Faculty of Materials & Chemical Engineering, Next-generation Biomaterials for Bone-tissue Regeneration: Mg-alloys on the move Dr Yasir F Joya Faculty of Materials & Chemical Engineering, GIK Institute of Engineering Sciences and Technology, Topi 23640, Pakistan The present review is to explore the recent developments in designing novel Mg-alloys and nanocomposites with tailored biodegradation in-vitro and highlight the most successful ways to optimize their surface properties for potential clinical use in bone-tissue healing. International Scientific School, March 13 - 17, 2017

Contents Introduction Healthcare Needs of the Society Existing Biomedical Implants Next-generation Implants Research in Mg-alloys and composites Applications in Tissue Engineering Summary & Future Outlook

Introduction Bone-disorders are becoming a significant concern due to a number of reasons, specifically aging human population. More than two million bone-surgeries are performed worldwide with an annual cost of $2.5 billion which is expected to double within next decade. Why this work? The adult human skeleton comprises 80% cortical bone and 20% trabecular bone. Bone mineral content is primarily hydroxyapatite [Ca10(PO4)6(OH)2] with small amounts of carbonate, magnesium, and acid phosphate.

Bone Disorders Arthritis affects 14 million Pakistanis while 6.7 million people are suffering from Osteoporosis*. Around the world, 1 in 3 women and 1 in 5 men are at risk of an osteoporotic fracture. Osteoporosis is when the rate of ‘bone formation’ and ‘bone resorption is not in equilibrium. People with osteoporosis most often break bones in the hip, spine and wrist. *http://medimoon.com/2012/10/6-7-million-people-in-pakistan-are-suffering-from-osteoporosis/ http://aaj.tv/2013/01/arthritis-affects-14-million-pakistanis-orthopedic-expert/

Bone Disorders

Bone Disorders Cases of bone disorders are rapidly increasing, even in the middle-aged populations. Lifestyle, work and food habits, lack of physical work, family history  main contributing factors. Low-cost and sustainable biomedical solutions are highly desired for bone-tissue replacement and/or regeneration. Typical bone disorders such as trauma, diseases, tumours, injuries, fractures have trended steeply upward in recent years.

Biomaterials for Healthcare Biomaterials are frequently used in bone, dental and cardio implants and scaffolds that interact with animal or human tissues/cells and biological fluids. The principle underlying the bulk of biomaterials development was to reduce to a minimum the immune response to the foreign body, and this is still valid 21 years later. Y. Chen, Z. Xu, C. Smith, and J. Sankar, Acta Biomaterialia, vol. 10, pp. 4561-4573, 2014.

Bone Implants Mostly use bioactive materials based on unique designs, compositions and properties challenged by the variable biological and mechanical conditions inside the body. How this work? Uduwage, Don Suranga Dhanushka, "Binder Jet Additive Manufacturing of Stainless Steel-Hydroxyapatite Bio-composite" (2015). All Theses, Dissertations, and Other Capstone Projects. Paper 432.

Biomaterials for Healthcare Metallic biomaterials continue to play vital roles in the repair/replacement of damaged or dead cells of bone tissues. Their demand to assist/replace organ functions has been rising due to aging population healthcare needs. The aim of using biomaterials ; They should be friendly to the human physiological system.

Biomaterials Evolution 1st Generation 2nd Generation 3rd Generation* 1960-80 1980-2000 2002-Present Designed to stimulate specific responses at molecular level, such as cells and genes In 2nd generation, Ceramics (Bioactive glass, glass–ceramics and calcium phosphates (CaPs) or their coatings on metals to make them bioactive from bio-inert. Resorbable fracture fixation plates and screws in orthopedics and controlled-release drug-delivery systems were in their infancy in 1984 Bioinert Bioactive and resorbable *L. L. Hench and J. M. Polak, "Third-Generation Biomedical Materials," Science, vol. 295, pp. 1014-1017, 2002.

3rd-Generation Biomaterials Are used in temporary implants to supporting the healing process of injured tissue. Such as in cardiovascular and orthopaedic applications. Improvements of first- and second-generation biomaterials are limited in part because all man-made biomaterials used for repair or restoration of the body represent a compromise. Polymer-based cardiovascular stent Plates and screws for bone fixation

3rd-Generation Biomaterials 3gen Biomaterials polymers metals Ceramics composites The concept of biodegradation was first applied in medicine through the use of biodegradable polymer sutures. D. Zhao et al. / Biomaterials 112 (2017) 287e302

Selection and Design Conventional biomaterials lead to stress shielding of the bone due to mismatch of Elastic Moduli. The fracture toughness of magnesium is greater than ceramic biomaterials such as hydroxyapatite, while the elastic modulus and compressive yield strength of magnesium are closer to those of natural bone. Magnesium is essential to human metabolism and is naturally found in bone tissue. Excess is harmlessly excreted by the body. *M.P. Staiger et al. / Biomaterials 27 (2006) 1728–1734

