Development and characterization of PLGA-Bupivacaine and PLGA-S75: R25 Bupivacaine (Novabupi®) biodegradable implants for postoperative pain

Abstract In the hospital environment, postoperative pain is a common occurrence that impairs patient recovery and rehabilitation and lengthens hospitalization time. Racemic bupivacaine hydrochloride (CBV) and Novabupi® (NBV) (S (-) 75% R (+) 25% bupivacaine hydrochloride) are two examples of local anesthetics used in pain management, the latter being an alternative with less deleterious effects. In the present study, biodegradable implants were developed using Poly(L-lactide-co-glycolide) through a hot molding technique, evaluating their physicochemical properties and their in vitro drug release. Different proportions of drugs and polymer were tested, and the proportion of 25%:75% was the most stable for molding the implants. Thermal and spectrometric analyses were performed, and they revealed no unwanted chemical interactions between drugs and polymer. They also confirmed that heating and freeze-drying used for manufacturing did not interfere with stability. The in vitro release results revealed drugs sustained release, reaching 64% for NBV-PLGA and 52% for CBV-PLGA up to 30 days. The drug release mechanism was confirmed by microscopy, which involved pores formation and polymeric erosion, visualized in the first 72 h of the in vitro release test. These findings suggest that the developed implants are interesting alternatives to control postoperative pain efficiently.

Medical Devices; Radiology Devices; Classification of the Absorbable Perirectal Spacer. Final order.

The Food and Drug Administration (FDA or we) is classifying the absorbable perirectal spacer into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the absorbable perirectal spacer's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens.

Catéteres y stents urinarios biodegradables. ¿Para cuándo? / Biodegradable catheters and urinary stents. When?

Una de los principales anhelos en el campo de los catéteres y stents urinarios es dotarlos de características biodegradables. Ya que se entiende como un fracaso de estos dispositivos la necesidad de retirada, el síndrome de catéter olvidado, así como los efectos adversos que provocan los dispositivos permanentes tras cumplir su finalidad. Los esfuerzos centrados en nuevos diseños, recubrimientos, así como biomateriales buscan incrementar la biocompatibilidad de estos dispositivos internos. En los últimos tiempos los principales retos con respecto a los dispositivos biodegradables ureterales han avanzado en la correcta dirección. Así, la tasa de degradación se ha conseguido modular gracias a los nuevos biomateriales y al empleo de copolímeros que permiten elegir el tiempo de permanencia al igual que se programa con los catéteres doble jota convencionales. La biocompatibilidad ha mejorado de la mano de nuevos polímeros que se adaptan mejor al medio urinario. Por último uno de los principales problemas, la eliminación de fragmentos degradados, demuestra a nivel experimental que con nuevos diseños que provocan la degradación controlada, de distal a proximal, empleando el trenzado y combinando copolímeros, la degradación se puede provocar por dilución, reduciendo la fragmentación a los últimos estadios de vida de la prótesis. Además se demuestra que potencialmente los catéteres biodegradables pueden provocar menor infección urinaria, menor incrustación y previsiblemente disminuirán la morbilidad de los catéteres, ya que su proceso de degradación reduce los efectos adversos. Con respecto al desarrollo de stents uretrales biodegradables se necesita encontrar biomateriales que permitan mantener sus propiedades biomecánicas a largo plazo, manteniendo la luz uretral abierta tanto en pacientes con HBP como en los casos de estenosis uretral. Se ha conseguido modular el tiempo de degradación de las prótesis, pero todavía la aparición de hiperplasia urotelial polipoidea es una constante en las fases iniciales post-implantación. El desarrollo de stents liberadores de fármaco, antiinflamatorio o antiproliferativos, al igual que stents biodegradables biorrecubiertos es un campo del que se espera venga la solución a estos efectos adversos. Son por tanto muchos aspectos que deben ser mejorados para obtener los ansiados stents biodegradables, pero en los últimos años se han ido cumpliendo hitos, gracias a los avances en Bioingeniería, que permiten vislumbrar en un futuro próximo soluciones seguras y eficaces

