Biomedical Implants for Regenerative Therapies

*Andrea Domingues Goncalves, Wendy Balestri and Yvonne Reinwald*

### **Abstract**

Regenerative therapies aim to develop novel treatments to restore tissue function. Several strategies have been investigated including the use of biomedical implants as three-dimensional artificial matrices to fill the defect side, to replace damaged tissues or for drug delivery. Bioactive implants are used to provide growth environments for tissue formation for a variety of applications including nerve, lung, skin and orthopaedic tissues. Implants can either be biodegradable or non-degradable, should be nontoxic and biocompatible, and should not trigger an immunological response. Implants can be designed to provide suitable surface area-to-volume ratios, ranges of porosities, pore interconnectivities and adequate mechanical strengths. Due to their broad range of properties, numerous biomaterials have been used for implant manufacture. To enhance an implant's bioactivity, materials can be functionalised in several ways, including surface modification using proteins, incorporation of bioactive drugs, growth factors and/or cells. These strategies have been employed to create local bioactive microenvironments to direct cellular responses and to promote tissue regeneration and controlled drug release. This chapter provides an overview of current bioactive biomedical implants, their fabrication and applications, as well as implant materials used in drug delivery and tissue regeneration. Additionally, cell- and drug-based bioactivity, manufacturing considerations and future trends will be discussed.

**Keywords:** biomaterials, bioactive biomedical implants, stem cells, drug delivery, manufacturing

### **1. Introduction to bioactive implants**

Implants are man-made devices that are fabricated for the implantation inside body to replace or support a biological structure, together with delivering drugs and monitoring body functions. They can remain in the body temporarily or permanently [1]. To date, biomedical implants are used not only as sensory devices [2]; brain and neural devices including neuronal, cochlear and retinal implants [3, 4]; subcutaneous implants [5]; cardiovascular devices such as vascular grafts, stent, heart valves, pacemakers [3]; sutures and wound dressings [6]; spinal [7] and dental implants [8]; cosmetic [9] and structural implants [10] including rods, braces, craniofacial, hip and knee replacements; but also as ophthalmic devices including glasses and contact lenses as well as insulin delivery devices [6].

#### *Biomaterials*

In recent years, scaffolds made of synthetic or natural polymers were developed to regenerate damaged or deteriorated tissues, or to deliver drugs to specific locations. Scaffolds are three-dimensional (3D) structures that mimic the native extracellular matrix (ECM) of tissues and provide a substrate for cell adhesion and proliferation.

These biomedical implants can be made of bioactive materials. The term "bioactive" means that a material can affect its surrounding tissue biologically. Scaffolds can include molecules that promote a biological response in the region where they are implanted. Moreover, cells can be included in these scaffolds to promote healing and regeneration, as they naturally secrete growth factors and cytokines [11].

The risks related to the surgery during the placement or removal of the implant include infection and implant failure. Also, inflammation reaction against the material or rejection needs to be taken into consideration [1]. Here, we report what it is known about bioactive biomedical implants, their desired properties and their applications, focusing on the techniques and materials used for their fabrication. We further provide an overview of cell-based and drug-based implants, implant manufacture and its considerations.

### **2. Biomaterials for implants in drug delivery and regenerative therapies**

To assist native tissue regeneration or/and replacement, implants are made of biomaterials, which support cell and tissue growth through cell adhesion, proliferation and differentiation, prevent unwanted cell and tissue growth, tailor tissue response and prevent immunological responses [12].

Biomaterials have been used for controlled drug delivery systems, sutures and adhesives including biodegradable and non-biodegradable materials, cardiovascular grafts, reconstructive and orthopaedic implants, ophthalmic devices such as corneas and contact lenses, and dental implants [13]. Various types of materials have been used to produce biomedical implants. These include bioceramics, polymers, metals and composites, which are further discussed below. **Table 1** summarises current biomedical applications for biomaterials.


**5**

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

Ceramics are chemically inert and possess low thermal and electric conductivity as well as physical properties, which make them a suitable material glass for biomedical implants [34, 35]. Bioceramics are osteoinductive and osteoconductive and possess mechanical properties like native bone. Their use as biomedical implants prevents the transmission of diseases and immunogenicity. To date, bioceramics are utilised for dental, periodontal, maxillofacial and orthopaedic applications [36]. In comparison to non-resorbable bioceramics, degradable ceramics exhibit lower mechanical strength. Their chemical and physical composition determines their

Ceramics produced from aluminium, zirconium and titanium oxides possess bending, tensile and compressive strength at least 3 times higher than natural bone and are used mainly for pin-type dental implants and root- and endosteal plate forms [38]. The first zirconia implants were reported in the 1970s. These implants exhibited the ability to integrate into bone tissue, accumulate less plaque and provide improved aesthetics compared to titanium implants [39, 40]. Hence, titanium-zirconium alloys, also called Straumann Roxolid or Roxolit (TiZr1317), are often used as dental implants due to their enhanced mechanical properties and osseointegrative properties that are often used as dental

Calcium phosphate-based bioceramics such as tricalcium phosphate (TCP) are similar in chemical composition to the inorganic phase natural bone tissue. TCP exhibits better biodegradation, restorability and bioactivity *in vivo* than hydroxyapatite and is commonly used for orthopaedic, dental and maxillofacial applications. Complete resorption of orthopaedic implants fabricated from TCP was reported after up to 2 years in the rat tibia and for the formation of cancellous

Amorphous or low crystalline hydroxyapatite (HAp) is bioactive and bioresorbable. The preparation of synthetic HA at high temperatures results in high crystallinity. Biodegradation and resorbability of HAp are very slow. HAp bioceramics are commonly used for small defects in the case of bone loss or fractures of the tibia, calcaneus and vertebra. HAp is not employed for load-bearing bone applications because of its poor mechanical properties. The modification of HAp with strontium, magnesium and silicon ions resulted in enhanced mechanical and biological properties [43]. Improved bioresorbability was achieved by zinc—[44] and

Dicalcium phosphates (DCP) are biodegradable ceramics composed of calcium phosphates and water. DCPs are widely added to material compositions to modify their physical properties. Dehydrated DCP is known as brushite, which is used in

Historically, ceramics have been used as dental and orthopaedic implant mate-

Polymers are macromolecules that consist of covalently bonded repeating units, which can be of the same (homopolymers) or different (co-polymers) molecule type [27]. A variety of natural and synthetic polymers are used as soft tissue transplants, facial prostheses, denture, hip and joint replacements as well as medical

rials. However, compared to other material classes, ceramics have not been used extensively as implant materials due to their limited load-bearing

**2.1 Bioceramics**

biological response [37].

implants [41].

bone [42].

capacity [14].

**2.2 Polymers**

manganese—[45] substitution of HAp.

adhesives, sealants and coatings [14].

tibial plate and distal metaphysis bone fractures [46].

**Table 1.** *Examples of biomedical applications for currently used biomaterials.*

### **2.1 Bioceramics**

*Biomaterials*

manufacture and its considerations.

response and prevent immunological responses [12].

current biomedical applications for biomaterials.

*Examples of biomedical applications for currently used biomaterials.*

Ophthalmic applications (contact lenses, intraocular lenses)

Cardiovascular applications (vascular prostheses, artificial valves, stents, cardiac-assisted pumps, blood bags and catheters)

Central nervous system and peripheral nervous system (scaffolds for nerve regeneration)

replacements)

Orthopaedic applications (total hip replacement, hip arthroplasty, total knee arthroplasty, bone screws, orthodontic brackets and wires; bone fillers and scaffolds as bone

In recent years, scaffolds made of synthetic or natural polymers were developed to regenerate damaged or deteriorated tissues, or to deliver drugs to specific locations. Scaffolds are three-dimensional (3D) structures that mimic the native extracellular matrix (ECM) of tissues and provide a substrate for cell adhesion and proliferation. These biomedical implants can be made of bioactive materials. The term "bioactive" means that a material can affect its surrounding tissue biologically. Scaffolds can include molecules that promote a biological response in the region where they are implanted. Moreover, cells can be included in these scaffolds to promote healing and regeneration, as they naturally secrete growth factors and cytokines [11].

