Polycaprolactone Implants Research Articles

Evaluating the Mechanical Strength of Three Dimensionally (3D) Printed Implants in Septorhinoplasty through Finite Element Analysis (FEA).

Autologous nasoseptal cartilage grafts are used to correct nasal asymmetry and deviation in rhinoplasty, but patients who have undergone multiple surgeries may have limited autologous cartilage tissue available. 3D-printed L-strut implants may address these challenges in the future, but their mechanical strength is understudied. Silk fibroin-gelatin (SFG), polycaprolactone (PCL), and polylactide (PLA) are bio-inks known for their strength. We present Finite Element Analysis (FEA) models comparing the mechanical strength of 3D-printed SFG, PCL, and PLA implants with nasoseptal cartilage grafts when autologous or allografts are not available. FEA models compared the stress and deformation responses of 3D-printed solid and scaffold implant replacements to cartilage. To simulate a daily force from overlying soft tissue, a unidirectional load was applied at the "keystone" region given its structural role and compared with native cartilaginous properties. 3D-printed solid SFG, PCL, and PLA and scaffold PCL and PLA models demonstrated lower deformations compared to cartilage. Solid SFG balanced strength and flexibility. The maximum stress was below all materials' yield stresses suggesting their deformations are unlikely permanent under a daily load. Our FEA models suggest that 3D-printed L-strut implants carry promising mechanical strength. Solid SFG's results mimicked cartilage's mechanical behavior. Thus, scaffold SFG merits further geometric optimization for potential use for cartilage substitution. 3D-printed septal cartilage replacement implants can potentially enhance surgical management of patients who lack available donor cartilage in select settings. Computational simulations can evaluate 3D-printed implant strength and their potential to replace septal cartilage in septorhinoplasty.

Tibial lengthening over a bioactive degradable intramedullary implant: a case report

Introduction Long duration of distraction osteosynthesis remains an unsolved problem. One of the promising ways to stimulate reparative regeneration of bone tissue is the technology of combined osteosynthesis with intramedullary elastic reinforcement with titanium wires coated with hydroxyapatite. A significant drawback of this combined distraction osteosynthesis is the planned removal of intramedullary wires several months after disassembling the Ilizarov apparatus.The purpose of this work is to demonstrate the possibility of stimulating reparative regeneration and reducing the duration of distraction osteosynthesis using an intramedullary degradable implant with bioactive filling.Methods We present the first in clinical practice case of surgical leg lengthening in a female 10-year-old patient using the Ilizarov apparatus an intramedullary degradable implant made of polycaprolactone (PCL) saturated with hydroxyapatite to stimulate reparative regeneration in the tibia. Monthly radiographic monitoring of the process of reparative regeneration of bone tissue was supplemented by computed tomography after disassembling the Ilizarov apparatus.Results The process of lengthening the tibia was accompanied by pronounced formation of a bone “sleeve” around the implant, which was directly connected to the endosteum of the tibia. The density of bone substance in the medullary canal reached 496.6 HU. The cortical layer of the tibia in the elongation zone increased to 4 mm, and its density was equal to 1288.8 HU.Discussion Leg lengthening of 4 cm was achieved along with simultaneous correction of valgus recurvatum bone deformity at IO = 15 days/cm, that is two times shorter than the generally accepted excellent IO in distraction osteosynthesis according to Ilizarov.Conclusions Biodegradable polycaprolactone implants saturated with hydroxyapatite might be not inferior to titanium wires coated with hydroxyapatite in regard to the degree of osteoinduction and do not require repeated surgical intervention to remove them.

3D-Printed Polycaprolactone Implants Modified with Bioglass and Zn-Doped Bioglass.

