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Nanodroplets and Microbubbles

 

Tissue repair and regeneration is an upcoming field which gives hope to a number of cases to help repair diseased and injured tissues and/or organs. Orthopaedic surgery is one such field as methods to regenerate bone are needed to treat bone fractures which do not heal naturally. These fractures are known as non-union and they occur in 10-15% of fractures. This results in a number of patients which have a reduced quality of life, repeated surgical procedures and prolonged hospital stays which in turn translates into increased financial burden on healthcare systems worldwide. 

 


The current ‘gold standard’ approach to treat non-unions is autologous bone grafts which involves a transplant of a section of healthy bone to the bone fracture site from the patient. There are a number of limitations associated with this procedure therefore an approach where the fractured bone can be induced to regenerate heathy bone is the ideal aim. Microbubbles are already in use both in diagnostics as they provide a contrast during US imaging enhancing image quality, and currently tested in therapeutics for drug delivery. A number of molecules have been identified which help induce local stem cells in the bone marrow to regenerate bone, however administrating these via the circulation causes undesired side effects which prevents its use. Therefore our research focuses on a method to deliver these molecules directly to the fracture site so as to eliminate the side effects on the rest of the body. This involves the development of a drug delivery system using microbubbles or nanodroplets to encapsulate the molecule and ultrasound to deliver the molecule to the target site and rupture the microbubble and release the drug/molecule. 


 A microbubble is a gas core surrounded by a shell which stabilises the bubble. Stability involves maintain high numbers of bubbles and maintain the diameter, as bubbles can fuse, deflate or burst, which alters their number and diameter. These bubbles are microbubbles as they range between 3-10um in diameter which is approximately the same size as erythrocytes (red blood cells) and share a similar rheology in microvessels and capillaries. Nandodroplets are in the nanometre range and can be expanded into a microbubble therefore can be used for smaller diameter capillaries and inflated when it arrives at the site of interest 

 

Microbubbles are composed of two parts: the gas core and the shell. The gas core is fundamental as this is what makes MBs a great vehicle to deliver drugs because of how they respond to US. Gas microbubbles without a shell are highly unstable, so it's fundamental to add a stabilizing shell. We are focusing on MBs made of a lipid shell which is biocompatible and provides stability.

As our aim involves bone regeneration, our bubbles need to reach a bone fracture site and deliver a drug or molecule that will induce the stem cells to regenerate new bone. Microbubbles can be used as drug delivery agents since they can be loaded with drugs in different ways. The drug/molecule can either be encapsulated into the core of the MB or within the lipid shell or even attached to the lipid shell as shown in the image below.  

 

Lin et al. 20062006

MBs are then injected into the blood stream and travel with the circulatory system. Previous studies have shown that liposomes and polymersomes accumulate at the fracture site. We are using US at the fracture site which causes the MBs to expand, contract and eventually cavitate, i.e. burst. Bubbles cavitation induces an increase in the permeability of cells which helps with delivering the content of the bubbles to the stem cells in the bone marrow. 

 

Developing MBs which can be stimulated by US to release a drug at the fracture site will help stimulate stem cells and induce bone formation and therefore heal fractures. This method can also be used to deliver other drugs to other parts of the body revolutionising drug delivery systems.