The risks related to the surgery during the placement or removal of the implant

include infection and implant failure. Also, inflammation reaction against the material or rejection needs to be taken into consideration [1]. Here, we report what it is known about bioactive biomedical implants, their desired properties and their applications, focusing on the techniques and materials used for their fabrication. We further provide an overview of cell-based and drug-based implants, implant

**2. Biomaterials for implants in drug delivery and regenerative therapies**

To assist native tissue regeneration or/and replacement, implants are made of biomaterials, which support cell and tissue growth through cell adhesion, proliferation and differentiation, prevent unwanted cell and tissue growth, tailor tissue

Biomaterials have been used for controlled drug delivery systems, sutures and adhesives including biodegradable and non-biodegradable materials, cardiovascular grafts, reconstructive and orthopaedic implants, ophthalmic devices such as corneas and contact lenses, and dental implants [13]. Various types of materials have been used to produce biomedical implants. These include bioceramics, polymers, metals and composites, which are further discussed below. **Table 1** summarises

**Application Material References**

Silicones, hydrogels [14]

Polycaprolactone (PCL), silk, collagen [11, 22–26]

[15–21]

[11, 12, 14, 27–33]

Polymers, metals and ceramics; polyurethane (PU); polyesters (PE); polybutesters (PBE); polypropylene (PP) and PTFE; stainless steel

Chromium, cobalt, molybdenum, nickel, titanium and zirconium alloys, ultrahigh molecular weight polyethylene (UHMWPE), Ti-6Al-4V, ceramic-coated steels, stainless steel, copper; natural polymers like collagen, chitosan, alginates, synthetic polymers, ceramics like bioglasses, hydroxyapatite and beta-TCP; poly(l-lactic acid) (PLLA); poly(lactic acid), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL)

**4**

**Table 1.**

Ceramics are chemically inert and possess low thermal and electric conductivity as well as physical properties, which make them a suitable material glass for biomedical implants [34, 35]. Bioceramics are osteoinductive and osteoconductive and possess mechanical properties like native bone. Their use as biomedical implants prevents the transmission of diseases and immunogenicity. To date, bioceramics are utilised for dental, periodontal, maxillofacial and orthopaedic applications [36]. In comparison to non-resorbable bioceramics, degradable ceramics exhibit lower mechanical strength. Their chemical and physical composition determines their biological response [37].

Ceramics produced from aluminium, zirconium and titanium oxides possess bending, tensile and compressive strength at least 3 times higher than natural bone and are used mainly for pin-type dental implants and root- and endosteal plate forms [38]. The first zirconia implants were reported in the 1970s. These implants exhibited the ability to integrate into bone tissue, accumulate less plaque and provide improved aesthetics compared to titanium implants [39, 40]. Hence, titanium-zirconium alloys, also called Straumann Roxolid or Roxolit (TiZr1317), are often used as dental implants due to their enhanced mechanical properties and osseointegrative properties that are often used as dental implants [41].

Calcium phosphate-based bioceramics such as tricalcium phosphate (TCP) are similar in chemical composition to the inorganic phase natural bone tissue. TCP exhibits better biodegradation, restorability and bioactivity *in vivo* than hydroxyapatite and is commonly used for orthopaedic, dental and maxillofacial applications. Complete resorption of orthopaedic implants fabricated from TCP was reported after up to 2 years in the rat tibia and for the formation of cancellous bone [42].

Amorphous or low crystalline hydroxyapatite (HAp) is bioactive and bioresorbable. The preparation of synthetic HA at high temperatures results in high crystallinity. Biodegradation and resorbability of HAp are very slow. HAp bioceramics are commonly used for small defects in the case of bone loss or fractures of the tibia, calcaneus and vertebra. HAp is not employed for load-bearing bone applications because of its poor mechanical properties. The modification of HAp with strontium, magnesium and silicon ions resulted in enhanced mechanical and biological properties [43]. Improved bioresorbability was achieved by zinc—[44] and manganese—[45] substitution of HAp.

Dicalcium phosphates (DCP) are biodegradable ceramics composed of calcium phosphates and water. DCPs are widely added to material compositions to modify their physical properties. Dehydrated DCP is known as brushite, which is used in tibial plate and distal metaphysis bone fractures [46].

Historically, ceramics have been used as dental and orthopaedic implant materials. However, compared to other material classes, ceramics have not been used extensively as implant materials due to their limited load-bearing capacity [14].

### **2.2 Polymers**

Polymers are macromolecules that consist of covalently bonded repeating units, which can be of the same (homopolymers) or different (co-polymers) molecule type [27]. A variety of natural and synthetic polymers are used as soft tissue transplants, facial prostheses, denture, hip and joint replacements as well as medical adhesives, sealants and coatings [14].

#### *Biomaterials*

Polymers are commonly selected based on their physical characteristics, composition, and mechanical properties; how easily they can be modified and moulded; their heat and electric conductivity as well as their ability to integrate into and attach to native tissue [47].

### *2.2.1 Natural polymers*

Natural polymers possess similar properties to native tissues. They are non-toxic and exhibit protein binding-sites and biochemical moieties that are important for tissue regeneration. However, natural polymers are often associated with immunological reactions, low mechanical strength and degradation at body temperature limiting their usability [14].

One of the most commonly used natural polymers is collagen. More than twenty different collagens are known in connective tissues such as bone, tendon, skin, cartilage and ligaments of the ECM of different species. Collagen type I is the main component in bone, skin and tendon, whereas type II is found in articular cartilage. Because of its abundance in nature, its importance for tissue homeostasis and growth, collagen has been investigated as material for bone, cartilage, tendon, skin and blood vessel regeneration [11]. In the clinic, collagen is used for the generation of dermal tissue, neo-tissue formation and wound healing [14]. Further natural polymers are chitosan, hyaluronic acid, fibrin and silk.

Silk, or silk fibroin, is a naturally occurring polymeric protein produced by insects and worms. The protein content gives rise to silk's biocompatibility and its high tensile strength making it an ideal biomaterial for biomedical applications as gels, sponges and films [11, 48–53]. Silk composites fabricated from silk-chitosan and silk-hydroxyapatite have been used to improve silk's elasticity, degradation and porosity [54, 55].

Hyaluronic acid (HA), a non-adhesive glycosaminoglycan (GAG), occurs mostly in connective, epithelial, and neural tissue [56]. HA is commonly used as hydrogel for the regeneration of bone, cartilage and the vascular system and for drug delivery [11].

Chitosan is a biodegradable polysaccharide produced through partial deacetylation of chitin. Chitosan scaffolds exhibit similar properties to naturally occurring GAGs, leading to their bioactivity, and support cellular adhesion [11, 57]. It has been investigated as scaffold material in combination with collagen and HA, as well as PCL for bone, cartilage and nerve regeneration [11].

#### *2.2.2 Synthetic polymers*

Synthetic polymers were developed with tailored physical and chemical properties depending on the desired application to overcome limitations of natural polymers. Synthetic polymers are linear, branched or cross-linked depending on their molecular arrangement [58] and possess amorphous or crystalline structures [27]. In addition, synthetic polymers are cheaper in production and enable improved functionality [11]. Commonly used synthetic polymers are poly(lactic acid-co-glycolic acid) (PLGA), polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL) and poly-hydroxybutyrate (PHB) [11, 27, 59, 60].

PGA, PLA and PCL are used for sutures, interference screws, fixation plates for meniscal repair and craniomaxillofacial fixtures and 3D scaffolds. However, they are known to induce inflammatory responses and are limited in mechanical integrity and controlled degradation. Hence, metal/polymer composites such as Mg/PCL have been developed [27]. Biodegradable synthetic polymers

**7**

characteristics (**Table 2**).

**2.3 Metals and alloys**

and Mg-Sr alloys [90].

implants [34].

