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From PLA to Bioprinting: Science Fiction Tools for the Medical Field

From PLA to Bioprinting: Science Fiction Tools for the Medical Field

3D printing is revolutionising the healthcare market, bringing new tools to all medical specialties.

This technology began to be introduced mainly in traumatology and maxillofacial surgery, where it was interesting to print bone models for learning and understanding complex fractures, deformities or scoliosis. Since the anatomy of each patient is different, 3D printing is essential to be able to manufacture individualised solutions. [1]

As expected, the idea of starting to print implants and custom surgical tools soon emerged. The two questions that arise are: how advanced is this technology today, and how far could we go with it?

What are we able to do today?

Today, 3D printing is more integrated into everyday medical practice than most people think.

Anatomical Models

Spinal pathology, for example, is much more complex to visualise than it seems. Since each of the vertebrae can be rotated through each of the three axes of space (x=transverse, y=longitudinal and z=antero-posterior), visualising them with a 3D model is useful to plan surgery or understand the position of the fragments of a fracture. [2]

In the printing of anatomical models, multi-material printing technology takes on importance in order to make it easier to distinguish the different tissues. One example could be the models fabricated by the company Stratasys.

Hospital 3D Printing — Anatomical Models — Skull Photo courtesy of Mr. Oliver Burley
Hospital 3D Printing — Anatomical Models — Skull Photo courtesy of Mr. Oliver Burley

Surgical guides and personalised surgical instruments

One of the advances with the greatest impact on orthopaedic and maxillofacial surgery is the impression of what we call surgical guides. These are tools provided with channels or guiding tubes that guide traditional surgical instruments on a path previously planned in radiological software. It should be added that these guides are designed to adapt to the anatomical contour of the patient and are therefore personalised. [3]

The field where they are most developed is in dentistry, although they are also being implemented in traumatology, maxillofacial surgery and oncology (Fig.2).

Figure 2: 3D printed patient-specific cutting guide, placed on a model of a distal femur.

However, I might add, that choosing the material is not an easy task.

As we have seen in previous Matmatch articles, guides, like any other surgical instrument, must be printed using a cheap material with extensive proven application in medical use (i.e. it is safe) and with good mechanical properties so as not to deform during use.

Therefore, the most widespread material today is PLA (polylactic acid), the safety of which is extremely well tested because it is the material used in absorbable sutures. For example, the Polysorb™ Braided Absorbable Sutures uses a synthetic polyester composed of glycolide and lactide (derived from glycolic and lactic acids). Also, PLA printing can be done by extrusion, the printing system for which is cheap and reliable.

Medical implants

As far as medical implants are concerned, research is much more extensive since not only can implants be printed with inert materials such as PEKK (poly-ether-ketone-ketone) used by Oxford Performance Materials or carbon fibre reinforced filament used by invibio but, in recent years, fully bio-compatible materials have appeared, which over time the body replaces with its own tissue and even full or partially functional human tissues have been printed. [4]

As an example of bio-compatible materials used in medical implants, again PLA is widely used in maxillofacial implants, for example, in the Inion CPS® Fixation System.

We can also find other less widespread materials such as the filler material MG-Osteodrive®, which is a mixture of inorganic compounds with a calcium base, and the membrane MG-Reguarde®, an absorbable material made from type I collagen fibres from the Achilles tendon of bovine cattle.

The biocompatible materials used for 3D printing, called bio-inks, allow the printing of a scaffold that serves as a structure to be colonised by the patient’s own cells. It is therefore vital to take into account the parameters of porosity and pore-interconnectivity to allow the cell movement into the scaffold. These are two essential characteristics in which 3D printing is by far more advantageous versus other production techniques. [5]

Bio-inks are usually natural polymers such as hyaluronic acid, elastin or even spider derived silk proteins. This last example is particularly interesting since there is a company, Spidey Tek, whose product, based on spider silk proteins, claims to have a tensile strength of 40,000 MPa (100 times that of carbon fibre). There are also salts that could be used to fabricate bone scaffolds, like one made of tricalcium phosphate produced by Cellink.

There are also synthetic polymers, for example, amphiphilic block copolymers, which stand out for having the ability to self-assemble. These are hydrophilic spherical structures on the outside with a hydrophobic interior. They allow the transport of some drugs or other liposoluble substances in an aqueous medium), forming micellar structures that are hydrophilic spherical structures on the outside and with a hydrophobic interior.

They, therefore, allow the transport of some drugs or other liposoluble substances in an aqueous medium, PEG (Polyethylene glycol), Poly(N-isopropylacrylamide) (PNIPA) and polyphosphazenes.

Figure 3: A Novax DMA cranial implant. Courtesy Novax DMA.

What does the future hold?

But how easy is it to print a functional organ or tissue? Take the example of a meniscus of the knee, whose function is merely mechanical. A meniscus can be imagined as a cushion between the femur and the crescent-shaped tibia that serves as a stop and stabilises the joint, as well as acting as a shock absorber.

The first thing we must ask ourselves is: how do we adapt the shape of the meniscus to each person? Luckily, under normal conditions, the meniscus presents a reasonable bilateral symmetry [6], that is to say, it would be enough to copy the one from the other knee. It may seem like a simple process but in practice a magnetic resonance imaging (MRI) scan must be carried out and, using radiological visualisation software. Then, the meniscus must be selected and separated from the rest of the structures (a process called segmentation) so that it can then be exported in STL format so that the printer can print it. Some software performs tissue segmentation automatically, with the newest using algorithms based on fractals or deep learning (neural networks). One software example is from Alma Medical Imaging.