One of the main wishes in the field of urinary catheters and stents is to arm them with biodegradable characteristics because we consider a failure of these devices the need for retrieval, the forgotten catheter syndrome as well as the adverse effects permanent devices cause after fulfilling their aim. The efforts focused in new designs, coatings and biomaterials aim to increase the biocompatibility of theses internal devices. Lately, there have been correct advances to answer the main challenges regarding biodegradable ureteral devices. Thus, modulation of the rate of degradation has been achieved thanks to new biomaterials and the use of copolymers that enable to choose the time of permanence as it is programmed with conventional double J catheters. Biocompatibility has improved with the use of new polymers that adapt better to the urine. Finally, one of the main problems is elimination of degraded fragments and experimentally it has be demonstrated that new designs elicit controlled degradation, from distal to proximal; using stranding and combination of copolymers degradation may be caused by dilution, reducing fragmentation to the last stages of life of the prosthesis. Moreover, it has been demonstrated that biodegradable catheters potentially may cause less urinary tract infection, less encrustation and predictably they will diminish catheter morbidity, since their degradation process reduces adverse effects. Regarding the development of biodegradable urethral stents, it is necessary to find biomaterials that enable maintaining their biomechanical properties in the long term, keeping open the urethral lumen both in patients with BPH and urethral stenosis. Modulation of the time of degradation of the prosthesis has been achieved, but the appearance of urothelial hyperplasia is still a constant in the initial phases after implantation. The development of drug eluting stents, anti-proliferative or anti-inflammatory, as well as biodegradable stents biocoated is a field from which it is expected the arrival of the solution of theses adverse effects. Therefore, many features need to be improved to obtain biodegradable stents, but over the last years some turning points have been accomplished thanks to the advances in Bioengineering, allowing to foresee safe and effective solutions in the nearest future

Medical devices; general and plastic surgery devices; classification of the absorbable lung biopsy plug. Final order.

The Food and Drug Administration (FDA) is classifying the absorbable lung biopsy plug into class II (special controls). The special controls that will apply to the device are identified in this order, and will be part of the codified language for the absorbable lung biopsy plug's classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device.

Attachment and proliferation of human osteoblast-like cells on guided bone regeneration (GBR) membranes in the absence or presence of nicotine: an in vitro study.

PURPOSE: To compare in vitro the attachment and proliferation of human osteoblast-like cells (MG63) on tissue culture plates and guided bone regeneration (GBR) membranes in the absence or presence of nicotine. MATERIALS AND METHODS: Membrane samples were fixed to wells and the cell number (CN) was counted after 24 hours (attachment assay) or 5 days (proliferation assay). The ratio of cell count (RCC) (CN at 5 days/CN at 24 hours) was calculated. The study had three parts: First, five different resorbable GBR membranes were compared (Resolut Adapt LT [RALT], Biocollagen [BC], Bio-Gide [BG], OsseoGuard [OG], and Demokritos Human Tissue Bank [DEM]). Next, cells were cultured on tissue culture plates with five different concentrations of nicotine. Finally, cells were cultured on the membrane that had demonstrated the highest RCC and CN in part 1 with four different concentrations of nicotine. RESULTS: At 24 hours, BG showed the highest CN and OG showed the lowest CN. At 5 days, BG showed the highest CN. The order of RCC was BG > OG > DEM > RALT ~ BC. At 24 hours, lower nicotine concentrations (0.3 and 3 µg/mL) showed higher CNs versus the control, whereas CNs for high nicotine concentrations (30 and 300 µg/mL) were lower than for the control. CN at 5 days and RCC were lowest with 300 µg/mL nicotine. At 24 hours and 5 days, all differences among wells with membrane were statistically insignificant. Nevertheless, CN at 5 days and RCC were highest with the lowest nicotine concentration (3 µg/mL) and lowest with high concentrations. CONCLUSIONS: Membrane materials influence attachment and proliferation of bone cells and, therefore, could affect the outcomes of GBR. On both tissue culture plates and membranes, there is a tendency toward a biphasic effect of nicotine, with stimulatory effects at low concentrations and inhibitory effects at high concentrations.