In this work, composite filaments in the form of sticks and 3D-printed scaffolds were investigated as a future component of an osteochondral implant. The first part of the work focused on the development of a filament modified with bioglass (BG) and Zn-doped BG obtained by injection molding. The main outcome was the manufacture of bioactive, strong, and flexible filament sticks of the required length, diameter, and properties. Then, sticks were used for scaffold production. We investigated the effect of bioglass addition on the samples mechanical and biological properties. The samples were analyzed by scanning electron microscopy, optical microscopy, infrared spectroscopy, and microtomography. The effect of bioglass addition on changes in the SBF mineralization process and cell morphology was evaluated. The presence of a spatial microstructure within the scaffolds affects their mechanical properties by reducing them. The tensile strength of the scaffolds compared to filaments was lower by 58-61%. In vitro mineralization experiments showed that apatite formed on scaffolds modified with BG after 7 days of immersion in SBF. Scaffold with Zn-doped BG showed a retarded apatite formation. Innovative 3D-printing filaments containing bioglasses have been successfully applied to print bioactive scaffolds with the surface suitable for cell attachment and proliferation.

Modulating Myofibroblastic Differentiation of Fibroblasts through Actin-MRTF Signaling Axis by Micropatterned Surfaces for Suppressed Implant-Induced Fibrosis.

Myofibroblasts, the primary effector cells for implant-induced fibrosis, contribute to this process by secreting excessive collagen-rich matrix and contracting. Thus, approaches that suppress myofibroblasts may achieve desirable suppression effects in the fibrotic process. As one of the important physical properties of materials, material topographical structures have been proven to affect various aspects of cell behaviors, so is it possible to manipulate the formation of myofibroblasts by tailoring the topographical properties of medical devices? In this study, polycaprolactone (PCL) surfaces with typical micropatterns (micro column and micro pit) were fabricated. The regulatory effects of surface micropatterns on the myofibroblastic differentiation of fibroblasts were investigated. Compared to the flat surfaces and surfaces with micro pit, surfaces with micro columns triggered the F- to G-actin transition, inhibiting the nuclear transfer of myocardin-related transcription factor-A. Subsequently, the downstream gene α-smooth muscle actin, which is a marker of myofibroblasts, was suppressed. Further in vivo investigation showed that PCL implants with micro-column-patterned surfaces inhibited the formation of peri-implant fibrotic capsules. Our results demonstrate that surface topographical properties are a potent regulator of fibroblast differentiation into myofibroblasts and highlight the antifibrotic potential of modifying surfaces with micro-column patterns.

Cranioplasty Using Three-Dimensional-Printed Polycaprolactone Implant and Free Latissimus Dorsi Musculocutaneous Flap in a Patient with Repeated Wound Problem following Titanium Cranioplasty.

Titanium mesh is an alloplastic material widely used for the reconstruction of moderate-to-large skull defects. Repeated wound problems or infection following these reconstructions inevitably lead to the replacement of the cranioplasty material. Among the various alloplastic materials, polycaprolactone implants are usually used for the coverage of small defects such as burr holes. 1 Herein, we present a case of a large cranial defect successfully reconstructed with three-dimensional-printed polycaprolactone implant and a free latissimus dorsi musculocutaneous flap. Until 1-year follow-up, the patient showed a favorable esthetic outcome with no complications or wound relapse.

Safety and efficacy of a biodegradable implant releasing tenofovir alafenamide for vaginal protection in a macaque model.

