The University of Southampton

How 3D Bioprinting will revolutionise Therapeutics

A lecture on tissue engineering introduced me to the concept of Bioprinting. Although I am fully aware of the idea of 3D printing. I wanted to look more into how biological materials are incorporated into 3D printing to create tools that can be utilised within our bodies. Bioprinting is ‘the use of 3D technology with materials that incorporate living cells’. They are most commonly known for organ growth to battle the organ transplant crisis. But did you know that they are also being used to improve therapeutics, specifically drug delivery? I was particularly drawn to this as it shows potential in making medicine more personalised – a topic that I have always had an interest in.

3D Bioprinting

Bioprinting and its biocompatibility

There are different types of 3D Bioprinting techniques such as stereolithography and fused deposition modelling. However, bioprinting with bioinks is able to produce structures that obtain many properties that can be used to  develop structures that can be efficient  for drug delivery.

Bioinks are hydrogels that can be made up from substances such as gelatin, alginate and hyaluronic acid – materials that are highly compatible within the body. The composition of the hydrogels can vary and as a result they can be modified so  the cross linkage  of the polymers can be made reversible or permanent depending on how the materials are treated physically or chemically. These are referred to as methacrylate hydrogels and the cross linkage can be used as a tool to be used to control the release of the drugs within the body. The bioinks can also incorporate synthetic polymers which can be used to further modify their properties such a degradation, increasing the biocompatibility.

Potential therapeutic uses

  • Drugs

The main issue in drug therapeutics is the distribution of the drug itself within the body. In addition to this due to individual differences, a set dosage doesn’t work for everyone and a patient may not necessarily take their medication correctly. (Martinez et al., 2017) was able to print drug-loaded hydrogel with water which was able to release the drug at rates that were dependent on the water content. A delivery system, that would combat the improper use of medication, release the drug at the correct site of absorption, and could be further modified to be dose specific for each patient.  

With further reading, I discovered that tuberculosis required two drugs for it to be treated, rifampicin and isoniazid. Multiple studies have shown that these two drugs can negatively impact the effectiveness of the other and they are also required to be absorbed in different areas within the body for effective treatment. (Genina et al., 2017) designed an oral dual-compartmental dosage (dcDU) unit via 3D printing and hot melt extrusion

Design of the Dual – compartmental dosage unit

The dcDU  was tested in vitro and in vivo using rats, where drug release was analysed and it was noted that sealing and the compartments improved the drug release of each drug.  This study particularly opened my eyes to the amazing things that could be achieved with bioprinting, it was here when I begun to realise how much of a big impact on therapeutics that bioprinting would be. An infection that could require a 2-week course of 2 different antibiotics would be reduced to one oral dosage.

  • Hormones

Like any other scientist, I began to work what else could we dispense and came across (Tappa et al., 2017). Intrauterine devices are the most common form of long term birth control. Although they are very efficient they are not necessarily personalised to the individual. Polycaprolactone pellets (PCL) were first coated with hormones and infused with silicone oil. Here is prime example of how synthetic polymers are used as the PCL allows for degradation and has a low melting temperature that will not interfere with the high degradation temperatures of the hormone. They then used this to print different 3D hormone-releasing IUDs which suggested promising uses in gynaecology applications.

Six different biodegradable hormone releasing IUDs that were bioprinted – different shapes could be printed that could be more suited to the patients dimensions making the implant more comfortable
  • Growth factors

I am very familiar with the growth factor VEGF and its role in bone vasculature, so I really enjoyed (Poldervaart et al., 2014) paper on designing gelatin microparticles which had a controlled release of VEGF. Migration assays showed that the VEGF release from these microparticles lasted up to 3 weeks and was able to induce migration on endothelial progenitor cells. I began to wonder if 3D printing could be used for the potential treatment of bone cancer. What if we combined the biodegradable IUD concept but instead of hormones it contained angiogenesis inhibitors?

Organoids and chip in organs

To test my IUD hybrid idea, I could also utilise bioprinting to create organoids which are tiny 3D tissue culture that allows us to test the effects of infectious diseases and drug therapies. Organoids are rarely studied alone and are often in association with chip-in-organs, which replicate the organ environment so the results are more accurate to the behaviours that would be seen within the body.

Emphasising the importance of chip-in-organs

Future Prospects

A lot of this research is very new and perhaps the two most obvious next steps for Bioprinting are refining the bioprinting mechanism itself and clinical trials, which some predict could occur within the decade. Most importantly, the ethical side of this needs to be discussed. Currently the FDA does not have an official definition for bioprinting, making it harder to set laws and guidelines for it. There is also a bit of worry about potential ‘black market’ uses of these resources – where do we draw the line? I could imagine that people could use this for recreational drugs such as nicotine for example or body builders could use it to increase their testosterone levels

However, the bioprinting world is such a new concept in the world of science with very promising results that could completely change the way we use therapeutics entirely and to be honest I am very excited to witness this.