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

Poly(l-lactic acid) (PLLA); poly (d-lactic acid) (PDLA)

PCL-gelatin, PCL-chitosan,

Low-density polyethylene (LDPE), high-density polyethylene (HDPE)

Polyamides (PA), e.g., nylon and

Carbon nanotubes (CNT) and

nylon-composites

composites

**Table 2.**

PCL-collagen

are chosen based on the required physical, chemical and mechanical material

**Synthetic polymer Application References**

atrophy (Scultra™)

implant; drug release

rhinoplasty surgery

aesthetics

peacemakers

hydroxyapatite

films, foams and moulded scaffolds

Total hip arthroplasty and treatment of osteolysis as polymer-ceramic composites;

cranioplasty, bone cement in hip joint replacement, dental implant for restoration and

and sensors, medical implants, oesophagus substitutes, catheters, shunts, blood pumps and

Sutures, fabrication of dentures; scaffold materials and nanofillers for bone regeneration

Metal coatings for load-bearing musculoskeletal implants to improve surface porosity, reduce metal ionisation and promote the formation of

Poly(lactic-co-glycolic acid) (PLGA) Drug delivery [11, 62]

Polycaprolactone (PCL) Long-term implant, maxillo-cranial facial

Poly-para-dioxanone (PPD) Internal fracture fixation, medical implant as

Poly(methyl methacrylate) (PMMA) Orbital medical implants, rhinoplasty,

Polydimethylsiloxane (PDMS) Enclosing implantable electronic devices

Sutures, drug delivery, vascular grafts, bone screws, fixation pins, dermal filler for facial

Tissue regeneration [60, 64, 65]

[11, 61]

[11, 63]

[47, 66, 67]

[68–71]

[72–76]

[77–80]

[81, 82]

[83]

Due to their mechanical properties, the ease of their processing and the possibility to sterilise them, metals and alloys are ideal materials for biomedical

Metals are commonly used as load-bearing orthopaedic implants such as wires, screws, fixation plates, artificial joints for hips, knees, shoulders and ankles, as well

Novel magnesium alloys have been investigated for orthopaedic and cardiovascular applications [84, 85]. Combining magnesium alloys with aluminium or rare earth metals improves their mechanical properties [86, 87]. However, the accumulation of these elements is associated with neurotoxicity and hepatotoxicity [88]; hence, these alloys are not suitable for biomedical applications. Instead, extensive research is carried out to develop nontoxic magnesium alloys [89], such as Mg-Si

Titanium alloys are among the most commonly used metal alloys [91] due to their biocompatibility [92] and corrosion resistance [93]. Their composition

as for dental, cardiovascular and craniofacial applications [14].

*Synthetic polymers commonly used for the fabrication of biomedical implants.*

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*


#### **Table 2.**

*Biomaterials*

attach to native tissue [47].

limiting their usability [14].

porosity [54, 55].

delivery [11].

*2.2.2 Synthetic polymers*

*2.2.1 Natural polymers*

Polymers are commonly selected based on their physical characteristics, composition, and mechanical properties; how easily they can be modified and moulded; their heat and electric conductivity as well as their ability to integrate into and

Natural polymers possess similar properties to native tissues. They are non-toxic and exhibit protein binding-sites and biochemical moieties that are important for tissue regeneration. However, natural polymers are often associated with immunological reactions, low mechanical strength and degradation at body temperature

One of the most commonly used natural polymers is collagen. More than twenty

different collagens are known in connective tissues such as bone, tendon, skin, cartilage and ligaments of the ECM of different species. Collagen type I is the main component in bone, skin and tendon, whereas type II is found in articular cartilage. Because of its abundance in nature, its importance for tissue homeostasis and growth, collagen has been investigated as material for bone, cartilage, tendon, skin and blood vessel regeneration [11]. In the clinic, collagen is used for the generation of dermal tissue, neo-tissue formation and wound healing [14]. Further natural

Silk, or silk fibroin, is a naturally occurring polymeric protein produced by insects and worms. The protein content gives rise to silk's biocompatibility and its high tensile strength making it an ideal biomaterial for biomedical applications as gels, sponges and films [11, 48–53]. Silk composites fabricated from silk-chitosan and silk-hydroxyapatite have been used to improve silk's elasticity, degradation and

Hyaluronic acid (HA), a non-adhesive glycosaminoglycan (GAG), occurs mostly

in connective, epithelial, and neural tissue [56]. HA is commonly used as hydrogel for the regeneration of bone, cartilage and the vascular system and for drug

Chitosan is a biodegradable polysaccharide produced through partial deacetylation of chitin. Chitosan scaffolds exhibit similar properties to naturally occurring GAGs, leading to their bioactivity, and support cellular adhesion [11, 57]. It has been investigated as scaffold material in combination with collagen and HA, as well

Synthetic polymers were developed with tailored physical and chemical properties depending on the desired application to overcome limitations of natural polymers. Synthetic polymers are linear, branched or cross-linked depending on their molecular arrangement [58] and possess amorphous or crystalline structures [27]. In addition, synthetic polymers are cheaper in production and enable improved functionality [11]. Commonly used synthetic polymers are poly(lactic acid-co-glycolic acid) (PLGA), polyglycolic acid (PGA), polylactic acid (PLA), polycaprolactone (PCL) and poly-hydroxybutyrate (PHB) [11, 27, 59, 60].

PGA, PLA and PCL are used for sutures, interference screws, fixation plates for meniscal repair and craniomaxillofacial fixtures and 3D scaffolds. However, they are known to induce inflammatory responses and are limited in mechanical

integrity and controlled degradation. Hence, metal/polymer composites such as Mg/PCL have been developed [27]. Biodegradable synthetic polymers

polymers are chitosan, hyaluronic acid, fibrin and silk.

as PCL for bone, cartilage and nerve regeneration [11].

**6**

*Synthetic polymers commonly used for the fabrication of biomedical implants.*

are chosen based on the required physical, chemical and mechanical material characteristics (**Table 2**).

#### **2.3 Metals and alloys**

Due to their mechanical properties, the ease of their processing and the possibility to sterilise them, metals and alloys are ideal materials for biomedical implants [34].

Metals are commonly used as load-bearing orthopaedic implants such as wires, screws, fixation plates, artificial joints for hips, knees, shoulders and ankles, as well as for dental, cardiovascular and craniofacial applications [14].

Novel magnesium alloys have been investigated for orthopaedic and cardiovascular applications [84, 85]. Combining magnesium alloys with aluminium or rare earth metals improves their mechanical properties [86, 87]. However, the accumulation of these elements is associated with neurotoxicity and hepatotoxicity [88]; hence, these alloys are not suitable for biomedical applications. Instead, extensive research is carried out to develop nontoxic magnesium alloys [89], such as Mg-Si and Mg-Sr alloys [90].

Titanium alloys are among the most commonly used metal alloys [91] due to their biocompatibility [92] and corrosion resistance [93]. Their composition and microstructure vary depending on their elemental composition [94]. The mechanical properties of B-titanium alloys have a Young's modulus like bone but possess a low fatigue strength. Their mechanical properties can be enhanced through the addition of silicon dioxide, zirconium dioxide and Yttrium oxide. Furthermore, to increase their wear resistance, titanium alloys are surface treated. Pure titanium alloys are used in pacemaker cases, ventricular devices, implantable drug pumps, screws and staples in spinal surgery, dental implants and craniofacial implants. Ti-6Al-4V alloys are used in hip and knee replacements and dental implants. Due to the release of aluminium and vanadium ions, which can cause neurological conditions such as Alzheimer's, Ti-6Al-4V alloys are not considered safe for long-term use. β-Titanium alloys substituted with stabilising elements like zirconium, tantalum and molybdenum are safer compared to Ti-6Al-4V [27], and alternative titanium alloys, vanadium free Ti-6Al-7Nb and Ti-5Al-2.5Fe, are being developed [95].

Titanium has become the material of choice for implants; however, components of prosthetics are still manufactured from gold alloys, stainless steel, nickel-chromium alloys and cobalt-chromium alloys [35]. Cobalt chromium alloys enable the fabrication of customised grafts including subperiosteal implants. They are mainly composed of cobalt, chromium and molybdenum, which give rise to corrosion resistance and mechanical properties [96, 97]. Stainless steel alloys such as iron-chromium-nickel-based alloys are used as orthopaedic implants such as ramus blade, ramus frame, stabiliser pins and some mucosal inserts. Due to its nickel content, these alloys possess a low corrosion resistance and induce immunological reactions in patients with nickel allergies [34, 38].