A short biodegradable helical spiral ureteric stent provides better antireflux and drainage properties than a double-J stent.

OBJECTIVE: The use of ureteric stents is a standard treatment for the relief of ureter blockages for benign or malignant reasons. The most common stent design in clinical use is a double-J stent with coiled ends to avoid stent displacement. However, there are a number of complications associated with stent use. A double-J stent design bypasses the ureterovesical junction, enables bladder pressure reflection to the renal pelvis and causes vesicoureteral reflux (VUR). This may result in scarring and renal failure. MATERIAL AND METHODS: An animal model was used to investigate whether VUR can be avoided in stented ureters using a short biodegradable partial helical spiral stent design that leaves the ureterovesical junction intact. MATERIALS AND METHODS: Eight female pigs were used. Ureters on the left side were stented using a short helical spiral SR-PLGA stent (group A) and ureters on the right side using double-J stents (group B). Simulated voiding cystoureterography and standard intravenous urography examinations were performed on all eight animals at 4 weeks and on the remaining four animals at 8 weeks. RESULTS: An SR-PLGA single coiled partial stent demonstrated superior drainage properties to a double-J stent at 4 weeks (p = 0.020). A marked but not statistically significant difference in favour of a SR-PLGA stent was also observed at 8 weeks (p = 0.102). A statistically significant difference was observed in VCUG findings in favour of group A at immediate postoperative control as well as in the 4 and 8 week follow-up studies (p = 0.011, p = 0.010, p = 0.046, respectively). CONCLUSION: A self-expandable, SR-PLGA partial ureteric stent presented with superior drainage and antireflux properties compared to a double-J stent. The reflux commonly related to double-J stent use can be minimized by using a partial ureteric stent design.

Bioabsorbable coronary stents--are these the next big thing in coronary angioplasty?

The role of percutaneous coronary intervention (PCI) in the treatment of coronary artery disease has grown at an astronomical pace. Drug eluting stents (DES) offer advantages over bare metal stents (BMS) such as reduction in early in-stent restenosis rates. However, they have disadvantages like from increased late stent thrombosis when compared with BMS. Furthermore, recent data suggest endothelial dysfunction in the DES stented segments of the arteries. Currently, bioabsorbable stents are under development to avert the complications of DES such as stent thrombosis via degradation of the stent over time. The hypothetical advantage of leaving behind a natural vessel and restoring vasoreactivity may be the almost normal physiology which can be achieved after an intervention with a stent. The ABSORB and the PROGRESS AMS are two of the recent clinical trials that have looked at the outcomes of using bioabsorbable stents. So far, data from these and other studies has yielded mixed results in terms of angiographic and clinical outcomes. Newer stents such as REVA and WHISPER are presently being tested in preclinical and clinical trials. The landscape for bioabsorbable stents is constantly evolving through continued improvisation on existing technology and emergence of new technology. Large scale randomized trials are still needed with adequate long term follow-up for safety and benefits to have mainstream application in coronary artery disease, bioabsorbable stents are a promising innovation in the field of PCI. We review some of the patents and the data that is emerging on bioabsorbable stents in addition to currently ongoing clinical trials.

