Peptide loaded polymeric nanoparticles by non-aqueous nanoprecipitation.

It is always a challenge to encapsulate water-soluble peptides in polymer nanoparticle (NP) systems. We establish and validate our newly developed non-aqueous nanoprecipitation method to encapsulate neuro-peptides drugs such as oxytocin and Luteinizing hormone-releasing hormone (LHRH) in poly(sebacic anhydride) (PSA) NPs. NPs were prepared by a solvent-antisolvent process under a strict anhydrous environment to obtain high drug loading and to avoid premature PSA degradation and drug release. Dynamic light scattering (DLS) and Scanning Electron Microscopy (SEM) reveal the size for both drug loaded PSA NPs to âˆ¼ 300 nm. The drug loaded NPs were dispersible and spherical in shape with uniform morphology. The in vitro release profile of oxytocin from PSA NPs occurs with the burst release of âˆ¼ 50% within the first hour in the aqueous release medium, whereas LHRH release is comparatively slow. Thus, looking into the fast degrading properties of PSA and drug release behavior, the developed NPs can be used for direct delivery of the neuropeptides to the olfactory epithelium using a refillable nasal atomizer that deposits mist onto the olfactory neuro-epithelium. We also applied our developed method to prepare NPs of poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), and poly(ε-caprolactone) (PCL). A Thyrotropin releasing hormone (TRH) was used as the sample neuropeptide drug to validate our non-aqueous method. The results reveal the formation of TRH loaded PLGA, PLA and PCL NPs with 100% drug loading. TEM analysis shows the formation of spherical NPs, having similar release properties as those of PSA NPs. Overall, we report that our developed method is suitable for co-encapsulating hydrophilic drugs in polymer NPs with high drug loading and release properties.

Biodegradable Breast Tissue Marker Clip.

Biodegradable soft tissue biopsy clips have been developed as implants with the potential to serve as visual markers for regions suspected to contain tumor growth in the breast. These clips are multidimensional tissue markers with better biocompatibility and imaging features. The clips were prepared using biodegradable polymers, poly(l-lactide-co-ε-caprolactone) and methoxy polyethylene glycol-co-l-lactide, that contain iodixanol or barium sulfate as contrast agents; they are further coated with hyaluronic acid or sodium alginate hydrogels. The clips were visible by imaging modalities such as mammography, ultrasound, and magnetic resonance imaging after implantation in Sprague-Dawley rats. The clips stayed intact in the implantation cavity of the animal for more than 3 months with unpretentious changes in their lengths and morphology. The histopathological examination of implanted clips revealed no signs of systemic toxicity in the rats. Overall, the interpretation of the results reveals that the developed clips can be a potential replacement for metal-based markers.

In vitro and in vivo degradation behavior and the long-term performance of biodegradable PLCL balloon implants.

Biodegradable poly(l-lactide-co-ε-caprolactone) (PLCL) are used to prepare inflatable balloon implants in treating rotator-cuff injuries and tissue separation. These balloon implants act as a temporary spacer for tissues, while reducing pain and allowing rehabilitation after surgery. It is essential to ensure that each balloon fulfill two requirements after implantation: (1) display a well-defined degradation profile, and (2) remain unaffected by premature rapture or leakage. Storage also affects the stability of a polymer-based implant. Since the balloons are implanted into humans, it is essential to understand their in vitro and in vivo degradation along with their physicochemical properties. It is unpredictable if balloon storage on their performance. Therefore, the in vitro and in vivo degradation behavior of PLCL balloons was examined during one year, and the information obtained was used to correlate reliability under prolonged storage conditions. We investigated changes in weight, melting temperature (Tm), molecular weight distribution (Mw, Mn and PDI), crystallinity (Χ), optical activity [α], and inherent viscosity (η) of the balloons during the entire degradation time. We also examined the molecular properties of the balloons under annealing and extreme temperature conditions, such as the combined effect of temperature and humidity that simulate various storage conditions. We have concluded that degradation of the PLCL balloons is slow, and they remain stable during the test period. Results reveal that the balloons retain their molecular properties under long-term storage, annealing, and extreme temperature conditions. The balloons did not show any variation from reference samples, and they exhibited a constant stability profile even after shelf-storage of more than 3 years. These findings can serve as a case study for evaluating various other biodegradable materials.

Effect of Ethylene Oxide and Gamma (γ-) Sterilization on the Properties of a PLCL Polymer Material in Balloon Implants.

Poly-l-lactide-co-ε-caprolactone (PLCL) is a unique polymer containing both polylactic acid and poly-ε-caprolactone (PCL) chain units, and thus it has better flexible and biodegradable properties. Based on these unique properties of PLCL, we have developed balloons that are now widely used in treating major medical problems [Biomaterials 2016, 105, 109-116]. One of the most important considerations needed for balloons is to ensure that the material properties remain similar after undergoing ethylene oxide (EtO) or gamma (γ-) sterilization treatments. From the biotechnological point of view, we focused on analyzing the vital molecular properties of the PLCL material after sterilization, such as changes in crystallinity, molecular weight distributions (M w, M n, and polydispersity index), and inherent viscosity (η). Analysis of the data reveals that EtO sterilization does not engender any change in crystallinity, melting temperature (T m), molecular weights, and η of the polymer. On the contrary, γ-radiations induce chain scission and consequential decrease of ∼33 and ∼15% in molecular weights and η values, respectively. Based on our observations, we recommend EtO sterilization instead of γ-radiation for PLCL. This ensures prolonged stability of the polymer against degradation in a biological environment, long-shelf life, and absolute assurance that balloon failures do not occur after implantation.