Biofilms Vs Implants

A lecture by Dr. Alex Dickinson on prosthetic implants highlighted how patient satisfaction rates are a rationale for continued research into implants. I remember learning in Year 2 about how biofilms were one of the major difficulties faced when it came to implants and wanted to look more into what is being done to combat this.  

According to the National Joint Registry in 2013, 34% of knee and hip implants had to be replaced due to infection. Infections of implants result in the patient experiencing similar symptoms to before they had the implant, such as swelling in the area, pain and stiffness.  I can see how frustrating this is for the patients as it must feel like you have gone back to square one. Furthermore, replacing an implant is quite costly and takes up time that could have been used for new patients who require the implant in the first place, not to mention the invasiveness of the treatment.

How does the infection occur ?

In able to understand how treatments are manufactured, I needed to understand how the infection occur in the first place. From my own knowledge, I know that bacteria and other microorganisms enjoy smooth surfaces where they attached on to and  form biofilms. Here they form communities where they ‘live’ which has a constant and stable supply of nutrients to support their survival.

Biofilm Formation

What I did not know is that there are two ways that this infection can occur on the implant. The first being during the surgical procedure – where the bacteria can come from the individuals flora or the operating environment. The second is the microorganisms can be carried by the blood and form a biofilm- this one occurs after the surgery has occurred. In both ways the biofilm maturation occurs over time and it takes some years before it becomes harmful.

By the time the infection is discovered the biofilm has developed so much it becomes difficult for the clinicians to identify what microorganisms that are included in this making it harder to treat them as it is time consuming and requires heavy reach.

What about antibiotics and our immune system ?

Well… multiple studies have shown that biofilms show hight antibiotic resistance due to their formation. When in the biofilm, the bacteria switches off certain genes which could be targeted by these antibiotic rendering them ineffective. Remarkably, one study showed that some bacteria in the biofilm were able express certain phenotypes which would result in the removal of the antibiotics! Due to the lack of blood supply within the implant the immune system is limited.

Current Treatments

So far the most common treatments is DAIR- debridement, antibiotics and implant retention. This procedure involves reopening the implant, washing it out with fluid, removing damage tissue followed by a course of antibiotics , which can vary in duration. The success rates of this treatment vary  due to the heterogeneity of the patients, length of infection and  type of infection. Typically study’s show that DAIR has a higher success rate with acute infection and when the infection has progressed there is an increased chance of the patients reinfection and them requiring are placement  implant. Although there are some success with this treatment , it is still invasive and costly and relies on early detection – which we have seen before is quite difficult.

Future Prospects

I decided to look into research about future therapies or ways to improve the DAIR. I learnt that in order for clinicians to improve the success of DAIR, they are looking into trying to detect the high levels of antibody within the patients so they could be able to intervene at an earlier point. But the invasiveness and time consuming aspects still remain

Antimicrobial peptides have been showing promising results in therapeutics. They already exist in our innate immune system. Their cationic charge allows them kill a range of different microorganisms but not attack the mammalian cells. In addition to this there are other antibiotics such as fluoroquinolones and rifampin penetrate biofilms. This type of treatment ideal but so far researchers have been unable to find a mechanisms for these in vivo.

Copper Vs Bacteria

So if the treatments are lacking, what can be done to prevent this from occurring in the first place? This is where I came across an fascinating paper about looking potential biomaterials which prevent biofilms from forming. The paper looking at what can be done to the biomaterials of the implants to  interfere with the biofilm formation. They conducted a lot of experiments on the metal roughness and tried coating different materials onto the implant. Most notably, the rougher the metal and coating the implants with ions made it harder for the biofilm to form. With this information I began to think that perhaps copper , an ion producing mental could be used to make the implants. Well after reading up on this making copper implants would be impractical but researchers are looking into coating the implants with copper – due to its antimicrobial properties

I was particularly interested in coating the implants with an acylase activity which is turn disrupts quorum -sensing. From studying my course quorum sensing is the way bacterial communicates with each other – so being able to stop that would be detrimental in winning the war against biofilms.

Quorum Sensing

Concluding thoughts

Coming into this, I honestly thought that there was not much hope for resolving biofilm infection of implants. This is mainly because there is not really a reliable , non-invasive treatment for this. However in this case I believe the best way beat biofilm is prevention. The biomaterials look highly promising- although a lot of research has to be done to assure that it doesn’t affect human cells. this is definitely an area that I will keep up to date on as there could be huge developments soon.