To advance the initiative of ending the global epidemic, long-lasting HIV protection is needed through sustained release of antiretroviral drugs for months to years. We investigated in macaques the safety and efficacy of biodegradable polycaprolactone implants releasing tenofovir alafenamide for HIV pre-exposure prophylaxis (PrEP). Implants were administered subcutaneously in the arm using a contraceptive trocar. Efficacy against vaginal simian-HIV (SHIV) infection was investigated in six pigtailed macaques that received two tenofovir alafenamide implants (0.35 mg/day), one in each arm, for a total release rate of tenofovir alafenamide at 0.7 mg/day. Macaques were exposed to SHIV twice weekly for 6 weeks. Statistical analyses were used to compare outcome with eight untreated controls. Histological assessments were performed on skin biopsies collected near implantation sites. Median (range) tenofovir diphosphate level in PBMCs was 1519 (1068-1898) fmol/106 cells. All macaques with tenofovir alafenamide implants were protected against vaginal SHIV infection. In contrast, 7/8 controls were infected after a median of 4 SHIV exposures (P = 0.0047). Histological assessment of tissues near tenofovir alafenamide implant sites showed inflammation and necrosis in 5/6 animals, which were not evident by visual inspection. We demonstrated complete protection against vaginal SHIV infection with two implants releasing a total of 0.7 mg of tenofovir alafenamide per day. We also identified tenofovir diphosphate concentrations in PBMCs associated with complete vaginal protection. Consistent with previous findings, we observed adverse local toxicity and necrosis near the tenofovir alafenamide implant site. Improved tenofovir alafenamide implants that are safe and maintain high efficacy have the potential to provide long-lasting protection against vaginal HIV infection.

Biodegradable implants for orbital wall fracture reconstruction.

BackgroundDue to the different handling properties of unsintered hydroxyapatite particles/poly-L-lactic acid (uHA/PLLA) and polycaprolactone (PCL), we compared the surgical outcomes and the postoperative implantation accuracy between uHA/PLLA and PCL meshes in orbital fracture repair.MethodsPatients undergoing orbital wall reconstruction with PCL and uHA/PLLA mesh, between 2017 and 2019, were investigated retrospectively. The anatomical accuracy of the implant in bony defect replacement and the functional outcomes such as diplopia, ocular motility, and enophthalmos were evaluated.ResultsNo restriction of eye movement was reported in any patient (n=30 for each group), 6 months postoperatively. In the PCL group, no patient showed diplopia or enophthalmos, while the uHA/PLLA group showed two patients with diplopia and one with enophthalmos. Excellent anatomical accuracy of implants was observed in 27 and 22 patients of the PCL and uHA/PLLA groups, respectively. However, this study showed that there were neither any significant differences in the surgical outcomes like diplopia and enophthalmos nor any complications with the two well-known implants.ConclusionPCL implants and uHA/PLLA implants are safe and have similar levels of complications and surgical outcomes in orbital wall reconstruction.

Cranial Reconstruction Using a Polycaprolactone Implant After Burr Hole Trephination

Aim: This retrospective study evaluated the safety of using polycaprolactone (PCL) burr hole covers over a 10-year period. Materials & methods: Patients with PCL burr hole cover implants inserted between 1 April 2006 and 31 September 2015 were identified and included in this study. Burr hole covers were used in surgery for chronic subdural hematoma, hydrocephalus and tumor biopsy. Results: 174 patients with a total of 275 implants inserted were included in the study. Overall, the use of PCL implants was safe and did not increase the rate of surgical complications. The radiology study of two cases and histology study of a removed PCL implant demonstrated evidence of soft tissue regeneration. Conclusion: PCL burr hole covers demonstrated safety in use for craniotomy burr hole reconstruction.

Bridging the gap: Using 3D printed polycaprolactone implants to reconstruct circumferential tracheal defects in rabbits.

1) To assess the feasibility of reconstructing 2-cm-long circumferential tracheal defects with a 3D printed polycaprolactone (PCL) implant in rabbits. 2) To evaluate endoscopic, histologic, and functional characteristics of a PCL tracheal implant over time. Ten New Zealand rabbits were included in this study. A 2-cm-long 3D printed PCL tracheal implant was created. All rabbits underwent surgical excision of a 2-cm-long cm segment of cervical trachea, which was reconstructed with the implant. Rabbits were sacrificed at the following time points: 0, 4, 5, 6, and 7 weeks postoperatively. At these time points, a rigid bronchoscopy was performed, and blinded evaluators calculated the percentage of airway stenosis. The tracheas were then harvested and prepared for histologic analysis. All rabbits survived to their date of sacrifice except for one. Rabbits were euthanized between 0 to 54 days postoperatively with a median of 30 days. All rabbits developed significant granulation tissue with an average percentage stenosis of 92.3% ± 6.1%. On histology, granulation was present with extensive neovascularization and mixed inflammatory cells. There was re-epithelialization present on the luminal surface of the PCL implant near the anastomoses but absent at the center of the implant. This study demonstrates that our 2-cm-long 3D printed PCL tracheal implant can be used to reconstruct a tracheal defect of equivalent size in a New Zealand rabbit model in the short term. However, significant granulation tissue formation limits long-term survival. Further research is warranted to limit the granulation tissue overgrowth. NA Laryngoscope, 2019.

