients presenting with manifestations of inflammatory bowel disease, especially in patients who live in or have traveled to endemic areas.

Electrosprayed nanoparticles of poly(p-dioxanone-co-melphalan) macromolecular prodrugs for treatment of xenograft ovarian carcinoma.

Ovarian cancer is considered to be the most fatal reproductive cancers. Melphalan is used to treat ovarian cancer as an intraperitoneal chemotherapy agent. However, elucidating its pharmacokinetic behavior and preparing it for administration are challenging since it undergoes spontaneous hydrolysis. In this study, melphalan is transformed into a macromolecular prodrug by copolymerizing with p-dioxanone. The hydrophobicity of copolymer chains protects melphalan from hydrolysis. Poly(p-dioxanone-co-melphalan; PDCM) is electrosprayed and converted into nanoparticles (PDCM NPs) with diameters of ~300-350 nm to facilitate its intracellular delivery. UPLC-MS and HPLC are applied to verify and monitor the release of melphalan from PDCM NPs. PDCM NPs could suppress the proliferation of SKOV-3 cells. The IC50 of 4.3% melphalan-containing PDCM-3 NP was 70 mg/L, 72 h post administration. These suppression characteristics not only affected by the degradation and then the extracellular release of melphalan from PDCM NPs, but also the uptake via phagocytosis phenomenon in SKOV-3 cells. As revealed by flow cytometry, phagocytosis is a first-order process. Once phagocytosed, PDCM NPs are digested by lysosomes, causing a rapid release of melphalan into the cytoplasm, which ultimately causes suppression of SKOV-3 cell proliferation. Finally, the in vivo antitumor effects of PDCM NPs are verified in xenograft ovarian carcinoma. After a 20-day treatment, the tumor growth rate of the PDCM-3 NP group was (266 ± 178%) which was lower than those in the free melphalan group (367 ± 150%) and control group (648 ± 149%). Besides, significant tissue necrosis and growth suppression were observed in animals administered injections of PDCM NPs. Furthermore, the in vivo tracing results of Nile red-labeled PDCM NPs demonstrated that PDCM-3 NPs might be phagocytosed by macrophages and then taken to adjacent lymph nodes, which is a way of prevention or early treatment of lymphatic metastasis of tumors.

Anti-Adhesive, Platelet Gathering Effects of c-RGD Modified Poly(p-dioxanone-co-l-Phe) Electrospun Membrane and Its Comprehensive Application in Intestinal Anastomosis.

Intestinal resection and anastomosis are performed in over a million people with various bowel diseases annually. Excessive fibrosis and anastomotic site leakage are the main complications of anastomosis surgery, despite great improvements in operative technique and equipment in recent years. In this study, cRGD modified poly(p-dioxanone-co-l-Phe) (PDPA) membranes are designed and applied in intestinal anastomosis to simultaneously solve the two aforementioned complications. cRGD is modified onto PDPA membranes through both physical absorption and π-π accumulation between d-Phe of cRGD and l-Phe of PDPA. Although cRGD modification enhanced the biocompatibility of PDPA membranes, cRGD modified PDPA membrane suppresses fibroblast proliferation both in vitro and in vivo as a result of degradation and subsequent release of fibroblast suppressive l-Phe from PDPA. Meanwhile, platelets are entrapped by cRGD modified PDPA membranes through the specific binding of cRGD and platelet GPIIbIIIa . cRGD modified PDPA membranes are applied in rat intestinal anastomosis, and both adhesion and stenosis are successfully prevented at anastomotic sites. At the same time, bursting pressure, which represents healing intensity at anastomotic sites, is promoted. The gathering and activation of platelets on PDPA membranes induce secretion of autologous PDGF and VEGF to facilitate angiogenesis and subsequent healing of anastomotic sites.

PLGA/PLCA casting and PLGA/PDPA electrospinning bilayer film for prevention of postoperative adhesion.

Postoperative adhesion is a common complication and preventing adhesions during or immediately after operation is particularly important. The application of solid barrier materials represents the most successful clinical strategy to prevent postoperative adhesion. However, a simple physical barrier effect might be insufficient in preventing adhesion satisfactorily. Multilayered structures can be designed with an outer layer as the barrier and an inner layer to respond to relative drug release. In this article, bilayer film composed of a PLGA/PLCA casting layer as barrier and PLGA/PDPA electrospinning layer to respond to the release of anti-fibrosis drug l-Phe was designed and synthesized. The adhesion prevention effect of the above PLGA/PLCA/PDPA bilayer film was examined and compared with single PLGA/PLCA casting film and single PLGA/PDPA electrospinning film by applying rabbit sidewall defect-cecum abrasion model. As demonstrated by histological observation and immunohistochemical analysis, the bilayer film was the most effective of the three films in postoperative adhesion prevention in terms of both physical barrier effect and anti-fibrosis effect of the PDPA macromolecular prodrug. Besides anti-fibrosis effect, PDPA could also suppress excess proliferation of vascular endothelial cells and microvessel caused by long-term stimulation of implantation materials to the surrounding tissues. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2030-2039, 2019.

The in vivo anti-fibrotic function of calcium sensitive receptor (CaSR) modulating poly(p-dioxanone-co-l-phenylalanine) prodrug.

In present study, the apoptosis induction and proliferation suppression effects of l-phenylalanine (l-Phe) on fibroblasts were confirmed. The action sites of l-Phe on fibroblasts suppression were deduced to be calcium sensitive receptor (CaSR) which could cause the release of endoplasmic reticulum (ER) Ca2+ stores; disruption of intracellular Ca2+ homeostasis triggers cell apoptosis via the ER or mitochondrial pathways. The down-regulation of CaSR were observed after the application of l-Phe, and the results those l-Phe triggered the increasing of intracellular Ca2+ concentration and calcineurin expression, and then the apoptosis and increasing G1 fraction of fibroblasts have verified our deduction. Hence, l-Phe could be seen as a kind of anti-fibrotic drugs for the crucial participation of fibroblast in the occurrence of fibrosis. And then, poly(p-dioxanone-co-l-phenylalanine) (PDPA) which could prolong the in-vivo anti-fibrotic effect of l-Phe for the sustained release of l-Phe during its degradation could be treated as anti-fibrotic polymer prodrugs. Based on the above, the in vivo anti-fibrotic function of PDPA was evaluated in rabbit ear scarring, rat peritoneum lipopolysaccharide, and rat sidewall defect/cecum abrasion models. PDPA reduced skin scarring and suppressed peritoneal fibrosis and post operation adhesion as well as secretion of transforming growth factor-ß1 in injured tissue. These results indicate that PDPA is an effective agent for preventing fibrosis following tissue injury. STATEMENT OF SIGNIFICANCE: We have previously demonstrated that poly(p-dioxanone-co-l-phenylalanine) (PDPA) could induce apoptosis to fibroblast and deduced that the inhibitory effect comes from l-phenylalanine. In present study, the inhibition mechanism of l-phenylalanine on fibroblast proliferation was demonstrated. The calcium sensitive receptor (CaSR) was found to be the action site. The CaSR was downregulated after the application of l-phenylalanine, and then the ER Ca2+ stores were released. The released Ca2+ can simultaneously activate Ca2+/calcineurin and then trigger apoptosis and G1 arrest of fibroblast. Hence, l-phenylalanine could be seen as anti-fibrosis drug and PDPA which conjugate l-phenylalanine by hydrolytic covalent bonds could be seen as l-phenylalanine polymer prodrug. Based above, the in vivo anti-fibrotic function of PDPA were verified in three different animal models.