### **3. Implant properties**

Implant materials should possess adequate chemical and physical properties to allow for host tissue infiltration and nutrient transport; biocompatibility to avoid immunological responses; and corrosion resistance, degradation and bioresorbability to enable normal cellular activity and controlled implant degradation [14, 27, 98]. In addition, temporary implants should possess a highly interconnected porous structure to allow cell migration and nutrient and waste transport, provide suitable surface topography to support cell adhesion and growth, as well as allow for the release of bioactive molecules if applicable [5, 11, 12].

Mechanical properties like Young's Modulus, tensile, compressive and shear strength, yield strength and fatigue strength are required to ensure uniform stress distribution, to minimise the movement or fracture of the implant [34].

#### **3.1 Surface properties**

Surface properties influence cell adhesion and cellular and tissue responses. Surface tension determines the wettability by a wetting fluid, such as blood or water [11, 34]. Implant surfaces are also categorised by roughness, texture and the orientation of irregularities [38, 99]. The surface textures can vary from concave or convex. Concave surface textures occur due to additive treatments such as hydroxyapatite coatings, whereas convex surfaces are created through etching and blasting. Furthermore, implant surfaces can either be isotropic, meaning that implant properties are independent from the measurement direction, or anisotropic, which means properties are directionally dependent [12, 34].

**9**

**Table 3.**

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

*3.2.1 Metal corrosion*

implants [98–100].

*3.2.2 Polymer degradation*

Crevice corrosion

Pitting corrosion

Galvanic corrosion

Corrosion fatigue and fretting

**3.2 Corrosion and degradation of implants**

Corrosion is the involuntary breakdown of metals by an electrochemical reaction and through the loss of ions from the metal surface in an acidic, an alkaline or a neutral environment. It is one of the most common reasons for implant failure [98]. **Table 3** summarises the types of corrosions that have been observed in metal

Magnesium for example corrodes faster with an increase of impurities such as nickel, copper and iron [101]. The higher the purity of magnesium, the slower its corrosion rate. However, pure magnesium is not suitable for medical implants due to its mechanical characteristics. Instead, calcium is used for the grain refinement in magnesium alloys [102]. Orthopaedic implants fabricated from Mg-Ca alloys were observed to corrode over a 3-month period after bone formation [103]. Magnesium's mechanical properties can also be enhanced through Mg-Zn with calcium, manganese, yttrium or zirconium [104, 105]. Mg-Zn alloys withstand galvanic corrosion and biocorrosion *in vitro*; however, biocorrosion *in vivo* resulted in a 2 mm/year

Polymer degradation, or biodegradation, occurs through a process called hydrolysis. The polymer surface is attacked by organisms, which secrete enzymes breaking down ester bonds in macromolecules. The resulting smaller polymer molecules are further converted into carbon dioxide and water. The process of biodegradation varies for each polymer [27, 107, 108]; however, all polymers lose their mechanical integrity. To date, PGA, PLA and PLGA among others have been explored for biomedical implants [27]. Their degradation into non-toxic by-products made them favourable materials for temporary biomedical implants [109]. Poly(l-lactic) acid

• Interfaces between screws/plates

• Orthopaedic and dental implants

• Bone plates and screws at the bone-

• Stem-cement interfaces of modular

• Oral/dental implants • Screws and nuts

• Femoral implants

stem interface

hip implant

and bone

**Corrosion type Explanation Biomedical implants**

• Occurs in narrow regions

charge in the crevice

• Metal ions create localised positive

• Occurs in implants with small surface pit • Metal ions react with chloride ions resulting in rough surfaces

• Occurs due to electrical gradient between

• Occurs due to cyclic stress • Bone cement

Co-Cr alloys, Ni-Cr, Ag-Pd,

Au-ternary Ti

*Types of corrosions observed in metallic biomedical implants.*

reduction of a Mg-Zn alloy used as rods in femur shafts [106].

### **3.2 Corrosion and degradation of implants**

### *3.2.1 Metal corrosion*

*Biomaterials*

developed [95].

allergies [34, 38].

**3. Implant properties**

**3.1 Surface properties**

and microstructure vary depending on their elemental composition [94]. The mechanical properties of B-titanium alloys have a Young's modulus like bone but possess a low fatigue strength. Their mechanical properties can be enhanced through the addition of silicon dioxide, zirconium dioxide and Yttrium oxide. Furthermore, to increase their wear resistance, titanium alloys are surface treated. Pure titanium alloys are used in pacemaker cases, ventricular devices, implantable drug pumps, screws and staples in spinal surgery, dental implants and craniofacial implants. Ti-6Al-4V alloys are used in hip and knee replacements and dental implants. Due to the release of aluminium and vanadium ions, which can cause neurological conditions such as Alzheimer's, Ti-6Al-4V alloys are not considered safe for long-term use. β-Titanium alloys substituted with stabilising elements like zirconium, tantalum and molybdenum are safer compared to Ti-6Al-4V [27], and alternative titanium alloys, vanadium free Ti-6Al-7Nb and Ti-5Al-2.5Fe, are being

Titanium has become the material of choice for implants; however, components of prosthetics are still manufactured from gold alloys, stainless steel, nickel-chromium alloys and cobalt-chromium alloys [35]. Cobalt chromium alloys enable the fabrication of customised grafts including subperiosteal implants. They are mainly composed of cobalt, chromium and molybdenum, which give rise to corrosion resistance and mechanical properties [96, 97]. Stainless steel alloys such as iron-chromium-nickel-based alloys are used as orthopaedic implants such as ramus blade, ramus frame, stabiliser pins and some mucosal inserts. Due to its nickel content, these alloys possess a low corrosion resistance and induce immunological reactions in patients with nickel

Implant materials should possess adequate chemical and physical properties to allow for host tissue infiltration and nutrient transport; biocompatibility to avoid immunological responses; and corrosion resistance, degradation and bioresorbability to enable normal cellular activity and controlled implant degradation [14, 27, 98]. In addition, temporary implants should possess a highly interconnected porous structure to allow cell migration and nutrient and waste transport, provide suitable surface topography to support cell adhesion and growth, as well as allow for

Mechanical properties like Young's Modulus, tensile, compressive and shear strength, yield strength and fatigue strength are required to ensure uniform stress

Surface properties influence cell adhesion and cellular and tissue responses. Surface tension determines the wettability by a wetting fluid, such as blood or water [11, 34]. Implant surfaces are also categorised by roughness, texture and the orientation of irregularities [38, 99]. The surface textures can vary from concave or convex. Concave surface textures occur due to additive treatments such as hydroxyapatite coatings, whereas convex surfaces are created through etching and blasting. Furthermore, implant surfaces can either be isotropic, meaning that implant properties are independent from the measurement direction, or anisotropic, which

distribution, to minimise the movement or fracture of the implant [34].

the release of bioactive molecules if applicable [5, 11, 12].

means properties are directionally dependent [12, 34].

**8**

Corrosion is the involuntary breakdown of metals by an electrochemical reaction and through the loss of ions from the metal surface in an acidic, an alkaline or a neutral environment. It is one of the most common reasons for implant failure [98]. **Table 3** summarises the types of corrosions that have been observed in metal implants [98–100].

Magnesium for example corrodes faster with an increase of impurities such as nickel, copper and iron [101]. The higher the purity of magnesium, the slower its corrosion rate. However, pure magnesium is not suitable for medical implants due to its mechanical characteristics. Instead, calcium is used for the grain refinement in magnesium alloys [102]. Orthopaedic implants fabricated from Mg-Ca alloys were observed to corrode over a 3-month period after bone formation [103]. Magnesium's mechanical properties can also be enhanced through Mg-Zn with calcium, manganese, yttrium or zirconium [104, 105]. Mg-Zn alloys withstand galvanic corrosion and biocorrosion *in vitro*; however, biocorrosion *in vivo* resulted in a 2 mm/year reduction of a Mg-Zn alloy used as rods in femur shafts [106].