Efficacy of eluted antibiotics through 3D printed femoral implants.

Costs associated with musculoskeletal diseases in the United States account for 5.7% of the Gross Domestic Product (GDP) (Weinstein et al. 2018). As such, there is a need to pursue new ideas in orthopaedic implants that can decrease cost and improve patient care. In the recent years, 3D printing of polymers using Fused Deposition Modeling (FDM) and metals using Direct Metal Laser Sintering (DMLS) has opened several exciting possibilities to create customized orthopaedic implants. Such implants can be engineered to release antibiotics in a controlled manner by infusing the drug into the material during manufacturing stage. However, the prevalence of high temperature could impact the anti-bacterial effectiveness of the eluted antibiotics in such implants. An alternative approach to circumvent this issue would be to modify the implant geometry to incorporate built-in design features such as micro-channels and reservoirs in which antibiotics can be introduced prior to the surgical procedure. Irrespective of the approach used, the ability of 3D printed orthopaedic implants to elute antibiotics, and the rate of elution are not well understood. The purpose of this article is to study the elution of doxycycline through 3D printed femoral implants using three different materials: Poly-Lactic Acid (PLA), Poly-Caprolactone (PCL) and Titanium grade Ti-6Al-4V. The PLA and Ti-6Al-4V implants were designed with built-in reservoirs and micro-channels in which doxycycline was introduced post the manufacturing stage. However, the PCL implants were printed from a PCL spool that was infused with doxycycline using an extruder. The PLA and Ti-6Al-4V experiments were run for a period of 31 days and the PCL experiment for one day. The antibacterial ability of eluted doxycycline from all implants were examined using Kirby-Bauer test on the bacteria E.coli k-12. The results show that most of doxycycline eluted through the three materials in the first 24 hours. After the initial spike, a steady release was achieved for the PLA and Ti-6Al-4V implants for 30 days. During this timeframe, Ti-6Al-4V implants released more doxycycline than the PLA implant. The eluted antibiotics through all the implants demonstrated the ability to kill bacteria in the subsequent Kirby-Bauer test. These outcomes show that irrespective of how the antibiotics were introduced, 3D printed polymeric and metallic implants have great potential in orthopaedic applications.

New application of three-dimensional printing biomaterial in nasal reconstruction.

Polycaprolactone (PCL) is an U.S. Food and Drug Administration-approved synthetic biodegradable polymer and is easily fabricated into three-dimensional (3D) structures. In this study, the 3D-printed PCL implant for nasal augmentation was further evaluated for its suitability for nasal surgeries such as septoplasty and rhinoplasty. Ten New Zealand White rabbits were included and divided into study and sham groups (7 and 3, respectively). A lateral incision was made on the nasal dorsum and a pocket formed in the subperichondrial plane between the upper lateral cartilage and nasal septum. Polycaprolactone was fabricated based on 3D printing technology into a 0.8 × 0.8-cm rectangular shape for use as a nasal implant. The material was inserted as a septal extension graft and sutured with alar cartilage for nasal reshaping. The implants were harvested 4, 8, and 12 weeks after implantation and evaluated by gross morphological assessment and histological examination. The initial shape of the implant was unchanged in all cases, and no definitive postoperative complications were seen over the 3-month period. Gross morphological evaluation confirmed that implants remained in their initial location without migration or extrusion. Histologic evaluations showed that the implant architectures were maintained with excellent fibrovascular ingrowth and minimal inflammatory reactions. Polycaprolactone can be used for nasal reconstruction such as nasal augmentation. Polycaprolactone is easy to work with and will avoid the increased operative time and morbidity associated with autograft harvesting. Therefore, PCL implants designed by 3D printing can serve as clinically biocompatible materials in craniofacial reconstruction in the future. NA. Laryngoscope, 127:1036-1043, 2017.

