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Nanomaterials to Enhance Regenerative Medicine

Who hasn’t ever seen a film in which a human being can regenerate their body after being shot or stabbed? 

A famous example is that of Wolverine’s self-healing. Although we are still some way from achieving such a feat, sometimes it is precisely these fantasies that drive scientific advances, and perhaps soon, we can make them come true. 

One big step in this direction is the production of man-made tissues to replace natural ones that have been lost or are no longer functional, like a titanium prosthesis.

Yet, to reach the level of Marvel characters in regenerating our bodies, we need to kick it up a notch and take our technology to the next level; and it seems like we have hit the ground running.

Scientists have developed a new strategy that helps the human body to regenerate its own tissues by using nanomaterials-based approaches to control the growth of cells, the immune response and tissue remodeling.

This exciting new field of science is known as regenerative medicine.

Let me tell you more about it!

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What do nanomaterials have to do with regenerative medicine?

In one of our previous articles Advanced Magnetic Nanoparticles for Cancer Detection and Treatment, we saw how when a material is shrunk to very small dimensions, it can acquire radically different properties. Science is managing, day by day, to find new applications for these nanotechnological properties.

One of the great promises of nanomaterials is the ability to ‘modulate’ the immune response by joining them to human biomolecules (antibodies, cytokines, hormones, etc…). 

But what does this ‘modulation’ mean?

Controlling the immune response

The immune system is the army of our body. And as with any army, soldiers are not only used to attack and destroy, but also as support resources. For instance, the immune system deals with all kinds of contingencies, such as renewing tissues after suffering an injury, and helps control environmental disbalances, by eliminating metabolism toxins or harmful foreign substances.

This control, or modulation, is orchestrated by an endless number of biomolecules (e.g. cytokines, interleukins and hormones) whose concentration acts as a signal to the cells telling them how they should behave at all times. 

When we use an artificial material in a patient to cover a burn, for example, it is desirable that it ultimately gets integrated into the patient’s body. Concretely, we would like the patient’s cells to colonise and grow into the new material so that eventually, it is replaced by the patient’s own tissue.  

Unfortunately, the immune system often recognises the material as an entity alien to our body and tries to isolate it by creating a wall around it composed of fibrous connective tissues via a process known as fibrosis. This is a material poor in cells but rich in molecules (macromolecules such as collagen or fibrine) that support the cells structurally. It has properties that are significantly different from those of the original tissue. Many of you would recognise how stiff a scar tissue feels compared to regular skin. A scar located in a joint can even impede its movement.

Figure 1 Hypertrophic scar formation with joint contracture Aarabi S, Longaker MT, Gurtner GC (2007) Hypertrophic Scar Formation Following Burns and Trauma: New Approaches to Treatment. PLoS Med 4(9): e234. doi:10.1371/journal.pmed.0040234 - http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0040234

Highlighted in my previous article From PLA to Bio-printing: science fiction tools for the medical field, a strategy to deal with this rejection by the immune system is to use biomaterials to build scaffolds (supportive structures to be colonised by the patient’s own cells)from molecules, such as collagen. Unfortunately, if we implant a scaffold composed only of collagen fibres, the body ends up reabsorbing this material and, in the best of cases, replacing it with fibrosis.

This can interest us if we want to create an “artificial scar”, for example, to repair the abdominal wall after an hernia; in which we could use, a Phasix™ Mesh made from Poly-4-hydroxybutyrate (P4HB) to patch-up the wall defect. 

To achieve functional integration of any implant, we must drive cell differentiation (i.e. give each cell its specific type and function) and avoid the possibility of the immune system rejecting the implant. We may do this by using nanomaterials as ‘carriers’ to deliver the biomolecules and as signals to drive this process.

But what if we could immobilise or direct those biomolecules to any place we want?

Could we control the immune system? 

For example, the combination of nanomaterials and antibodies can be used to boost the immune response, such as in the fight against cancer (antibody-modified iron oxide nanoparticles).