### *3.2.2 Polymer degradation*

Polymer degradation, or biodegradation, occurs through a process called hydrolysis. The polymer surface is attacked by organisms, which secrete enzymes breaking down ester bonds in macromolecules. The resulting smaller polymer molecules are further converted into carbon dioxide and water. The process of biodegradation varies for each polymer [27, 107, 108]; however, all polymers lose their mechanical integrity. To date, PGA, PLA and PLGA among others have been explored for biomedical implants [27]. Their degradation into non-toxic by-products made them favourable materials for temporary biomedical implants [109]. Poly(l-lactic) acid


#### **Table 3.**

*Types of corrosions observed in metallic biomedical implants.*

(PLLA) has been shown to induce inflammatory responses *in vivo* upon degradation due to its high crystallinity; hence, poly(d, l-lactic acid) (PDLA) was synthesised [110, 111].

PLGA degrades into acidic moieties, which in higher concentrations can affect the microenvironment of the implant's surrounding tissue. This can be especially important for drug delivery applications, where pH-sensitive drugs are used [11]. By increasing the amount of poly(glycolic acid) (PGA) compared to poly(lactic acid) (PLA) in PLGA, the degradation rate is reduced; hence, less acidic by-products are formed [11].

### **3.3 Biocompatibility**

Biocompatibility indicates a desired response of the implant to its biological surrounding [34] and depends on biodegradability and corrosion. The ISO 10993 standard series is used to assess biocompatibility of medical grade materials and medical devices [112]. Test categories investigate the materials' cytotoxicity, sensitization, irritation, toxicity, implantation and biodegradation [71]. Materials that meet these criteria include noble metals and titanium, their alloys, cobalt-based alloys, but also alumina, zirconia, quartz, fused silica, bioglass, silicon, biocompatible polymers like epoxies, silicones, polyurethanes, polyimides, silicon-polyimides, polycyclic-olefins, silicon-carbons, and liquid crystal polymers [113].

#### **3.4 Foreign body response**

Foreign body response (FBR) is a non-specific immune reaction of the body to implanted materials. This inflammatory reaction can happen in response to surgical implantation of biodegradable or non-biodegradable materials present in medical devices or implants [114, 115]. FBR can modulate the safety and/or function of the implanted material. FBR is characterised by distinct phases, namely onset, progression and resolution [116] (**Figure 1**). The onset starts with the surgical implantation of the biomaterial, for example, subcutaneously, which causes local tissue damage [117]. Upon tissue damage, vessel permeation to cells and proteins increases and coagulation occurs where inflammatory mediators like vascular endothelial growth factor (VEGF) plays an important role along with neutrophils and macrophages to initiate the wound healing process. In parallel, angiogenic factors stimulate local vasculature.

FBR comprises of a biomaterial-dependent and biomaterial-independent reaction (**Figure 1**). If biodegradable materials are present, the FBR will persist until the material is fully degraded. With non-degradable or long-term implants, a fibrotic capsule creating a barrier between the material and the body will form.

Progression of FBR depends on the material's surface chemistry and wettability [118], where protein, antibody and macrophage adsorption can vary due to the material's intrinsic properties. Additionally, fibrinogen can be adsorbed by the implant altering its structure. During FBR's progression, leukocyte extraversion occurs from the blood vessels. These migrate towards the foreign body. Consequently, polymorphonuclear neutrophils (PMNs) are activated, which recruit cells including macrophages to the site. Macrophage activation leads to the recruitment of fibroblasts, monocytes and more PMNs [116], which ultimately increases production of extracellular matrix and hence implant encapsulation and fibrosis.

Phagocytosis occurs from the onset when antibodies are non-specifically adsorbed by the biomaterials, thus recruiting phagocytes. During progression,

**11**

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

the material through biodegradation.

*formation and foreign body giant cell formation (adapted from [117]).*

or prevalence of fibrosis [114].

compatibility and design [122–124].

formation [120].

**Figure 1.**

phagocytosis by macrophages is continuously promoted through the degradation of

*Foreign body response to implant materials. Sequence of events and responses leading to the fibrous capsule* 

Material particles too large to be phagocyted cause the formation of larger multinucleated cells by fusion of macrophages. These so-called foreign body giant cells possess an irregular shape with more than 20 nuclei dispersed randomly. Giant cells will usually disappear once the foreign body is fully degraded. Surface roughness and surface/volume ratio of the implant can influence the adhesion of macrophages

As part of FBR, fibrosis is critical in tissue engineering, since capsule formation can prevent the diffusion of molecules (e.g., drugs) and continuous fibrosis formation can lead to capsule shrinkage thus affecting the implant structure [119]. It has been shown that inhibition of TGF-β can reduce capsule

Finally, resolution of the foreign body response involves the degradation of the

Biomaterials' characteristics partly determine the body's immune response to the implant. Implant pore size and morphology are critical since they can allow immune cells and macromolecules to interact with the implant. In addition, degradation products derived from implants like scaffolds and medical devices, as well as their constantly changing surfaces, can trigger the immune response [121]. Recent implants can carry therapeutic cells. These cellular implants provoke an immune response due to encapsulated cells, posing further challenges besides biomaterial

biomaterial or removal of the non-degradable material.

*3.4.1 Immunomodulation for circumventing the foreign body response*

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

**Figure 1.**

*Biomaterials*

[110, 111].

formed [11].

**3.3 Biocompatibility**

**3.4 Foreign body response**

vasculature.

(PLLA) has been shown to induce inflammatory responses *in vivo* upon degradation due to its high crystallinity; hence, poly(d, l-lactic acid) (PDLA) was synthesised

PLGA degrades into acidic moieties, which in higher concentrations can affect the microenvironment of the implant's surrounding tissue. This can be especially important for drug delivery applications, where pH-sensitive drugs are used [11]. By increasing the amount of poly(glycolic acid) (PGA) compared to poly(lactic acid) (PLA) in PLGA, the degradation rate is reduced; hence, less acidic by-products are

Biocompatibility indicates a desired response of the implant to its biological surrounding [34] and depends on biodegradability and corrosion. The ISO 10993 standard series is used to assess biocompatibility of medical grade materials and medical devices [112]. Test categories investigate the materials' cytotoxicity, sensitization, irritation, toxicity, implantation and biodegradation [71]. Materials that meet these criteria include noble metals and titanium, their alloys, cobalt-based alloys, but also alumina, zirconia, quartz, fused silica, bioglass, silicon, biocompatible polymers like epoxies, silicones, polyurethanes, polyimides, silicon-polyimides,

Foreign body response (FBR) is a non-specific immune reaction of the body to implanted materials. This inflammatory reaction can happen in response to surgical implantation of biodegradable or non-biodegradable materials present in medical devices or implants [114, 115]. FBR can modulate the safety and/or function of the implanted material. FBR is characterised by distinct phases, namely onset, progression and resolution [116] (**Figure 1**). The onset starts with the surgical implantation of the biomaterial, for example, subcutaneously, which causes local tissue damage [117]. Upon tissue damage, vessel permeation to cells and proteins increases and coagulation occurs where inflammatory mediators like vascular endothelial growth factor (VEGF) plays an important role along with neutrophils and macrophages to initiate the wound healing process. In parallel, angiogenic factors stimulate local

FBR comprises of a biomaterial-dependent and biomaterial-independent reaction (**Figure 1**). If biodegradable materials are present, the FBR will persist until the material is fully degraded. With non-degradable or long-term implants, a fibrotic

Progression of FBR depends on the material's surface chemistry and wettability [118], where protein, antibody and macrophage adsorption can vary due to the material's intrinsic properties. Additionally, fibrinogen can be adsorbed by the implant altering its structure. During FBR's progression, leukocyte extraversion occurs from the blood vessels. These migrate towards the foreign body. Consequently, polymorphonuclear neutrophils (PMNs) are activated, which recruit cells including macrophages to the site. Macrophage activation leads to the recruitment of fibroblasts, monocytes and more PMNs [116], which ultimately increases production of extracellular matrix and hence implant encapsulation and

Phagocytosis occurs from the onset when antibodies are non-specifically adsorbed by the biomaterials, thus recruiting phagocytes. During progression,

capsule creating a barrier between the material and the body will form.

polycyclic-olefins, silicon-carbons, and liquid crystal polymers [113].

**10**

fibrosis.