Integrating Image-Based Design and 3D Biomaterial Printing to create Patient Specific Devices within a Design Control Framework for Clinical Translation.

Despite significant advances in 3D biomaterial printing, the potential of 3D printing for patient specific implants and tissue reconstruction has not been fully exploited. This is due in part to the lack of integration of image-based patient specific design with 3D biomaterial printing within a relevant regulatory framework, namely design control, required by the FDA. In this manuscript, we describe the integration of image-based, multi-scale patient specific design with 3D biomaterial printing within a design control framework for clinical translation. Specifically, we define design inputs for patient specific implants and scaffolds, and utilize image-based patient specific design to achieve these design inputs. We then illustrate realization of these topology designed patient specific implants by laser sintering of polycaprolactone (PCL). Finally, we present initial results in large animal models using 3D printed PCL implants addressing two challenging problems in tissue reconstruction: 1) designing and 3D printing implantable devices to allow growth in pediatric airway applications and 2) utilizing 3D printed scaffolds as foundations for pre-fabricated flaps to obtain vascularization and bone formation for large volume bone/soft tissue reconstruction. We illustrate these challenging problems as they need to be incorporated in design control, but as of yet there is little data to direct how growth and vascularization should be utilized in design control.

SLM produced porous titanium implant improvements for enhanced vascularization and osteoblast seeding.

To improve well-known titanium implants, pores can be used for increasing bone formation and close bone-implant interface. Selective Laser Melting (SLM) enables the production of any geometry and was used for implant production with 250-µm pore size. The used pore size supports vessel ingrowth, as bone formation is strongly dependent on fast vascularization. Additionally, proangiogenic factors promote implant vascularization. To functionalize the titanium with proangiogenic factors, polycaprolactone (PCL) coating can be used. The following proangiogenic factors were examined: vascular endothelial growth factor (VEGF), high mobility group box 1 (HMGB1) and chemokine (C-X-C motif) ligand 12 (CXCL12). As different surfaces lead to different cell reactions, titanium and PCL coating were compared. The growing into the porous titanium structure of primary osteoblasts was examined by cross sections. Primary osteoblasts seeded on the different surfaces were compared using Live Cell Imaging (LCI). Cross sections showed cells had proliferated, but not migrated after seven days. Although the cell count was lower on titanium PCL implants in LCI, the cell count and cell spreading area development showed promising results for titanium PCL implants. HMGB1 showed the highest migration capacity for stimulating the endothelial cell line. Future perspective would be the incorporation of HMGB1 into PCL polymer for the realization of a slow factor release.

Multi-layer polymeric implants for sustained release of chemopreventives

Poor oral bioavailability limits the use of many chemopreventives in the prevention and treatment of cancer. To overcome this limitation, we report an improvised implant formulation (“coated” implants) using curcumin, individual curcuminoids, withaferin A and oltipraz. This method involves the coating of blank polycaprolactone implants with 20–30 layers of 10–20% polycaprolactone solution in dichloromethane containing 0.5–2% of the test agent. The in vitro release showed that while oltipraz was released with almost zero-order kinetics over 8weeks, curcumin, individual curcuminoids and withaferin A were released with some initial burst. The in vivo release was determined by grafting implants subcutaneously in A/J mice. When delivered by coated implants, oltipraz significantly diminished lung DNA adducts in mice treated with dibenzo[a,l]pyrene compared with sham treatment (28±7 versus 54±17 adducts/109 nucleotides). Withaferin A also diminished DNA adducts, but it was insignificant. Curcumin and individual curcuminoids were ineffective. Analysis of lung, liver and brain by UPLC-fluorescence showed the presence of the three test curcuminoids indicating effectiveness of the implant delivery system. Further, based on its known antitumor activity in vivo, withaferin A given via the implants significantly inhibited human lung cancer A549 xenograft in athymic nude mice, while it was ineffective when the same total dose was administered i.p. and required over 2-fold higher dose to elicit effectiveness. Together, our data suggest that coated polymeric implants can accommodate heat-labile compounds, can furnish sustained release for long duration, and elicit DNA damage-inhibiting and anti-tumor activities.