Research in Biodegradable metals Research in Mg-alloys and composites

Challenges in Clinical use of Mg Pure Mg corrodes too quickly in the physiological environment, loosing mechanical strength before the tissue has sufficiently healed. The implant/fixture should remain for at least 12 weeks for the bone-healing process to complete. The in vivo corrosion of magnesium-based materials involves the formation of soluble, nontoxic corrosion products that are harmlessly excreted in the urine. Several possibilities exist to tailor the corrosion rate of magnesium by using alloying element and protective coatings that must lead to a non-toxic and biocompatible material. A typical Mg-based screw pre-implantation a) and 8 weeks post-implantation b)

Biodegradable Magnesium Alloys Can we control their biodegradation rates? Can we make them friendly to the variable physiological environment in-vivo? The biodegradable implants should remain in the body and maintain mechanical integrity for 12 to 18 weeks whilst the bone tissue heals, and eventually, the implant will be replaced by natural tissue

Optimizing through Mg-alloys One possible solution is through compositional control Selecting the type and concentration of the alloying elements to achieve suitable mechanical properties with the optimised degradation profile. clinicians stress the relevance of toxicity assessment that must be considered during material design

Biodegradable Mg-alloys Recent research focuses on several groups of Mg-alloys. Mg-alloys for bone implants Mg-Al-Zn (AZ) Mg-Zn Mg-Ca Mg-RE The first group contains aluminium (Al) as main alloying element with trace additions of zinc and manganese. Cerium (Ce), lanthanum (La), scandium (Sc) and yttrium (Y), Neodymium Nd are the RE generally added to Mg alloys.

Mechanical Properties *Y. Chen et al. / Acta Biomaterialia xxx (2014) xxx–xxx

Biodegradation rates Binary and Tertiary Mg-alloys *Y. Chen et al. / Acta Biomaterialia xxx (2014) xxx–xxx

Optimizing through Mg-Alloys Mg-alloys designs continue to improve their bulk and surface properties to stimulate regeneration of bone-tissues as well as drug delivery. BIOTRONIK magnesium bioabsorbable drug eluting stent Screws used to correct mild hallux valgus (foot disease)

Recent Advancements: Porous Mg-Foams Low density Mg-based porous scaffolds for tissue engineering and bone regeneration. Increased porosity leads to better osseointegration The porosity assists in anchoring the implant within the bone, as new bone grows into the pores. A number of fabrication techniques have been used to prepare porous metal foams for use in orthopaedic applications such as W. Ding, Regenerative Biomaterials, 2016, 79–86

Nano-Composite Mg-Alloys Various phases of synthetic hydroxyapatite (HAp)* SEM image of HAp samples SEM image of Mg-nHAp nanocomposite *Z Sheikh et al, Materials 2015, 8, 5744-5794; doi:10.3390/ma8095273

Surface engineering of Mg-Alloys

Surface-Coated Mg-Alloys Brushite coating on Mg-Nd-Zn alloy HAp coated Mg-Al-Zn (AZ31) alloy *G. Wu et al. / Surface & Coatings Technology 233 (2013) 2–12

Bone-Tissue Engineering Bone-cells are seeded onto modified resorbable scaffolds (such as Mg-alloy+HAp). The cells grow outside the body and become differentiated and mimic naturally occurring tissues. Tissue Engineering: The use of cells and biomaterials (such as degradable matrices and scaffolds) to generate tissues. Examples are mini, implantable bioreactors that contain liver cells and like the liver, may remove toxins from the circulation.

Advanced technologies: Additive Manufacturing 3D-printed bone and craniofacial implants

Bio-Extrusion or Bio-printing Printing of living cells together with hydrogels-based scaffolds. Inkjet-based printing Extrusion-based deposition G. Narayanan et al. / Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

Future Work New research on correlating the influence of the microstructure on degradation Studies on the microstructure grain size and the secondary phase type, size, amount, and distribution and their influence of corrosion Nanocomposite Mg-alloys consisting of HAp and other phases of Calcium phosphates. 3D-bioprinting of Mg-composite scaffolds for bone-tissue engineering 3D printing is emerging as a key manufacturing technology in future biomedical engineering.

SHUKRIA (THANK YOU)

Mg-RE alloys The second main group of Mg alloys contains a mixture of rare earths (RE) elements in combination with another metal, generally zinc or yttrium. Such as WE43 alloy (4 wt% Y, 3 wt% RE) Minor additions of zirconium enhances mechanical properties by grain refinement. Like Al, these elements increase the strength by both solid solution and precipitation hardening.

Outlook