*Foreign body response to implant materials. Sequence of events and responses leading to the fibrous capsule formation and foreign body giant cell formation (adapted from [117]).*

phagocytosis by macrophages is continuously promoted through the degradation of the material through biodegradation.

Material particles too large to be phagocyted cause the formation of larger multinucleated cells by fusion of macrophages. These so-called foreign body giant cells possess an irregular shape with more than 20 nuclei dispersed randomly. Giant cells will usually disappear once the foreign body is fully degraded. Surface roughness and surface/volume ratio of the implant can influence the adhesion of macrophages or prevalence of fibrosis [114].

As part of FBR, fibrosis is critical in tissue engineering, since capsule formation can prevent the diffusion of molecules (e.g., drugs) and continuous fibrosis formation can lead to capsule shrinkage thus affecting the implant structure [119]. It has been shown that inhibition of TGF-β can reduce capsule formation [120].

Finally, resolution of the foreign body response involves the degradation of the biomaterial or removal of the non-degradable material.

#### *3.4.1 Immunomodulation for circumventing the foreign body response*

Biomaterials' characteristics partly determine the body's immune response to the implant. Implant pore size and morphology are critical since they can allow immune cells and macromolecules to interact with the implant. In addition, degradation products derived from implants like scaffolds and medical devices, as well as their constantly changing surfaces, can trigger the immune response [121]. Recent implants can carry therapeutic cells. These cellular implants provoke an immune response due to encapsulated cells, posing further challenges besides biomaterial compatibility and design [122–124].

#### *Biomaterials*

Polymers such as collagen, alginate, chitosan, polyethylene glycol, polyvinyl alcohol and polyurethane are used in several implantable products that may have an inherent biocompatibility. Understanding how these polymer's chemical and physical properties can be used to either avoid immune response or modulate it, while improving their functionality, is crucial for the advancement of these systems [121].

Strategies to circumvent the FBR include changing the biomaterial's surface properties like wettability, its chemical moieties, and surface charge, because they affect protein adhesion to the biomaterial [121, 125].

To create more hydrophilic surfaces, monolayers of hydrophilic polymers such as polyethylene glycol (PEG) and polyethylene oxide (PEO) are added, thus preventing protein adsorption altogether [126]. The deposition of chemical moieties like amino (▬NH2), carboxyl (▬COOH), hydroxyl (▬OH), and methyl (▬CH3) groups allows the modulation of cellular adhesion influencing inflammatory cell infiltration and macrophage response affecting the fibrotic capsule thickness around the implant [121]. Surface charge is important for the FBR immunomodulation. There have been contradicting reports on how exactly neutral, positive or negative charges reduce the inflammatory response connected to the FBR. Generally, negatively charged surfaces tend to inhibit the immune response through reduced cell adhesion [127].

Moreover, implant topography including texture, shape and size has shown to trigger an FBR [121]. Therefore, several manufacturing techniques like particles, assembled monolayers and photolithography are used to create variety of shapes, sizes and surface topographies [128, 129]. Surface roughness at the nanoscale can modulate protein adsorption [130], while variations in surface roughness at microscale affect cells directly [131]. For example, the inflammatory response of titanium used for dental or orthopaedic applications can be decreased by altering its surface nano-and microstructures via physical or chemical procedures [121].

Macrophage interaction with differently shaped biomaterials demonstrated preferred internalisation of nanorods via pinocytosis compared to nanospheres. Additionally, sharper cornered surfaces led to more acute immune responses than smoother surfaces [121, 132]. Moreover, spherical alginate capsules of 1.5 mm or greater were reported to be more biocompatible than their smaller, non-spherical comparators, demonstrating that larger, rounder, smoother capsules could diminish the FBR [133].

The use of decellularised ECM as scaffolds by removing immunogenic components to avoid an acute response but keeping the original structure has been studied. While decellularised ECMs contribute to a pro-regenerative environment [134], it has been discussed that the immune response modulation still depends on the original tissue from which the ECMs have been obtained. Therefore, this option still presents a potential solution with more research needed to advance its understanding, manufacturing and impact [134].

The incorporation of bioactive molecules such as adhesion molecules, drugs and growth factors to promote immunological interaction with the host attenuating its response has been investigated. Bioactive molecules bound to the biomaterial for controlled release aiding tissue regeneration [125] include proinflammatory molecules like prostaglandins [135] and anti-inflammatory molecules like cytokines [136]. Combining their delivery with glucocorticoids improved tissue regeneration and attenuation of inflammation [137]. In recent years, the encapsulation of immune cells that act as producers or inducers of specific biological responses to reduce inflammation and/or induce repair has been investigated as immunomodulation strategy [125]. Examples include the encapsulation of MSCs to decrease the fibrosis in FBR [138] or the encapsulation of macrophages to mediate pro-angiogenic activation [139].

**13**

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

body's response towards implants.

**4. Bioactive implants**

regeneration.

Overall, understanding the fundamental biological systems associated with FBR and the structural, physical and chemical properties of biomaterials will lead to new designs and strategies allowing to circumvent or work together with the natural

Implants can be bioactive, inducing an alteration to the surrounding tissue, by their own biomaterials imparting this alteration to the surrounding tissue, by releasing a drug (or drugs) inducing bioactivity, or by containing cells that can produce bioactive molecules. In the following sub-sections, we discuss the implant bioactivity induced by drugs and cells implicating in drug delivery and in tissue

Bioactive implants may incorporate active substances including small chemicals, peptides, proteins, hormones and even cells, which will have a therapeutic function in the human body. For drug delivery, these systems are commonly administered via parenteral route by injection or implantation. There are also implantable drug delivery systems that can be administered via ocular administration or via surgical procedures such as brain implants (e.g., Gliadel®). Implantable drug delivery systems are designed to slowly release the active substance(s) that they carry, thus avoiding repetitive injection. The active substance is delivered at a consistent predictable rate creating a drug release profile. This avoids peaks and troughs in the drug-blood level, which is common for non-long acting injectable products (e.g., intravenous solutions). Implantable drug delivery systems can be also injected subcutaneously, intramuscular or via other sites including intra-articular. They include implants and suspensions of micro- or nano-particles. Typically, these systems are preferred when the active substance has a poor absorption by other means of administration or a short half-life. The major advantages of such systems are improved pharmacokinetics, control of the drug release rate, and enhanced patient acceptability due to the reduction of side effects by maintaining the drug-blood level constant and by

Sustained drug release is obtained via diffusion of the active substance through a biomaterial matrix, or released through biomaterial biodegradation, or a combination of both mechanisms. To date, commonly used biomaterials for drug delivery are either biodegradable like PCL and PLA or non-biodegradable like polydimethylsiloxane, polyethyl vinyl acetate, or titanium alloy [141]. Several approaches have been developed to produce implantable drug delivery systems [142] and to control the drug release. These include (i) using diffusion via membrane permeation, either porous or semi-porous membranes; (ii) controlling drug release by matrix diffusion using porous polymers; (iii) reservoir systems, where the drug is encapsulated in an inner reservoir; and (iv) actively releasing the drug from the implant via osmotic pressure, electric current, vapour pressure, hydrolysis or ultrasound activation. Typically, simple rod-like solid implants, produced by hot melt extrusion processes using biodegradable polymers like PLA, PCL, PLGA and PEVA, often display a biphasic drug release kinetics showing a burst release due to the drug being deposited on the surface or near the surface of the implant, followed by a zero-order kinetics reflected by drug diffusion, matrix erosion, or a combination of both depending on the polymeric biomaterial used. **Table 4** summarises drug release systems that are currently commercially available or

**4.1 Bioactive implantable and injectable drug delivery systems**

decreasing administration frequency [140, 141].

Overall, understanding the fundamental biological systems associated with FBR and the structural, physical and chemical properties of biomaterials will lead to new designs and strategies allowing to circumvent or work together with the natural body's response towards implants.

### **4. Bioactive implants**

*Biomaterials*

cell adhesion [127].

the FBR [133].

ing, manufacturing and impact [134].