Controlled-release systemic delivery - a new concept in cancer chemoprevention

Many chemopreventive agents have encountered bioavailability issues in pre-clinical/clinical studies despite high oral doses. We report here a new concept utilizing polycaprolactone implants embedded with test compounds to obtain controlled systemic delivery, circumventing oral bioavailability issues and reducing the total administered dose. Compounds were released from the implants in vitro dose dependently and for long durations (months), which correlated with in vivo release. Polymeric implants of curcumin significantly inhibited tissue DNA adducts following the treatment of rats with benzo[a]pyrene, with the total administered dose being substantially lower than typical oral doses. A comparison of bioavailability of curcumin given by implants showed significantly higher levels of curcumin in the plasma, liver and brain 30 days after treatment compared with the dietary route. Withaferin A implants resulted in a nearly 60% inhibition of lung cancer A549 cell xenografts, but no inhibition occurred when the same total dose was administered intraperitoneally. More than 15 phytochemicals have been tested successfully by this formulation. Together, our data indicate that this novel implant-delivery system circumvents oral bioavailability issues, provides continuous delivery for long durations and lowers the total administered dose, eliciting both chemopreventive/chemotherapeutic activities. This would also allow the assessment of activity of minor constituents and synthetic metabolites, which otherwise remain uninvestigated in vivo.

Abstract 2883: Enhanced anti-tumor activity and bioavailability of chemopreventives by coated polymeric implants

Abstract Poor oral bioavailability limits the use of many chemopreventives in the prevention and treatment of cancer. We previously reported a novel concept in which polycaprolactone (PCL) implants embedded with test agents provide sustained delivery for long duration (months to >1year), reduce effective dose substantially and increase bioavailability. While tested successfully for various agents, this formulation results in an initial burst release and does not apply to heat-labile compounds. Furthermore, it takes 2 or more years for the polymeric implant to biodegrade. To overcome these limitations, we hypothesized that formulation of low mol wt polymeric implants will provide more sustained and higher release compared with higher mol. wt polymers; the low mol. wt polymers are also expected to biodegrade in weeks to months. To test part of this hypothesis, we used three different mol wt PCL polymers and two co-polymers, poly(D, L-lactide-co-glycolide) (PLGA). The method involves i) preparation of blank PCL implants (1.4 mm dia), and ii) coating of 30-40 layers by dipping blank implants, with intermittent drying, in 10-20% of different mol wt PCL solutions in dichloromethane containing 10% curcumin in tetrahydrofuran. The curcumin implants when tested for in vitro release showed that i) the burst release effect and the amount released varied with mol wt of the polymer. Implants prepared with PCL of 3,600 mol wt (PCL-3.6K) did not show any burst release phenomenon. Instead, these implants took nearly 7 days to render maximum daily release and thereafter the rate of release declined gradually over a period of two weeks. Implants prepared from higher mol wt polymers (PCL-31K and PCL-112K) were accompanied with some initial burst release and the rate of release declined gradually. Cumulative release measured over two weeks was found to be inversely proportional to the mol wt of PCL: PCL-3.6K (30%) > PCL-31K (24%) > PCL-112K (21%). On the other hand, the co-polymers, PLGA (50:50) and PLGA (75:25) showed only 1% and 0.5% total release, respectively. To determine if the implant delivery reduced the effective dose in a tumor model, nude mice were inoculated with human lung cancer (A549) cells and then treated with coated implants of withaferin A, a potent triterpenoid isolated from the traditional Ayurvedic herb “Ashwagandha”. Withaferin A given via the coated implants significantly inhibited (>50%) human lung cancer (A549) xenograft, while it was ineffective when the same dose was administered i.p. Together, our data suggest that coated implants of low mol wt PCL can accommodate heat-labile compounds, enhance bioavailability, furnish more sustained and higher cumulative release, and elicits anti-tumor activity. Our ultimate goal is to use low mol polymeric implants that will biodegrade in few months and provide continuous release of the drug. (Supported from CA-118114, KLCRP and Duggan Endowment). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2883. doi:1538-7445.AM2012-2883