Biodegradable implantable balloons: Mechanical stability under physiological conditions.

Rotator cuff tendons injuries occurs as a result of trauma, e.g. due to falling, mechanical injuries and frequent overhead activity and as natural degenerative tears in elderly people. Biodegradable balloon shaped spacer of Poly-(L-lactide-co-ε-caprolactone) (PLCL) are applied in the treatment of these injuries. This type of treatment involves insertion of inflated biodegradable implant into the tissues of the damaged region in the shoulder to avoid shoulder impingement and reduce friction between the acromion and the humeral head and propagation of inflammation. The implant must maintain integrity under significant mechanical loading in order to remain effective. However, with time, the implant is exposed to the risk of failure due to the high pressure caused by the muscular motion and the friction with the bones. We report in this study the limits of the mechanical stability of the PLCL balloon shape spacer (implant) under prolonged cyclic loading, so as to be able to predict their physical stability in vivo. We have demonstrated in an in vitro settings that the implant withstands fatigue cycles for significantly longer than 8 weeks, which provides sufficient time window for patients to perform substantial rehabilitation and recover from an injury. The data presented herein is expected to assist medical practitioners in safety and efficacy measurements and assessment following spacer implantation.

Stable polyanhydride synthesized from sebacic acid and ricinoleic acid.

Poly(anhydride) are unstable and prone to hydrolytic degradation and depolymerisation via anhydride interchange. They are stored at -20°C, packed under inert atmosphere until use. We synthesized a new poly(anhydride) from ricinoleic (RA) and sebacic (SA) acid with alternating ester-anhydride structure that is stable at 25°C for over 18months. The copolymer is also stable in chloroform solution and under γ-irradiation. The polymer hydrolyses through anhydride cleavage lasting ~7days to form oligoesters, which are stable for >30days. The release of gentamycin from the synthesized alternate polymer matrix is sustained compared to the random copolymer.

Biodegradable inflatable balloons for tissue separation.

Confining radiation to a specific region (during radiation therapy) minimizes damage to surrounding tissues. Biodegradable inflatable balloons (bio-balloons) were developed. The device protects the normal tissues by increasing the gap between radiation source and critical structures. The radiation fades away while passing through the inflated balloon preventing the surrounding tissues from harmful radiation. These bio-balloons have also found clinical use to treat massive rotator cuff tear. This review summarizes the chemistry, engineering, and clinical development of these biomedical devices. These balloons are made of biodegradable polymers folded into the edge of a trocar and inserted between the tissues to be separated, and inflated by normal saline in the site of the application. The inserted balloon protects the tissues from radiation or mechanical stress. They remain inflated on site for two months and are finally eliminated within 12 months.

Alternating Poly(ester-anhydride) by Insertion Polycondensation.

We report on a synthetic method where polyanhydride is used as starting material and the ester monomers are inserted through complete esterification, leading to an alternating ester-anhydride copolymer. The molar ratio of ricinoleic acid (RA) and sebacic acid (SA) was optimized until polysebacic acid is completely converted to carboxylic acid-terminated RA-SA and RA-SA-RA ester-dicarboxylic acids. These dimers and trimers were activated with acetic anhydride, polymerized under heat and vacuum to yield alternating RA-SA copolymer. The resulting alternating poly(ester-anhydride) have the RA at regular intervals. The regular occurrences of RA side chains prevent anhydride interchange, enhancing hydrolytic stability, which allows storage of the polymer at room temperature.

Biocompatibility and safety of PLA and its copolymers.

PLA and its copolymers are commonly used for a wide variety of applications. While they are considered to be biocompatible, side effects resulting from their implantation have been reported. The implantation of biomaterials always results in a foreign body reaction. Such a reaction has also been reported following PLA and its copolymers. This article reviews the process of inflammatory reaction that is to be expected following implantation of PLA, and it highlights specific cases in which the inflammatory reaction can result in safety concerns. The authors also review selected cases from different medical fields to demonstrate possible clinical side effects resulting from its use.

Castor Oil-Based Biodegradable Polyesters.

This Review compiles the synthesis, physical properties, and biomedical applications for the polyesters based on castor oil and ricinoleic acid. Castor oil has been known for its medicinal value since ancient times. It contains ∼90% ricinoleic acid, which enables direct chemical transformation into polyesters without interference of other fatty acids. The presence of ricinoleic acid (hydroxyl containing fatty acid) enables synthesis of various polyester/anhydrides. In addition, castor oil contains a cis-double bond that can be hydrogenated, oxidized, halogenated, and polymerized. Castor oil is obtained pure in large quantities from natural sources; it is safe and biocompatible.

In vivo degradation and elimination of injectable ricinoleic acid-based poly(ester-anhydride).

The in vivo degradation and elimination after subcutaneous implantation of injectable p(SA-RA) 3:7 copolymer in rats, followed by characterization of the polymer matrix composition during hydrolysis and erosion, is reported. Major chemical changes were observed during the first few days post implantation, the anhydride bonds hydrolyzed along with about 45% weight loss and a significant decrease in the molecular weight. 1H NMR spectral analysis was used to determine the structures and content of ricinoleic acid containing oligomeric chains present in the degraded polymer. The polymer degrades into ester oligomers of 2-4 ricinoleic acid units which further degrade to ricinoleic acid, a natural fatty acid. The polymer hydrolytic degradation process fit the in vitro degradation process.