Polymers such as collagen, alginate, chitosan, polyethylene glycol, polyvinyl alcohol and polyurethane are used in several implantable products that may have an inherent biocompatibility. Understanding how these polymer's chemical and physical properties can be used to either avoid immune response or modulate it, while improving their functionality, is crucial for the advancement of these systems [121]. Strategies to circumvent the FBR include changing the biomaterial's surface properties like wettability, its chemical moieties, and surface charge, because they

To create more hydrophilic surfaces, monolayers of hydrophilic polymers such as polyethylene glycol (PEG) and polyethylene oxide (PEO) are added, thus preventing protein adsorption altogether [126]. The deposition of chemical moieties like amino (▬NH2), carboxyl (▬COOH), hydroxyl (▬OH), and methyl (▬CH3) groups allows the modulation of cellular adhesion influencing inflammatory cell infiltration and macrophage response affecting the fibrotic capsule thickness around the implant [121]. Surface charge is important for the FBR immunomodulation. There have been contradicting reports on how exactly neutral, positive or negative charges reduce the inflammatory response connected to the FBR. Generally, negatively charged surfaces tend to inhibit the immune response through reduced

Moreover, implant topography including texture, shape and size has shown to trigger an FBR [121]. Therefore, several manufacturing techniques like particles, assembled monolayers and photolithography are used to create variety of shapes, sizes and surface topographies [128, 129]. Surface roughness at the nanoscale can modulate protein adsorption [130], while variations in surface roughness at microscale affect cells directly [131]. For example, the inflammatory response of titanium used for dental or orthopaedic applications can be decreased by altering its

The use of decellularised ECM as scaffolds by removing immunogenic components to avoid an acute response but keeping the original structure has been studied. While decellularised ECMs contribute to a pro-regenerative environment [134], it has been discussed that the immune response modulation still depends on the original tissue from which the ECMs have been obtained. Therefore, this option still presents a potential solution with more research needed to advance its understand-

The incorporation of bioactive molecules such as adhesion molecules, drugs and growth factors to promote immunological interaction with the host attenuating its response has been investigated. Bioactive molecules bound to the biomaterial for controlled release aiding tissue regeneration [125] include proinflammatory molecules like prostaglandins [135] and anti-inflammatory molecules like cytokines [136]. Combining their delivery with glucocorticoids improved tissue regeneration and attenuation of inflammation [137]. In recent years, the encapsulation of immune cells that act as producers or inducers of specific biological responses to reduce inflammation and/or induce repair has been investigated as immunomodulation strategy [125]. Examples include the encapsulation of MSCs to decrease the fibrosis in FBR [138] or the encapsulation of macrophages to mediate pro-angiogenic

surface nano-and microstructures via physical or chemical procedures [121]. Macrophage interaction with differently shaped biomaterials demonstrated preferred internalisation of nanorods via pinocytosis compared to nanospheres. Additionally, sharper cornered surfaces led to more acute immune responses than smoother surfaces [121, 132]. Moreover, spherical alginate capsules of 1.5 mm or greater were reported to be more biocompatible than their smaller, non-spherical comparators, demonstrating that larger, rounder, smoother capsules could diminish

affect protein adhesion to the biomaterial [121, 125].

**12**

activation [139].

Implants can be bioactive, inducing an alteration to the surrounding tissue, by their own biomaterials imparting this alteration to the surrounding tissue, by releasing a drug (or drugs) inducing bioactivity, or by containing cells that can produce bioactive molecules. In the following sub-sections, we discuss the implant bioactivity induced by drugs and cells implicating in drug delivery and in tissue regeneration.

### **4.1 Bioactive implantable and injectable drug delivery systems**

Bioactive implants may incorporate active substances including small chemicals, peptides, proteins, hormones and even cells, which will have a therapeutic function in the human body. For drug delivery, these systems are commonly administered via parenteral route by injection or implantation. There are also implantable drug delivery systems that can be administered via ocular administration or via surgical procedures such as brain implants (e.g., Gliadel®). Implantable drug delivery systems are designed to slowly release the active substance(s) that they carry, thus avoiding repetitive injection. The active substance is delivered at a consistent predictable rate creating a drug release profile. This avoids peaks and troughs in the drug-blood level, which is common for non-long acting injectable products (e.g., intravenous solutions). Implantable drug delivery systems can be also injected subcutaneously, intramuscular or via other sites including intra-articular. They include implants and suspensions of micro- or nano-particles. Typically, these systems are preferred when the active substance has a poor absorption by other means of administration or a short half-life. The major advantages of such systems are improved pharmacokinetics, control of the drug release rate, and enhanced patient acceptability due to the reduction of side effects by maintaining the drug-blood level constant and by decreasing administration frequency [140, 141].

Sustained drug release is obtained via diffusion of the active substance through a biomaterial matrix, or released through biomaterial biodegradation, or a combination of both mechanisms. To date, commonly used biomaterials for drug delivery are either biodegradable like PCL and PLA or non-biodegradable like polydimethylsiloxane, polyethyl vinyl acetate, or titanium alloy [141]. Several approaches have been developed to produce implantable drug delivery systems [142] and to control the drug release. These include (i) using diffusion via membrane permeation, either porous or semi-porous membranes; (ii) controlling drug release by matrix diffusion using porous polymers; (iii) reservoir systems, where the drug is encapsulated in an inner reservoir; and (iv) actively releasing the drug from the implant via osmotic pressure, electric current, vapour pressure, hydrolysis or ultrasound activation.

Typically, simple rod-like solid implants, produced by hot melt extrusion processes using biodegradable polymers like PLA, PCL, PLGA and PEVA, often display a biphasic drug release kinetics showing a burst release due to the drug being deposited on the surface or near the surface of the implant, followed by a zero-order kinetics reflected by drug diffusion, matrix erosion, or a combination of both depending on the polymeric biomaterial used. **Table 4** summarises drug release systems that are currently commercially available or


*Biomaterials*

**Table 4.**

**15**

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

tion, let it erode and release the drug with time.

approval [154].

chosen biomaterial [153].

are shown in **Table**

immune response.

replacement of damaged tissues [156].

under development. There are numerous advantages to using implants in drug delivery such as the possibility of removal after treatment, the consistent and predictable drug release, and versatility in manufacture using various bioma

terials. However, there are potential disadvantages of this dosage form, where often a specialised device (e.g., trocar) and technique are needed for implanta

tion and removal requires minor surgical procedures. Additionally, there may be complications in locating the implant for removal since it can migrate from its original location. From a commercialisation point of view, this type of bioactive implant may require complex regulatory and commercial strategies for market

Injectable drug delivery systems, such as particulate suspensions or hydrogels like *in situ* forming gel depots, are designed from biodegradable biomaterials, injected (e.g., subcutaneous, intramuscular), form a depot, erode when in contact with body fluids, and release the drug by diffusion and erosion [149]. Injectable depots are not designed to be retrieved. Examples of injectable depots are micro- or nano-scale particles, where the drug is encapsulated within the polymer matrix. The polymeric particles are commonly prepared from biodegradable materials (e.g., PLGA, PCL, or silica) since the intent is to deliver the depot system once by injec

Choosing the polymer grade, type and combining polymer types can help tune the drug release as necessary [149, 154]. Key points in preparing these bioactive depots are the choice of the biomaterial (biodegradable/erodible), the physicochemical properties of drug to be encapsulated (i.e., hydrophobic or hydrophilic), the drug loading needed to deliver the therapeutic dose, and the inherent phar

macokinetics of the drug. This will inform the choice of manufacturing methods, often by emulsification. Common polymers used in these preparations are PLGA and PLA, where their long safety records deem these polymers as preferred, even

Hydrogels, prepared from different types of biomaterials (e.g., hyaluronic acid, polyesters and chitosan) have been extensively investigated as carriers for sustained drug release [152, 155]. *In situ* forming hydrogels as injectable depots pose major advantages over other drug release systems since they allow for rapid, painless and easier administration through smaller needle sizes. These biodegradable *in situ* depots are of low viscosity prior injection and solidify into a gel or solid depot after injection, typically due to a specific trigger depending on the chemistry of the

Before commercialising a cellular implant, it needs to be approved by FDA's Cellular, Tissue and Gene Therapies Advisory Committee. The Committee evaluates the safety and effectiveness of cellular implants for the reconstruction, repair or

Cell-based drug delivery systems can be defined as technologies capable of treating diseases using living cells to deliver the therapeutic bioactive molecules in the body, as either transport system or as production units [157]. Some examples of commercially available or under development cell-based implants

producers of bioactive molecules in the form of implant devices. Judging by the current developments in this technology, a major driving force behind this type of delivery is the improvement in treatment of insulin-dependent diabetes mellitus. The biggest challenge in cell-based drug delivery systems is avoiding

**5**. These cell-based drug delivery systems are used as constant

though some minor inflammatory responses can still be reported [150].