Development and validation of a High Performance Liquid Chromatographic method for determination of etoposide in biodegradable polymeric implants

A method using HPLC-UV was developed and validated for the determination of etoposide incorporated into polycaprolactone implants. The method was carried out in isocratic mode using a C18 column (250 x 4.6 mm; 5 µm), at 25 ºC, with acetonitrile and acetic acid 4% (70:30) as mobile phase, a flow rate of 2 mL/min, and UV detection at 285 nm. The method was linear (r² > 0.99) over the range of 5 to 65 µg/mL, precise (RSD < 5%), accurate (recovery of 98.7%), robust, selective regarding excipient of the sample, and had a quantitation limit equal to 1.76 µg/mL. The validated method can be successfully employed for routine quality control analyses.

Curcumin implants for continuous systemic delivery: safety and biocompatibility.

Curcumin, an anti-oxidant, anti-inflammatory, and anti-neoplastic agent, exhibited limited oral efficacy due to its poor bioavailability. To overcome this limitation, polymeric implants for continuous systemic delivery of curcumin were developed and tested for their safety and biocompatibility. Two 2-cm polycaprolactone implants containing polyethylene glycol and 20% (w/w) curcumin were grafted subcutaneously at the back of the Augustus Copenhagen Irish rats. Rats were euthanized and blood was analyzed for various hematological parameters; biochemical markers of liver/kidney function and local tissues were analyzed for local inflammatory reactions. Curcumin implants exhibited biphasic release kinetics with ∼3.6 + 0.8, 5.8 ± 1.1, 13.1 ± 2.1, 21.8 ± 0.3, 38.1 ± 0.6, and 47.2 ± 1.6mg cumulative curcumin being released from both the implants after 1, 4, 12, 25, and 90days. No significant differences in various hematological parameters (like white blood cells, red blood cells, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin), liver enzymes (like aspartate transaminase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, amylase, or lipase), or biochemical parameters of kidney function (like blood urea nitrogen, creatinine, Ca(2+), Na(+), and Cl(-) levels) were observed at any of these time points. However, a significant increase in serum phosphorus levels was observed at all the time points in sham implants as well as in curcumin diet and implant groups. Local implantation site showed foreign body granulomatous reaction with influx of histiocytes and occasional multi-nucleated giant cells with sham implants and was minimal around the curcumin implants. These polymeric implants were found to have little or no systemic toxicity with an acute reaction at local site which was reduced significantly by curcumin implants.

Sustained Systemic Delivery of Green Tea Polyphenols by Polymeric Implants Significantly Diminishes Benzo[a]pyrene-Induced DNA Adducts