Some nanomaterials themselves already have direct inhibitory or stimulating effects (depending on the material) on the immune response (noble metals, metal oxide nanoparticles, cerium oxide or dendrimers are some examples). Thus, by simply coating the surface of an implant with those nanoparticles, we can actually stop an immune system attack on it.  [1]

Figure 2 Nanomaterials with direct inhibitory effects on the immune response Ngobili Terrika A, Daniele Michael A. Nanoparticles and direct immunosuppression.1 May, 2016 Experimental Biology and Medicine 106 Volume: 241 issue: 10, pages: 1064-1073 ; https://doi.org/10.1177/1535370216650053 https://journals.sagepub.com/doi/abs/10.1177/1535370216650053

Strategies to immobilise nanomaterials & biomolecules on implant surfaces

As we have already mentioned, there are two main reasons for wanting to coat the surface of an implant: either to increase its biocompatibility (to prevent the immune system from attacking it) or to fix biomolecules that stimulate and direct cell proliferation (to replace the implant with the patient’s own tissue).

The idea of implanting a biodegradable scaffold (coated with growth factors) to be replaced over time by the patient’s tissue is a subject that we already discussed in From PLA to Bio-printing: science fiction tools for the medical field. Such scaffolds are still in the research phase but it is only a matter of years before we potentially start to see them entering clinical practice.

Increasing the biocompatibility of foreign materials is a current necessity for the industry. To make sure that the human body does not reject an implanted biomaterial, we have to stick the coating (nanomaterials or biomolecule-nanomaterial complexes) that regulates the immune system to the surface of our implant. Thus, when a cell of the immune system gets too close to it, the coating inhibits the cell and prevents the generation of an inflammatory reaction around the implant. 

But how can we make such a coating? 

There are basically two ways to ‘stick’ the coating to an implant: non-covalent immobilisation and covalent immobilisation. 

Non-covalent immobilisation (NCI):

NCI is the simplest and cheapest strategy to coat the implant,but it depends largely on how hydrophilic the implant material is. It is based on the electrostatic charges that would generate a force of attraction between the material we are implanting and the coating. 

This method provides a quick release of biomolecules, so it is most convenient when we are interested in an abrupt but short-lived response. Its biggest advantage, moreover, is its low manufacturing cost. 

NCI may be applied either by adsorption (tiny particles of sizes between 500 Ȧ and 1 mm adhering to the surface) or entrapment (particles entrapped in a porous matrix). [2]

In entrapment, the matrix is made with water-soluble polymers such as carrageenan, partially hydrolyzed collagen (gelatin), alginate, agar or cellulose triacetate.[2, 3]

But what happens when the implant material is hydrophilic and the biomolecule is hydrophobic (or vice versa)? 

One simple idea can be an effective solution: encapsulation of the biomolecule!

Encapsulation in the enclosing of the biomolecule, which can easily be carried out using polymers, such as agarose, poly(ethyleneglycol) (PEG), or poly(N-vinylpyrrolidone) (PVP). 

An example of this method is the use of a polysulfone scaffold filled with a biomolecule-infused agarose gel solution to guide the regeneration of nerve fibres and reduce inflammation [4]. 

Moreover, if the scaffold is not quite hydrophilic, the best strategy to immobilise the biomolecule is to encapsulate it in a separate aqueous phase via a process called water-in-oil-in-water (or double emulsion). We can also carry out direct absorption on the surface of the material using organic solvents.

An example of a hydrophobic polymer widely used in immobilising biomolecules like hormonal factors or even drugs is poly(lactic-co-glycolic acid) (PLGA).

Covalent immobilisation (CI)

Covalent immobilization consists of creating an irreversible bond between our specific biomolecules and the polymer of which our implant is made using what we call crosslinker agents; those are chemical compounds that react to a physical condition (heat, light…) and help us to create a bond that could link, for example, one polymer chain to another (we could imagine them as shackles that are closed using light or heat to link both polymers).

This method leads to a much less abrupt effect on the immune system, albeit it is much longer lasting; hence it is preferable to use it when we are interested in a long-term and stable response.

The major advantage of this method is that it allows us to perform stratified tissue differentiation. This means we can design different binding points into our scaffold for different factors, thus creating regions with different biomolecule concentrations to promote a differentially structured tissue.

As a base element, collagen-glycosaminoglycan (CG) scaffolds can be used (using carbodiimide as crosslinker given the ubiquity of NH2 groups on their surface).

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An example of covalent immobilization would be the conjugation of polyethylenimine (PEI) with heparin to create a sheath in order to increase the biocompatibility of NiTi alloy surfaces [5].