Novedades en stents farmacoactivos. Actualización y futuros desarrollos / News in drug-eluting stents. update and future developments

Con el objetivo de mejorar las limitaciones de la primera generación de stents farmacoactivos, las nuevas generaciones se han desarrollado para mejorar su seguridad y su biocompatibilidad optimizando sus tres principales componentes: la plataforma, el polímero y el fármaco. Además de estas, otras líneas de investigación se centran en desarrollar nuevos dispositivos con polímeros biodegradables, sin polímero, entre los que se incluyen los llamados stents bioactivos, que introducen mejoras en la superficie del stent para optimizar la reendotelización arterial, y finalmente prototipos completamente biodegradables. Es impresionante el esfuerzo en investigación básica, estudios de anatomía patológica e ingeniería de diseño que se ha realizado en los últimos años en este campo. Por lo tanto, la información que ha surgido en poco tiempo también es increíble. En esta revisión se hace un análisis de las novedades y los estudios aparecidos en los últimos 3 años en relación con los stents farmacoactivos. Se analizan las mejoras en la segunda generación y se describe la llamada tercera o siguiente generación de stents farmacoactivos (AU)

With the aim of overcoming the limitations of firstgeneration drug-eluting stents, a new generation of stents has been developed to improve safety and biocompatibility by optimizing their three main components: the stent platform, coating and drug. In addition, other lines of research have focused on developing new devices either with biodegradable polymers or without polymers, including so-called bio-active stents, in which the stent surface is modified to optimize arterial endothelialization. Finally, prototypes of fully biodegradable stents are also being developed. The effort put into basic research, studies of anatomy and pathology, and engineering design in recent years in this field has been impressive. As a result, the amount of data that has been produced in a short time has also been remarkable. This review provides an analysis of developments in and studies on drugeluting stents that have taken place in the last 3 years. Improvements in second-generation stents are discussed and the nature of the so-called third or next generation of drug-eluting stents is described (AU)

Treatment of incisional hernias adopting an intra-abdominal approach with a new low-density composite prosthetic material: proceed: our preliminary experience on 50 cases.

INTRODUCTION: The management of incisional hernias remains a challenge for the general surgeon. Repairing by using prosthetic materials has reduced the relapse rate, but intra-abdominal mesh placement continues to be a source of controversy. OBJECTIVE: An evaluation is made of the results of treating incisional hernias with a new intra-abdominal low-density composite mesh through both the open and the laparoscopic approach. PATIENTS AND METHODS: A prospective analysis was made on the first 50 patients operated upon for incisional hernia through the open (n=20) or laparoscopic route (n=30), with intra-abdominal repair using the Proceed composite mesh, composed of low-density polypropylene and a hydrophilic antiadherent membrane of oxidized regenerated cellulose. RESULTS: There were no patient deaths. Reintervention proved necessary in one case due to hemoperitoneum caused by a trocar. The mean duration of stay was 3 days, and all patients recovered bowel transit within 24 hours. During follow-up there were no intra-abdominal complications associated with the use of the mesh (intestinal occlusion or subocclusion, prolonged ileus, infections, rejection, fistulas, or relapses). CONCLUSIONS: Incision hernia repair using the intra-abdominal low-density composite mesh is safe and well tolerated. Proceed mesh facilitates laparoscopic hernioplasty maneuvering.

The closure of oroantral communications with resorbable PLGA-coated beta-TCP root analogs, hemostatic gauze, or buccal flaps: a prospective study.

OBJECTIVE: The aim of this study was to compare the treatment of oroantral communications (OACs) with bioresorbable root analogs made of poly(lactide-co-glycolide) (PLGA)-coated beta-tricalcium phosphate (beta-TCP), hemostatic gauze or a buccal flap technique. STUDY DESIGN: In this prospective clinical study, 30 patients with oroantral communications were randomly assigned to a treatment. Clinical success, vestibular depth at the defect site, pain, and swelling were monitored. RESULTS: The OAC closure was successful in all cases. The vestibular depth stayed constant in the groups treated with the PLGA-beta-TCP composite or hemostatic gauze. In contrast, a vestibular depth reduction of 1.2 +/- 0.2 mm was observed in the buccal flap group, indicating atrophy of the alveolar ridge in these patients. Furthermore, pain and swelling were more pronounced in this group. CONCLUSION: Closures of OACs with PLGA-beta-TCP composite or hemostatic gauze are reliable minimally invasive methods that minimize atrophy of the alveolar ridge, swelling, and pain compared with a buccal flap technique.