The polyphenolics in green tea are believed to be the bioactive components. However, poor bioavailability following ingestion limits their efficacy in vivo. In this study, polyphenon E (poly E), a standardized green tea extract, was administered by sustained-release polycaprolactone implants (two, 2-cm implants; 20% drug load) grafted subcutaneously or via drinking water (0.8% w/v) to female S/D rats. Animals were treated with continuous low dose of benzo[a]pyrene (BP) via subcutaneous polymeric implants (2 cm; 10% load) and euthanized after 1 and 4 weeks. Analysis of lung DNA by (32)P-postlabeling resulted in a statistically significant reduction (50%; p = 0.023) of BP-induced DNA adducts in the implant group; however, only a modest (34%) but statistically insignificant reduction occurred in the drinking water group at 1 week. The implant delivery system also showed significant reduction (35%; p = 0.044) of the known BP diolepoxide-derived DNA adduct after 4 weeks. Notably, the total dose of poly E administered was >100-fold lower in the implant group than the drinking water group (15.7 versus 1,632 mg, respectively). Analysis of selected phase I, phase II, and nucleotide excision repair enzymes at both mRNA and protein levels showed no significant modulation by poly E, suggesting that the reduction in the BP-induced DNA adducts occurred presumably due to known scavenging of the antidiolepoxide of BP by the poly E catechins. In conclusion, our study demonstrated that sustained systemic delivery of poly E significantly reduced BP-induced DNA adducts in spite of its poor bioavailability following oral administration.

Abstract 4603: Bioavailability of ellagic acid/ellagitannins from black raspberry and pomegranate

Abstract Chemoprevention by polyphenolics in fruits, particularly in berries and pomegranate, is gaining increased attention. To determine bioavailability of ellagic acid/ ellagitannins, first, we fed ACI rats with dietary black raspberry powder (5% w/w; 75 ppm ellagic acid in diet). Analysis of plasma samples by solvent extractions and HPLC showed that the levels of ellagic acid in plasma had plateaued at 3 weeks: 399 ± 85, 249 ± 98 and 344 ± 23 ng/ml at 3, 12 and 28 weeks, respectively. In the second study, we fed ACI rats with ellagic acid at 400 ppm in diet. In order to increase bioavailability, we also delivered ellagic acid systemically by subcutaneous silastic implants. The circulating levels of ellagic acid were found to plateaue at 8 weeks in the experimental diet group: 1,167 ± 171, 1,458 ± 302 and 1,272 ± 192 ng/ml at 8, 16 and 28 weeks, respectively. The ellagic acid levels, however, continued to increase when delivered by silastic implants: 53 ± 15, 130 ± 30 and 185 ± 72 ng/ml at 8, 16 and 28 weeks, respectively. Notably, it required nearly 130-fold higher dose via diet (4 mg/day) compared with implant route (0.03 mg/day) to achieve nearly 7-fold higher plasma ellagic acid levels. The oral bioavailability of ellagic acid was estimated at only 0.2%, whereas over 5% was bioavailable when administered by sustained systemic delivery. To determine if oral bioavailability of ellagic acid can be increased by administering it in the form of ellagitannins, tissues were taken from another study where female S/D rats were fed diet supplemented with equimolar doses of punicalagins (1,500 ppm) or ellagic acid (430 ppm) and treated with benzo[a]pyrene. Groups of animals were also administered punicalagins and ellagic acid via subcutaneous polycaprolactone implants (20% and 10% load, respectively). Punicalagins were undetectable by either route of administration, but its break down product ellagic acid was detected in the plasma. Dietary administration of punicalagins (17 mg/day) resulted in plasma ellagic acid levels of 3.84 ± 1.37 ng/ml corresponding to only slight (&amp;lt;0.0002%) bioavailability. On the other hand, the polycaprolactone implant delivery (570 µg/day) resulted in &amp;gt;150-fold higher plasma ellagic acid levels (589 ± 78 ng/ml), resulting in much higher bioavailability (0.85%). Ellagic acid administration via the diet (5 mg/day) and polycaprolactone implants (about 0.16 mg/day) showed 317 ± 39 and 673 ± 101 ng/ml plasma ellagic acid, respectively. In conclusion, i) when administered via the diet either as pure compound or as a component of black raspberry, there was no significant difference in the bioavailability of ellagic acid; however sustained, systemic delivery enhanced the bioavailability of ellagic acid by 25-fold; and ii) oral bioavailability of ellagic acid when administered as free ellagic acid was much higher than when administered as ellagitannins. (USPHS CA-18114 (RCG), CA-143676 (MVV) and the Duggan Endowment (RCG)). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4603. doi:10.1158/1538-7445.AM2011-4603