Genipin crosslinker releasing sutures for improving the mechanical/repair strength of damaged connective tissue.

The most common mode of surgical repair of ruptured tendons and ligaments involves the use of sutures for reattachment. However, there is a high incidence of rerupture and repair failure due to pulling out of the suture material from the damaged connective tissue. The main goal of this research was to achieve a localized delivery of crosslinking agent genipin (GP) from rapid-release biodegradable coatings on sutures, for strengthening the repair of ruptured connective tissue. Our hypothesis is that GP released from the suture coating will lead to exogenous crosslinking of native connective tissue resulting in beneficial effects on clinically relevant mechanical parameters such as tear resistance, tissue strength, and energy required to rupture the tissue (toughness). Sutures were successfully coated with a biodegradable polymer layer loaded with the crosslinking agent genipin, without compromising the mechanical properties of the suture. The rapid-release of genipin was achieved under both in vitro and ex vivo conditions. Exogenous crosslinking using these genipin releasing sutures was demonstrated using equine tendons. The tendons treated with genipin releasing sutures showed significant improvement in failure load, energy required for pull-out failure, and stiffness. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2199-2205, 2017.

Comparison of sequential drug release in vitro and in vivo.

Development of drug-delivery devices typically involves characterizing in vitro release performance with the inherent assumption that this will closely approximate in vivo performance. Yet, as delivery devices become more complex, for instance with a sequential drug release pattern, it is important to confirm that in vivo properties correlate with the expected "programming" achieved in vitro. In this work, a systematic comparison between in vitro and in vivo biomaterial erosion and sequential release was performed for a multilayered association polymer system comprising cellulose acetate phthalate and Pluronic F-127. After assessing the materials during incubation in phosphate-buffered saline, devices were implanted supracalvarially in rats. Devices with two different doses and with different erosion rates were harvested at increasing times post-implantation, and the in vivo thickness loss, mass loss, and the drug release profiles were compared with their in vitro counterparts. The sequential release of four different drugs observed in vitro was successfully translated to in vivo conditions. Results suggest, however, that the total erosion time of the devices was longer and that release rates of the four drugs were different, with drugs initially released more quickly and then more slowly in vivo. Many comparative studies of in vitro and in vivo drug release from biodegradable polymers involved a single drug, whereas this research demonstrated that sequential release of four drugs can be maintained following implantation. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1302-1310, 2016.

Treatment of growth plate injury using IGF-I-loaded PLGA scaffolds.

Growth plate fracture can lead to retarded growth and unequal limb length, which may have a lifelong effect on a person's physical stature. The goal of this research was to develop an in vivo tissue-engineering approach for the treatment of growth plate injury via localized delivery of insulin-like growth factor I (IGF-I) from cell-free poly(lactic-co-glycolic acid) (PLGA) scaffolds. Mass loss and drug release studies were conducted to study the scaffold degradation and IGF-I release patterns. In vitro cell studies showed that rat bone marrow stromal cells seeded on the porous scaffolds colonized the pores and deposited matrix within the scaffolds. These in vitro evaluations were followed by a proof-of-concept animal study involving implantation of scaffolds in proximal tibial growth plate defects in New Zealand white rabbits. Histological analysis of tissue sections from the in vivo studies showed regeneration of cartilage, albeit with disorganized structure, at the site of implantation of IGF-I-releasing scaffolds; in contrast, only bone was formed in empty defects and those treated with IGF-free scaffolds. The present findings show the potential for treating growth plate injury using in vivo tissue engineering techniques.

Bioerodible system for sequential release of multiple drugs.

Because many complex physiological processes are controlled by multiple biomolecules, comprehensive treatment of certain disease conditions may be more effectively achieved by administration of more than one type of drug. Thus, the objective of the present research was to develop a multilayered, polymer-based system for sequential delivery of multiple drugs. The polymers used were cellulose acetate phthalate (CAP) complexed with Pluronic F-127 (P). After evaluating morphology of the resulting CAPP system, in vitro release of small molecule drugs and a model protein was studied from both single and multilayered devices. Drug release from single-layered CAPP films followed zero-order kinetics related to surface erosion of the association polymer. Release studies from multilayered CAPP devices showed the possibility of achieving intermittent release of one type of drug as well as sequential release of more than one type of drug. Mathematical modeling accurately predicted the release profiles for both single layer and multilayered devices. The present CAPP association polymer-based multilayer devices can be used for localized, sequential delivery of multiple drugs for the possible treatment of complex disease conditions, and perhaps for tissue engineering applications, that require delivery of more than one type of biomolecule.

Design of a multiple drug delivery system directed at periodontitis.

Periodontal disease is highly prevalent, with 90% of the world population affected by either periodontitis or its preceding condition, gingivitis. These conditions are caused by bacterial biofilms on teeth, which stimulate a chronic inflammatory response that leads to loss of alveolar bone and, ultimately, the tooth. Current treatment methods for periodontitis address specific parts of the disease, with no individual treatment serving as a complete therapy. The present research sought to demonstrate development of a multiple drug delivery system for stepwise treatment of different stages of periodontal disease. More specifically, multilayered films were fabricated from an association polymer comprising cellulose acetate phthalate and Pluronic F-127 to achieve sequential release of drugs. The four types of drugs used were metronidazole, ketoprofen, doxycycline, and simvastatin to eliminate infection, inhibit inflammation, prevent tissue destruction, and aid bone regeneration, respectively. Different erosion times and adjustable sequential release profiles were achieved by modifying the number of layers or by inclusion of a slower-eroding polymer layer. Analysis of antibiotic and anti-inflammatory bioactivity showed that drugs released from the devices retained 100% bioactivity. The multilayered CAPP delivery system offers a versatile approach for releasing different drugs based on the pathogenesis of periodontitis and other conditions.

Fibrin-targeted block copolymers for the prevention of postsurgical adhesions.

Despite advances in surgical methods, postsurgical adhesions (PSA) remain a significant clinical challenge affecting millions of patients each year. These permanent fibrous connections between tissues result from the bridging of wounded internal surfaces by an extended fibrin gel matrix (FGM). Adhesion formation is a result of a systems level convergence of wound healing pathways, complicating the design of materials that could inhibit their occurrence. In this study, a systematic approach that identifies key material properties required for functional performance optimization was used to design a new fibrin-targeted PSA prevention material. A series of multifunctional polymers with varied molecular architectures was synthesized to investigate the effect of changing polymer structural parameters on the ability to disrupt the formation of an extended FGM. Initial studies in a murine adhesion model demonstrated a statistically significant reduction in the degree of PSA formation, demonstrating the potential value of this systematic approach.