Healing patterns of critical size bony defects in rat following bone graft.

PURPOSE: The aim of the present study was to evaluate the healing patterns of critical size calvarial bony defects treated with different bone substitutes and to compare them to an autogenous graft and an ungrafted control group. MATERIALS AND METHODS: Thirty-six Sprague-Dawley rats (200-230 g) were used. A periosteal flap was raised and an 8 mm defect was trephined. Rats were divided into six groups and treated as follows: group 1 was treated with a deproteinized bovine xenograft (XO), group 2 was treated with a bovine xenograft and covered with a resorbable membrane (XOCM), defects in group 3 were filled with a decalcified freeze-dried bone allograft (DFDBA), group 4 was treated with a composite bone substitute made of bovine xenograft and collagen (XOC), group 5 was filled with autogenous bone (AUTO), and group 6 was left untreated (control). The animals were euthanized at 2 months. RESULTS: Mean bone formation was 2.97 +/- 1.82 mm2 in group 5 (AUTO) followed by 2.93 +/- 1.93 mm2 in group 3 (DFDBA) and 2.25 +/- 1.94 mm2 in group 4 (XOC). Groups 1, 2, and 6 (XO, XOCM, and control, respectively) were not significantly different (p > 0.05) with a mean bone formation of 1.97 +/- 1.64, 1.87 +/- 1.07, and 1.85 +/- 1.04 mm2, respectively. CONCLUSIONS: This work confirmed the superiority of autogenous bone when it comes to bone grafting. Nevertheless, some bone substitutes can improve bone formation when compared to the control. New bone substitutes with growth factors to improve their abilities to induce bone formation should be experimented.

Non-hyaluronic acid fillers.

Fillers are numerous, and the products currently available have effects that may last from a few months to many years. These are used to treat facial wrinkles, and some of the new fillers exert a stimulatory effect, restoring volume in focal areas of the face by inducing collagen fibers. The dermasurgeon should thoroughly understand the indications and uses of these fillers to meet fully a patient's expectations. Some fillers are biodegradable (12-18 months), others slowly biodegradable (2-5 years), whereas others are permanent implants. The disadvantage of the traditional biodegradable fillers is their short duration (6-12 months). Over the past decade, semipermanent fillers (polylactic acid and ceramics) have been used: they do have a longer effect, but they might induce granulomas especially on the lips. Also, permanent fillers are traditionally linked to a higher incidence of granulomas and extrusions, although with the new formulations, the adverse events are decreased.

Medical devices; general and plastic surgery devices; classification of absorbable poly(hydroxybutyrate) surgical suture produced by recombinant DNA technology. Final rule.

The Food and Drug Administration (FDA) is classifying the absorbable poly(hydroxybutyrate) surgical suture produced by recombinant deoxyribonucleic acid (DNA) technology into class II (special controls). The special control that will apply to the device is the guidance document entitled "Class II Special Controls Guidance Document: Absorbable Poly(hydroxybutyrate) Surgical Suture Produced by Recombinant DNA Technology." The agency is classifying these devices into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of these devices. Elsewhere in this issue of the Federal Register, FDA is announcing the availability of the guidance document that will serve as the special control for this device.

[Results of treatment of orbital fractures with polydioxanone sheet]. / Ocena wyników leczenia zlaman oczodolów z uzyciem folii polidioksanowej.

