Below follows a succinct description of a few of our research areas.

Biodegradable polymers and their role in medical devices

The scientific and technological importance of biodegradable polymers continues to grow, as their clinical use steadily expands. Aiming at expanding their clinical applicability, we developed a family of biodegradable polymers tailored to meet multifaceted and complex sets of chemical, physical and biological requirements, depending on their clinical role. Most of our work was devoted to designing block copolymers comprising aliphatic poly(ester) segments (such as polylactic (PLA) and polycaprolactone (PCL), and poly(ether oxide) chains, for example polyethylene oxide (PEO) and polypropylene oxide (PPO). The poly(ester)s create the hard, and typically crystalline blocks of the copolymer, rendering the system with the required degradability, while the poly(ether) chains are responsible for the elastic recovery and high flexibility of the material.

Among other implants, these polymers were part of a selectively biodegradable artificial blood vessel developed in my lab that allows the regeneration of vascular tissue, as shown below.

4D, 5D and 6D printed, personalized functional medical devices 

The ability to construct custom-made medical devices and to implant them in a minimal invasive manner are two of the leading trends in modern surgery. The personalization of the device is achieved by its 3D printing, while the capacity to deploy it via minimally invasive procedures stems from the shape memory behavior displayed by the “inks” used to print them. 
In our lab we print 4D, 5D and 6D architectures, where the fourth and so on dimensions are clinically relevant functionalities we bestow to the device. This strategy is implemented in our lab in a diversity of novel medical devices. This is illustrated by a personalized, flexible, low profile, shape memory displaying, 3D printed tracheal stent (see the figure below). To this end, we designed and synthesized novel photo-curable acrylate-based triblock “inks” consisting of a flexible polypropylene glycol (PPG) chain as their middle segment and semi-crystalline polycaprolactone (PCL) blocks of controllable length on both sides. The triblocks were then end-capped with photocurable carbon double bonds, to render them printable. Additionally, seeking to minimize detrimental bio-film formation processes, polyethylene glycol (PEG) chains were covalently grafted onto the surface of the stent, resulting in surfaces displaying enhanced anti-fouling properties. Due to the frequent and dangerous post- implantation infections in devices deployed along the airway, ciprofloxacin, an efficient antibacterial drug, was added to the ink prior to the printing of the stent and released over time.

The figure below presents a heart model printed in our lab to test various devices aimed at treating various cardiac pathologies, in collaboration with the Heart Institute of the Hadassah Medical Center. 

Prevention of post-surgical adhesions 

Adhesion development is a major source of postoperative morbidity and mortality following most surgical procedures. Pericardial adhesions are a common complication of pericardiotomy and cardiac surgeries. A flexible, transparent biodegradable adhesion barrier consisting of polyethylene oxide (EO) and polylactic acid (PLA) blocks, was developed in our lab and was approved by the FDA to prevent adhesions after cardiac surgery.  

In situ welding: A novel strategy for engineering medical devices in vivo 

The minimally invasive implantation of medical devices depends on their insertion profile and, therefore, minimizing their implantation size constitutes a leading trend fueling much research activity in the field. My group recently introduced a new strategy to in situ assemble medical devices, by sequentially implanting their basic components and welding them together, rapidly and securely, at their site of clinical performance. The in situ welding strategy is exemplified here through the development of an endovascular device. Endovascular Aneurysm Repair (EVAR) procedures are based on the implantation of a stent-graft consisting of a metallic stent and a polymeric fabric sewn to it. Decoupling the stent and the graft, deploying them sequentially and welding them in situ greatly reduces the required insertion profile, which largely eases implantation and makes them much safer. Polyurethane thermoplastic elastomers developed in our lab were used to produce the graft. The device was successfully implanted in pigs for three months and demonstrated that the strength of the welded connection was retained, with no de-welding being observed. To our knowledge, this is the first time that the welding phenomenon is performed inside the human body. 

 

Reverse thermo-responsive medical polymers

“Smart” polymers are an advanced class of materials tailored to display substantial property changes, as a response to minor chemical, physical or biological stimuli, such as temperature, pH, biochemical agents, and electrical and magnetic fields. “Smart” polymers are termed “reverse thermo-responsive” (RTR) when their aqueous solutions display low viscosity at a low temperature and exhibit a sharp viscosity increase as temperature rises within a very narrow temperature interval, forming a semi-solid gel at body temperature. In light of the major shortcomings of existing RTR polymers that rendered them clearly unsuitable for most biomedical applications, we have developed a new generation of RTR polymers consisting of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) segments. The gels formed by these novel RTR polymers not only display superior rheological and mechanical properties but also enhanced biodurability and tunable properties when they perform as matrices for controlled drug release. I some cases the RTR polymers are thermoplastic and in other cases they form a crosslinked matrix, as shown in the figure below, where the nanofibers are apparent.

 

 

In situ generated liquefiable wound dressings  

My group has developed a “smart” in situ generated hydrogel wound dressing based on our reverse thermo-responsive (RTR) polymers. Due to their low viscosity at deployment, the RTR aqueous solutions are fully conformable to the shape of the wound, regardless of its type, anatomy and complexity. Owing to their RTR behavior, the cold RTR aqueous solution administered heats up to body temperature when in contact with the tissue and rapidly gels, in situ generating the hydrogel wound dressing. Their ease of placement, universal adaptability and the comfort they offer the patient are additional advantageous features of our in situ formed wound dressings. Moreover, since their administration is rapid, clean, hands-free and straightforward, higher patient levels of compliance are achieved.  

The removal of the dressing after a period of intimate contact with the wounded tissue and its secretions, results in the tight adherence of the dressing to the tissue bed. Each dressing change is, therefore, not only terribly painful but also results in tearing and injuring the wound, significantly erasing the progress made by the healing process, since the previous dressing change. 

Our RTR-displaying smart wound dressings remarkably overcome this huge clinical hurdle since they generate a unique liquefiable interface with the tissue bed, enabling the dressing in contact with the tissue and its secretions to liquefy on command upon suitable cooling. This results in a gentle, painless and non-injurious detachment and removal of the dressing, not disruptive to the healing and repair processes, which is of the utmost clinical importance. 

The figure below schematically shows the deployment of the gelling solution on the wound

An animal study was conducted in a pig model. The figure below shows the deployment of the solution on a de-epithelized wound, by simply spraying the in situ gelling solution on the wound (left) and the commencement of the removal of the liquefiable dressing (right).

Reverse thermo-responsive polymeric nano-shells 

The unique properties displayed by nano-sized materials has converted this field in one of the most exciting and rapidly growing scientific and technological areas. Our group introduced hollow thermo-responsive nano-structures able to display a remarkable and reversible change in size, within a narrow temperature interval. The nano-constructs developed are essentially hollow polyethylene oxide-rich shells with the core being only spatially demarcated by hydrophobic polypropylene oxide segments. As a result, fully reverse thermo-responsive nano-shells able to dramatically expand and contract within a very narrow temperature range, were engineered. hese nano-constructs can be loaded with various “payloads” of clinical importance, aiming to perform as advanced vehicles for drug and gene delivery. The figure below shows the dimensional response of tubular nano-shells as a function of temperature. The size of these novel nano-constructs was 3000 nanometers at 15oC and contracted notably around 34oC, generating a compressed structure of approximately 300 nanometers at body temperature.

The nano-shells were bestowed with additional features, such as pH-responsiveness and biodegradability and the capacity to bind selectively to specific cells.