Beads of nacre, also known as mother of pearl
When you ponder biomimicry, think design, intelligent design, and creation, but please don’t think evolution. And when considering biomimetic applications, let your imagination know no bounds.
This installment in our series on biomimicry examines biomaterials and tissue engineering, with an emphasis on the foreign body response and normal wound healing. This subject matter is intended to glorify God and His creation, which includes human beings as a special creation.
A biomaterial may be thought of as engineered material (derived synthetically or naturally-occurring) placed into the body to minimize loss of structure and function. In some cases a biomaterial may be referred to as a biomedical material. In fact, The Williams Dictionary of Biomaterials (1999) defines a biomaterial as “material intended to interface with biological systems to evaluate, treat, augment or replace any tissue, organ or function of the body” (p. 42). Examples of the body systems where medical implants can be applied include the following:
- Skeletal system—joint replacements, bone cement, bony defect repair, artificial tendon/ligament, and dental implants
- Mollusk shells, such as oyster shells and mussel shells, have been studied as biomineralization models. In fact, the inner lustrous lining of shells such as oysters is nacre, otherwise known as mother of pearl (Luz and Mano, 2009).
- Cardiovascular system—blood vessel prosthesis (grafts or stents), heart valves, implantable generators (pacemakers, defibrillators, and cardiac resynchronization therapy devices)
- Organs—artificial heart, artificial kidney, artificial pancreas, and skin templates
- Senses—neuromodulation stimulators (cochlear implants, and deep brain or spinal cord stimulators), intraocular lenses, contact lenses, implantable seizure-detection devices, and pain pumps
- The article by Wininger, Bester, & Deshpande (2012) in Pain Management Nursing called “Spinal Cord Stimulation to Treat Postthoracotomy Neuralgia: Non–Small-Cell Cancer: A Case Report” offers an excellent case history of a medical implant application. The article not only examines the medical necessity and benefits of the application, but also outlines how the benefits outweigh the risks.
The goal of biomaterials science is to achieve biocompatibility. The Williams (1999) definition of biocompatibility is “the ability of a material to perform with an appropriate host response in a specific application” (p. 40). This implies survival of the material in a tissue matrix without causing significant inflammation or irritation on an ongoing basis. A truly biocompatible material would promote little-to-no such effects. Despite advances in technology, however, all currently available biomaterial implants are viewed by the body as foreign objects, also called foreign bodies. Foreign body implants trigger the body’s foreign body response, which is a protective immunological response that occurs in several steps. The final step is encapsulation, a process that effectually walls off the implant with stands of fibrous, connective tissue.
— Immunogenicity and the Foreign Body Response —
The term immunogenicity describes the likelihood of a foreign object triggering an immune response, such as the foreign body response. What follows is a synopsis of the foreign body response to an implant:
- First, neutrophils (a type of white blood cell) and tissue react to the implant by a process known as the inflammatory reaction. Simultaneously, certain proteins cover the surface of the implant with a thin film. These proteins also serve as signaling agents and markers, and are collectively known as matricellular proteins (Ratner, 2001).
- Second, the inflammatory reaction can bring macrophages (a type of white blood cell) to the implant site. However, whether or not the macrophages are able to successfully engulf and extrude the foreign body determines the next step.
- Neutrophils and macrophages are the two types of white blood cells of most importance in the scope of this discussion. White blood cells are also known by their group name leukocytes.
- Third, in most, if not all cases of implanted foreign bodies, like those intended as medical devices and implants, macrophages are unable to extrude them. Consequently, the macrophages coalesce around the implant to form multi-nucleated giant cells, which act to encase the implant in granulated tissue called a granuloma. Over time, because of its fibrous connective tissue capsule, the granuloma effectually walls off the implant.
- Figure 1 in the aforementioned article by Wininger, Bester, & Deshpande (2012) shows three locations, after time, where fibrous capsules are most likely to develop with an implantable spinal neurostimulator. These locations are the epidural space, the incision site for the tunneled lead wires, and the gluteal pocket that accepts the rechargeable battery. Figure 2 in the same article is the fluoroscopic image showing the lead wires in the epidural space of the thoracic spine. Again, the article examines the medical necessity and benefits of the application, and outlines how the benefits outweigh the risks in the case presented.
— Foreign Body Response: Fibrous, Connective Tissue Capsule —
Tissue encapsulation is the primary long-term defense to a foreign body implant. However, tissue encapsulation ultimately impacts the usefulness of the implant. In many cases, the thickness of the capsule plays a major role, with thicker capsules being more detrimental to the effectiveness of some implants than thinner ones around the same device type. Regardless of capsule thickness, however, the interface between the implant and tissue will encounter ongoing macrophage activity, which can be detrimental to the success and longevity of certain types of implants. For instance, osteoclasts (a macrophage-related cell associated with bony tissue) can eat away at bone adjacent to the surface of orthopedic implants, and thus loosen the integrity of the application.