The second consideration is the material itself. All of the supporting structure (the scaffolding we have talked about before), which forms part of the tissue, is what in medicine is called the extracellular matrix. The extracellular matrix of a meniscus is composed mainly of collagen. There are companies such as Advanced Biomatrix that commercialise it in the form of bio-inks, although we can also opt for a synthetic absorbable polymer such as polycaprolactone (PCL). Scientific literature supports the use of both. [7]

However, not all printers can print with bio-inks and each bio-ink has to be approved by the corresponding sanitary authority of the country. But today there are some companies that produce bio-printers like Bio-Dan Group, EnvisionTEC or Aether 3D.

It is not enough to print the scaffolding with the same materials we see on a meniscus, nor is it enough that the final shape and texture are the same. The final product must offer the same mechanical properties as the natural one and, therefore, the polymer fibres we choose must have the same placement as in reality (i.e. similar to the native meniscus). That is to say, our meniscus must mimic the native architecture of the collagen fibres both in orientation and in the joints between the different polymer chains (these joints are called, using a technical language, cross-links). [5]

Nowadays, we have also photo-cross-linkable and thermo-responsive materials, but these two concepts would give us enough for another article.

Unfortunately, form, material and internal architecture are not the only factors to consider. Once manufactured, we must incubate our scaffold with the patient’s stem cells to colonise it. This process is of vital importance, since a depopulated extracellular matrix would disappear with the passage of time. These cells will maintain the extracellular matrix and gradually replace it with natural matrix components. [8]

Figure 4: 3D automatic segmentation from abdominal CT scan

In a normal meniscus there are different types of cells and these are not uniformly distributed. On the external part there are more fibroblasts and on the medial part there are more chondrocytes. Therefore, the outer part will have more fibrous tissue (as in a scar) and the inner part more collagen, resulting in different mechanical properties. [5]

A solution to this problem was published in the journal Science Translational Medicine in 2014 by Chang H. Lee et al. This consists of seeding our scaffold with poly (lactic-co-glycolic acid) (PLGA) microspheres that encapsulate different growth factors (these are chemical signals that guide the differentiation of stem cells indicating which cells should be converted). In this way, we can achieve the corresponding cell distribution in the implant. [9]

During the incubation process, it is also important to simulate the normal mechanical conditions to stimulate the production by these cells of an initial matrix with a suitable orientation. This objective can be achieved by culturing the cells in a mechanobioreactor. [10]

Figure 5: Damaged ears could be replaced with made-to-measure organs grown in a dish. Courtesy: Andrew Craft

Conclusions

3D printing is today more than validated in medicine by a multitude of publications as a tool for printing anatomical models, surgical guides and personalised implants.

But despite the rapid implementation of this technology in the healthcare sector, printing a functional tissue is not a trivial process. That is why today, despite the fact that the market is directing its efforts in this direction [11], bio-printing has not yet reached operating rooms, except for a few specific exceptions restricted to the field of research.

Personally, I believe that if companies, universities and doctors are able to work together as a team, having in mind the benefit of the patient, we will be able to see this dream come true in the next few years.

"By writing articles for Matmatch, I am able to give a part of me to society by sharing knowledge and inspiring new ideas".

References:

[1] Wilcox B, Mobbs RJ, Wu AM, Phan K. Systematic review of 3D printing in spinal surgery: the current state of play. J Spine Surg. 2017;3(3):433-443.
[2] D’Urso PS, Barker TM, Earwaker WJ, et al. Stereolithographic biomodelling in cranio-maxillofacial surgery: a prospective trial. J Craniomaxillofac Surg 1999;27:30-7. 10.1016/S1010-5182(99)80007-9.
[3] Ramasamy M, Giri, Raja R, Subramonian, Karthik, Narendrakumar R. Implant surgical guides: From the past to the present. J Pharm Bioallied Sci. 2013;5(Suppl 1):S98-S102.
[4] Do AV, Khorsand B, Geary SM, Salem AK. 3D Printing of Scaffolds for Tissue Regeneration Applications. Adv Healthc Mater. 2015;4(12):1742-62.
[5] Alexander Szojka, Karamveer Lalh, Stephen H.J. Andrews, Nadr M. Jomha, Martin Osswald, Adetola B. Adesida, Biomimetic 3D printed scaffolds for meniscus tissue engineering. Bioprinting, Volume 8, 2017, Pages 1-7. ISSN 2405-8866.
[6] J.-R. Yoon, et al., The use of contralateral knee magnetic resonance imaging to predict meniscal size during meniscal allograft transplantation, Arthrosc. J. Arthrosc. Relat. Surg. 30 (10) (2014) 1287–1293.
[7] I.F. Cengiz, et al., Building the basis for patient-specific meniscal scaffolds: from human knee MRI to fabrication of 3D printed scaffolds, Bioprinting 1 (2016) 1–10.
[8] Chen C, Bang S, Cho Y, et al. Research trends in biomimetic medical materials for tissue engineering: 3D bioprinting, surface modification, nano/micro-technology and clinical aspects in tissue engineering of cartilage and bone. Biomater Res. 2016;20:10. Published 2016 May 4. doi:10.1186/s40824-016-0057-3
[9] C.H. Lee, S.A. Rodeo, L.A. Fortier, C. Lu, C. Erisken, J.J. Mao, Protein-releasing polymeric scaffolds induce fibrochondrocytic differentiation ofendogenous cells for knee meniscus regeneration in sheep, Sci. Transl. Med. 6 (266) (2014) (266ra171266ra171, Dec.).
[10] Weber J.F., Perez R., Waldman S.D. (2015) Mechanobioreactors for Cartilage Tissue Engineering. In: Doran P. (eds) Cartilage Tissue Engineering. Methods in Molecular Biology, vol 1340. Humana Press, New York, NY
[11] Frost & Sullivan. 3D Bioprinting: Transforming The Future of Healthcare Sector (Technical Insights). Published 2015 March 30.

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