UNLABELLED: Orbital fractures are one of the most frequent consequences following midfacial trauma. If not treated they can lead to serious optical complications as: double vision (diplopia), restriction of ocular motility, eyeball sinking (enophthalmos). Autogenic bone grafts although still wide and effectively used for reconstruction of the fractured orbital walls present some disadvantages. This is morbidity of the donor site, unforeseen resorption, time-consuming procedure and longer postoperative care. Because of that introduction of new materials for orbital reconstruction seems to be desirable. The aim of the work was to evaluate usefulness of the polydioxanone sheets (PDS) as a reconstructive material for orbital floor fractures. MATERIAL AND METHODS: From 1. 09. 2004 to 1. 02. 2006 111 patients with orbital fractures were treated in the Department of Maxillofacial Surgery Klinikum Minden. Age of the patients was between 15- 89 years (mean 43 y.); m:w ratio 78:33. There were 54 isolated orbital floor fractures (in 3 cases with additional medial wall fracture) and 57 zygomatico-orbito-maxillary fractures. The diagnosis was based on the clinical picture and coronal CT scans. The patients were operated through a transconjunctival (72%) or an infraorbital-Mustarde (28%) access and the orbital floor (medial orbital wall) was reconstructed with PDS sheet. Control examination was performed immediately, 1 moth and 6 months after the operative treatment. RESULTS: There were 47% true "blow-out", 34% "trap-door" and 19% "en-clapet" fractures. The most important preoperative symptom was double vision (23%), restriction of ocular motility (18%), enophthalmos (3,6%), impairment of function of the infraorbital nerve (41%). Size of the defect was 3+/-1,13 cm(2) in "blow out" fracture, 1,8 +/-0,9 cm(2) in "trap-door" and 2+/-0,5 cm(2) in ,"en-clapet" ones. The primary reconstruction was successful in 97,3% of the cases. Any inflammation or reaction against implant was noted. Persistent double vision was present in 2,7%, restriction of ocular motility in 1,8% and enophthalmos in 0,9% after the primary procedure. These patients were submitted to reoperation. In 1 case badly positioned PDS sheet causing diplopia was removed. In another one, eyeball movement restriction was due to adhesions between the sheet and periorbital tissue. Visual status of this patient has improved after adhesiolysis. In 1 patient with a large bony destruction reconstruction only with PDS sheet was an inadequate treatment. In 7,2% of patients disturbances in the field of innervation of the infraorbital nerve were present 6 months after the surgery. CONCLUSIONS: Alloplastic, resorbable PDS sheets in most cases were a valuable material for the reconstruction of the orbital floor (medial orbital wall). Mechanical properties of PDS seem to be not sufficient for the reconstruction of extremely large bony defects. In these cases use of autogenic bone grafts or a titanium mesh should be rather considered.

Selection of biomaterials for peripheral nerve regeneration using data from the nerve chamber model.

Peripheral nerve regeneration has been studied in a variety of animal models. Of these, the nerve chamber model has clearly dominated. It has been used to generate a large base of data that, however, cannot be analyzed usefully due to lack of standardization of experimental conditions and assays. Lack of standardization of critical experimental parameters of the model has, however, greatly limited the opportunity to compare directly data from independent investigators; as a result, progress in understanding conditions for optimal nerve regeneration has been stunted. In this article, we provide an overview of the major experimental parameters that must be controlled in order to generate data from independent investigators that can be compared directly (normalized data). Such parameters include the gap length, animal species, and the identity of assays used to evaluate the product of the regenerative process. Use of the recently introduced concept of critical axon elongation, the gap length at which the probability of axonal outgrowth (reinnervation) across the gap is 50%, leads to generation of a normalized database that includes data from several independent investigators. Conclusions are drawn about the relative efficacy of the various biomaterials and devices employed. Nerve chamber configurations that had the highest regenerative activity were those in which the tube wall comprised collagen and certain synthetic biodegradable polymers rather than silicone, and was cell-permeable rather than protein-permeable. In addition, the following tube fillings showed very high regenerative activity: suspensions of Schwann cells; a solution either of acidic or basic fibroblast growth factor; insoluble ECM substrates rather than solutions or gels; polyamide filaments oriented along the tube axis; highly porous, insoluble analogs of the ECM with specific structure and controlled degradation rate.