One crosslinking method that is gaining importance in recent years is the use of Acrylates to polymerize PEG hydrogels. Acrylates are functional groups sensitive to ultraviolet light. These groups can be added to peptides (or other growth factors), thus guiding the synthesis by photopolymerization of scaffolds composed of polymer-biomolecule hybrids. The possibility of integrating this process with 3D printing to give a structural pattern to our scaffold is making photopolymerization one of the most relevant methods to immobilize biomolecules.

Alternative photolithography  processes have also been designed, for example, the Fraunhofer Institute for Interfacial Engineering and Biotechnology uses a method that consists of attaching growth factors to CG scaffolds using benzophenone (BP). [6, 7]  

Another more selective target, due to its lower ubiquity with respect to the NH2 group, is the SH group. Sulfhydryl-based crosslinkers are widely used to create a coating that inhibits the activation of the complement (a very important component of the immune system) against our graft [8].

Figure 3 Example of Enzyme Immobilisation by Covalent Binding Fu J, Reinhold J, Woodbury NW (2011) Peptide-Modified Surfaces for Enzyme Immobilization. PLoS ONE 6(4): e18692. https://doi.org/10.1371/journal.pone.0018692 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018692


So, clearly there are different strategies to immobilise biomolecules on the surface of a material to control the immune response or the differentiation process. 

Before choosing one immobilisation method, it is important to know the properties of the material that you are going to use and the biomolecule release profile curve that you want to achieve. The best approach is a combination of different conjugation methods, bearing in mind that the immune system does not have a static nature. It shows a dynamic variation over time. 

The coating of implants using nanomaterials (or nanomaterials-biomolecule complexes) to augment the biocompatibility of implants is widely used nowadays. However, this fact contrasts sharply with the case of fabrication of scaffolds with a stratified concentration of encapsulated or bonded biomolecules. Despite the enormous amount of activity in this field, there are not a lot of companies today that provide these scaffolds, and there are plenty of regulatory actions yet to be addressed before bringing these products to the market.  

That means that we will have to wait a little more to be able to conduct a complete scar free healing. But the wait, most probably, will not be long. This promising technology may well be used in daily medical practice in as soon as a few years.

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1. Ngobili Terrika A, Daniele Michael A. Nanoparticles and direct immunosuppression. Experimental Biology and Medicine 2016; 241(10): 1064-1073 ; https://doi.org/10.1177/1535370216650053  

2. Cherng-Kang Perng, Yng-Jiin Wang, Chi-Han Tsi, Hsu Ma. In Vivo Angiogenesis Effect of Porous Collagen Scaffold with Hyaluronic Acid Oligosaccharides. Journal of Surgical Research 2011; 168(1): 9-15. ISSN 0022-4804, https://doi.org/10.1016/j.jss.2009.09.052.

3. Sun G, Zhang X, Shen YI, et al. Dextran hydrogel scaffolds enhance angiogenic responses and promote complete skin regeneration during burn wound healing. Proc Natl Acad Sci U S A. 2011; 108(52):20976-81.

4. Mokarram N, Merchant A, Mukhatyar V, Patel G, Bellamkonda RV. Effect of modulating macrophage phenotype on peripheral nerve repair. Biomaterials. 2012; 33(34):8793-801.

5. Dong, Ping & Hao, Weichang & Wang, Xu & Wang, Tianmin. Fabrication and biocompatibility of polyethyleneimine/heparin self-assembly coating on NiTi alloy. Thin Solid Films 2008; 516: 5168-5171. https://doi.org/10.1016/j.tsf.2007.07.084.

6. Martin TA, Caliari SR, Williford PD, Harley BA, Bailey RC. The generation of biomolecular patterns in highly porous collagen-GAG scaffolds using direct photolithography. Biomaterials. 2011 Jun; 32(16):3949-57. 

7. Megan Carve, Donald Wlodkowic. 3D-Printed Chips: Compatibility of Additive Manufacturing Photopolymeric Substrata with Biological Applications. Micromachines 2018; 9: 91; https://doi.org/10.3390/mi9020091.

8. Wu YQ, Qu H, Sfyroera G, et al. Protection of nonself surfaces from complement attack by factor H-binding peptides: implications for therapeutic medicine. J Immunol. 2011; 186(7):4269-77.



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