A better understanding of the foreign body response, especially the factors that determine the thickness of fibrous tissue encapsulation, is an active area in biomaterials research. According to Anderson (2004):
The form and topography of the surface of the biomaterial determine the composition of the foreign-body reaction. With biocompatible materials, the composition of the foreign-body reaction in the implant site may be controlled by the surface properties of the biomaterial, the form of the implant, and the relationship between the surface area of the biomaterial and the volume of the implant. (p. 311)
Given the importance of the foreign body response and the consequences of tissue encapsulation, the role of the macrophage cannot be overestimated. In fact, researchers have discovered numerous macrophage phenotypes involved in both the foreign body response and normal wound healing (Kohl and DiPietro, 2011).
— A Closer Look: Normal Wound Healing —
In normal wound healing, “neutrophils and macrophages clean the wound site of bacteria, debris, and damaged tissue” (Ratner, 2001, p. 1343). Within this setting, macrophages along with other cells reconstruct the site with vascularized tissue. Noticeably, as part of the reconstruction and revascularization phases, numerous proteins, again, collectively called matricellular proteins, are involved. However, once a wound is healed (i.e., a vascularized network is achieved), the matricellular proteins are no longer needed, and they vanish from the wound site.
What is more, some suggest the matricellular proteins play the key role in the applications of implanted biomaterials. According to Ratner (2001), “an understanding of the matricellular proteins involved in wound healing suggests novel surface modification approaches to improve the performance of implants, including endosseous devices” (p. 1343).
All of this leaves us with the impression that the supportive tissue around a medical implant site, including the cells adjacent to the site, plays a crucial role. This zone contains the extracellular matrix.
— The Extracellular Matrix and the Idea of Tissue Scaffolds —
Apart from blood, all cells in the human body reside within what is called the extracellular matrix. Chan and Leong (2008) reviewed five functions of the extracellular matrix:
- Structural support for cells (i.e., a physical environment for cells)
- Mechanical properties that are associated with normal tissue function, such as rigidity and elasticity
- A regulatory function that provides cues for residing cells to regulate their activities
- A growth factor reservoir that helps to regulate the activities of these factors
- A degradable physical environment not only for new vascularization, but also for remodeling. This plasticity is a response to developmental, physiological, and pathological changes during tissue morphology, homeostasis (i.e., maintenance of equilibrium), and wound healing, respectively.
From a functional point of view, a tissue scaffold is the bioengineered analog of the extracellular matrix. What is more, O’Brien (2011) describes tissue scaffolds as one part of a three-pronged approach to tissue engineering. The remaining two prongs are the cells and the growth factors/bioreactor.
The concept of tissue engineering
In the late 20th century, the process of fabricating tissue in the laboratory became known as tissue engineering, and this effectually caused a paradigm shift in reconstructive surgery (Bell, 2000).
- This exact argument can be made for regenerative medicine, which is a subject explored in greater detail later in this series. However, for now we may consider regenerative medicine as a branch of medicine that attempts to improve structure and function at the biological tissue level, and very often at the cellular level. Ultimately, the purpose is to prevent deficits that can lead to functional impairments at the organ and whole-body levels. In fact, the goals of tissue engineering, regenerative medicine, and even biomaterials, are closely related: minimize loss of (or attempt to improve) structure and function. What is more, because of the importance of minimizing loss, particularly functional loss at the whole-body level, the notion of regenerative rehabilitation has become a meaningful issue within the field of physical therapy to assist patients in improving their functional capacity.
Three examples of biomimicry applied to tissue engineering
With respect to biomimicry and bony tissue engineering, no other material has been examined as intensely as nacre. This is because of nacre’s inherently high biocompatibility. What is more, the mechanical properties of nacre have also played a role in its investigation as a viable biomimetic. Nacre, as a biomineral, has a consistent hierarchal structure of mineral layering (Kakisawa & Sumitomo, 2011, and Luz & Mano, 2009). The use of nacre has been investigated in dental, oral and facial surgery, as well as various orthopedic applications (Gerhard et al., 2017, and Ratner, 2001). In fact, in recent years, biomimetic dentistry has emerged as a branch of dentistry, and nacre organic matrix extract has been used for enamel remineralization (Green, Lai, & Jung, 2014).
Bone/marine sponge collagen scaffolds
A recent approach in the development of a biocompatible bony matrix centers on the feasibility of modeling the marine sponge. Interest in developing sponge-based matrices exists because of the diversity in the types of sponges available and because of the porous properties of their skeletal frameworks that invite cellular infiltration (Green, Howard, Yang, Kelly, & Oreffo, 2003).
Heart/cardiac tissue engineering
Because of the unique makeup of cardiac tissue, the work surrounding cardiac tissue scaffolds has focused on mimicking the physiological properties of the heart itself. This fact is true whether we are talking about designing artificial heart valves that mimic the mechanical properties of native heart valve tissue (Capulli et al., 2017), or boldly seeking to engineer myocardial tissues that elicit the unique mechanical, biological, and electrical properties existing at cell-tissue interfaces throughout the heart (Kaiser & Coulombe, 2015).
For you formed my inward parts; you knitted me together in my mother’s womb. I praise you, for I am fearfully and wonderfully made. Wonderful are your works; my soul knows it very well.
– Psalm 139:13,14 (ESV)
Can you imagine a career researching and developing tissue scaffolds that might even mimic nature – God’s great creation?
Christian scholarship extending into professional roles is sincerely needed in education and culture. Chemical engineering and bioengineering can be a promising career for those who like to study physiology, microbiology, and biochemistry. As a starting point, we encourage you to reach out to teachers at Christian colleges. Undergraduate studies that include anatomy and physiology, as well as kinesiology, can provide a firm basis for learning the practical implications of biology and chemistry. This foundation can lead to future studies in biomaterials and tissue engineering, including biomimetic applications, as graduate students.
- To get a head-start in anatomy and physiology, please see the 2018 article in Answers Research Journal called “Biblical Integration in Anatomy and Physiology: A Design Approach,” by Elizabeth Sled, PhD.
Anderson, J.M. (2004). Inflammation, wound healing, and the foreign-body response. In Ratner, B., Hoffman, A., Schoen, F., & Lemons, J. (Eds.), Biomaterials science: An introduction to materials in medicine (2nd ed., pp. 296-303). San Diego, CA: Elsevier Academic Press.
Bell, E. (2000). Tissue engineering in perspective. In Lanza, R.P., Langer, R., & Vacanti, J. (Eds.), Principles of tissue engineering (2nd ed., pp. xxxv-xli). San Diego, CA: Academic Press.
Capulli, A.K., Emmert, M.Y., Pasqualini, F.S., Kehl, D., Caliskan, E., Lind, J.U., … Parker, K. (2017). JetValve: Rapid manufacturing of biohybrid scaffolds for biomimetic heart value replacement. Biomaterials, 133, 229-241. [View in article]
Chan, B.P. & Leong, K.W. (2008). Scaffolding in tissue engineering: General approaches and tissue-specific considerations. European Spine Journal, 17(supplement 4), 467-479. [View in article]
Gerhard, E.M., Wang, W., Li, C., Guo, J., Ozbolat, I.T., Rahn K.M., … Yang, J. (2017). Design strategies and applications of nacre-based biomaterials. Acta Biomaterialia, 54, 21-34. [View in article]
Green, D., Howard, D., Yang, X., Kelly, M., & Oreffo, R.O. (2003). Natural marine sponge fiber skeleton: a biomimetic scaffold for human osteoprogenitor cell attachment, growth, and differentiation. Tissue Engineering, 9(6), 1159-1166. [View in article]
Green, D.W., Lai, W., & Jung, H. (2014). Evolving marine biomimetics for regenerative dentistry. Marine Drugs, 12(5), 2877-2912. [View in article]
Kaiser, N.J., & Coulombe, K.L.K. (2015). Physiologically inspired cardiac scaffolds for tailored in vivo function and heart regeneration. Biomedical Materials, 10(3), 1-26. [View in article]
Kakisawa, H., & Sumitomo, T. (2011). The toughening mechanism of nacre and structural materials inspired by nacre. Science and Technology of Advanced Materials, 12(6), 1-14. [View in article]
Koh, T.J., & DiPietro, L.A. (2011). Inflammation and wound healing: The role of the macrophage. Expert Reviews in Molecular Medicine, 13(e23), 1-14. [View in article]
Luz, G.M., & Mano J.F. (2009). Biomimetic design of materials and biomaterials inspired by the structure of nacre. Philosophical Transactions of the Royal Society A, 367, 1587-1605. [View in article]
O’Brien, F.J. (2011). Biomaterials & scaffolds for tissue engineering. Materials Today, 14(3), 88-95. [View in article]
Ratner, B.D. (2001). Replacing and renewing: Synthetic materials, biomimetics, and tissue engineering in implant dentistry. Journal of Dental Education, 65(12), 1340-1347. [View in article]
Sled, E. (2018). Biblical integration in anatomy and physiology: A design approach. Answers Research Journal, 11, 141-148. [View in article]
Williams, D.F. (Ed.) (1999). The Williams dictionary of biomaterials. Liverpool, England: Liverpool University Press.
Wininger, K.L., Bester, M.L., & Deshpande, K.K. (2012). Spinal cord stimulation to treat postthoracotomy neuralgia: Non–small-cell cancer: A case report. Pain Management Nursing, 13(1), 52-59. [View in article]
Previous articles in this series:
The next installment in our biomimetic series focuses on cardiovascular medicine!
Our next installment will discuss biomimetic applications in cardiovascular medicine, including commentary on how much of the work in cardiac tissue engineering is focusing on regenerative medicine. However, with respect to regenerative medicine, we will try to center our discussion on methods that think outside-the-stem-cell box.