**4.2 Bioactive cell-based implants as drug delivery systems**





*Drug delivery systems as implantable and injectable depots.*

#### *Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

*Biomaterials*

**Clinical status**

Approved by FDA

**14**

**System** Implants [143–148]

Zoladex® (PLGA solid rod, 1 × 10 mm)

Nexplanon® (radiopaque PEVA solid

ITCA 650 (Medici technology, former

Duros®)

MK-8591 (PCL solid implant)

Microparticles

[149–151]

Risperdal Consta® (PLGA microspheres)

Decapeptyl SR® (PLGA microspheres)

Sandostatin LAR® (PLGA microspheres)

Bydureon® (PLGA microspheres)

Vivitrol® (PLGA microspheres)

Eligard® (Atrigel® technology)

Posidin® (Sabre® technology)

Relday® (Sabre® technology)

Sublocade® (Atrigel® technology)

*Summarised are current systems that are commercially available or under development. Table was adapted from [140, 141, 148, 151, 153].*

**Table 4.** *Drug delivery systems as implantable and injectable depots.*

Buprenorphine

Indivior

Risperidone

Durect/Zogenix

Schizophrenia/bipolar

disorder

Severe opioid use disorder

Approved by FDA

*In situ* hydrogels [152,

153]

Exenatide Naltrexone Leuprolide acetate

Bupivacaine

Octreotide

Triptorelin

Risperidone

Janssen Debiopharm/Ferring/

Ipsen

Novartis Amylin/AstraZeneca

Alkermes Sanofi-Aventis Durect/Sandoz

Type 2 diabetes

Opioid/alcohol dependence

Prostate cancer

Postoperative pain

Approved by FDA

Approved by FDA

Clinical Phase III/

NDA

Phase I

Acromegaly

Approved by FDA

Approved by FDA

rod)

release)

Etonogestrel (release up to

Merck

Contraception

Approved by FDA

3 years)

Exenatide (release up to

Ipsen

Type 2 diabetes

Clinical Phase III/

NDA

Pre-clinical/Phase I

2 years)

EFdA (long-term release)

Merck

HIV treatment and

prevention

Antipsychotic Prostate cancer

Approved by FDA

Approved by FDA

Goserelin (up to 3 month

**Product**

**Drug**

**Manufacturer**

AstraZeneca

**Indication** Prostate cancer

under development. There are numerous advantages to using implants in drug delivery such as the possibility of removal after treatment, the consistent and predictable drug release, and versatility in manufacture using various biomaterials. However, there are potential disadvantages of this dosage form, where often a specialised device (e.g., trocar) and technique are needed for implantation and removal requires minor surgical procedures. Additionally, there may be complications in locating the implant for removal since it can migrate from its original location. From a commercialisation point of view, this type of bioactive implant may require complex regulatory and commercial strategies for market approval [154].

Injectable drug delivery systems, such as particulate suspensions or hydrogels like *in situ* forming gel depots, are designed from biodegradable biomaterials, injected (e.g., subcutaneous, intramuscular), form a depot, erode when in contact with body fluids, and release the drug by diffusion and erosion [149]. Injectable depots are not designed to be retrieved. Examples of injectable depots are micro- or nano-scale particles, where the drug is encapsulated within the polymer matrix. The polymeric particles are commonly prepared from biodegradable materials (e.g., PLGA, PCL, or silica) since the intent is to deliver the depot system once by injection, let it erode and release the drug with time.

Choosing the polymer grade, type and combining polymer types can help tune the drug release as necessary [149, 154]. Key points in preparing these bioactive depots are the choice of the biomaterial (biodegradable/erodible), the physicochemical properties of drug to be encapsulated (i.e., hydrophobic or hydrophilic), the drug loading needed to deliver the therapeutic dose, and the inherent pharmacokinetics of the drug. This will inform the choice of manufacturing methods, often by emulsification. Common polymers used in these preparations are PLGA and PLA, where their long safety records deem these polymers as preferred, even though some minor inflammatory responses can still be reported [150].

Hydrogels, prepared from different types of biomaterials (e.g., hyaluronic acid, polyesters and chitosan) have been extensively investigated as carriers for sustained drug release [152, 155]. *In situ* forming hydrogels as injectable depots pose major advantages over other drug release systems since they allow for rapid, painless and easier administration through smaller needle sizes. These biodegradable *in situ* depots are of low viscosity prior injection and solidify into a gel or solid depot after injection, typically due to a specific trigger depending on the chemistry of the chosen biomaterial [153].

### **4.2 Bioactive cell-based implants as drug delivery systems**

Before commercialising a cellular implant, it needs to be approved by FDA's Cellular, Tissue and Gene Therapies Advisory Committee. The Committee evaluates the safety and effectiveness of cellular implants for the reconstruction, repair or replacement of damaged tissues [156].

Cell-based drug delivery systems can be defined as technologies capable of treating diseases using living cells to deliver the therapeutic bioactive molecules in the body, as either transport system or as production units [157]. Some examples of commercially available or under development cell-based implants are shown in **Table 5**. These cell-based drug delivery systems are used as constant producers of bioactive molecules in the form of implant devices. Judging by the current developments in this technology, a major driving force behind this type of delivery is the improvement in treatment of insulin-dependent diabetes mellitus. The biggest challenge in cell-based drug delivery systems is avoiding immune response.



**17**

models.

cell types [167].

of teratoma [169].

homeostasis [170].

apoptosis [174, 175].

*4.3.1 Primary cells versus stem cells*

biopsies and then seeded on the scaffold (**Figure**

they have difficulties adhering and proliferating *in vitro* [168].

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

**4.3 Bioactive cellular implants as tissue replacements**

When damages due to disease, injury or trauma lead to the degeneration of tissues, it is necessary to provide support for their repair, replacement or regeneration. Common approaches include tissue transplantation, both from the patient's own body (autograft) and from a donor (allograft). However, harvesting autografts is expensive and invasive and the patient may experience infections and hematomas. While for the allografts, there are risks of rejection along with the infections due to the surgery or the transplanted tissue [158]. With tissue engineering, biological implants are developed that restore, maintain and improve the tissue function [159]. Implants provide the environment for cell adhesion and proliferation to grow new tissues. They can also include active substances like growth factors and drugs as well as cells to aid tissue regeneration [11]. Cell-based scaffolds are either cultured *in vitro* with the aim of synthetizing tissues that can be implanted, or to be implanted directly in the damaged region [158]. **Table**

summarises some of the recent studies about cell-based implants tested on *in vivo*

The advantage of using cell-based scaffolds is the possibility to customise the construct using cells derived from the patient (primary cells). In this way, there is no risk of rejection due to immunological incompatibility. Cells can be isolated from

ferentiated, post-mitotic cells. This leads to a limited lifespan, where after a limited number of cell doubling, they will enter in senescence and stop dividing, but are still viable [166, 167]. Moreover, primary cell types are difficult to culture, because

To overcome problems associated with primary cells, stem cells have been

Embryonic stem cells (ESCs) are isolated from inner cell mass of embryo at the blastocyst stage. They can differentiate in any cell type (pluripotency) and have a high rate of self-renewal. Unfortunately, they can cause an immune response, as they are derived from a different body, so immunosuppression is necessary to avoid rejection. Moreover, the injection of undifferentiated ESC can lead to the formation

Adult stem cells (ASCs) are multipotent cells that can differentiate in a limited number of cell types, which reside in a specific microenvironment, the stem cell niche. Their role is to replace damaged and dead cells in the tissue to maintain

ASCs can be isolated from bone marrow, blood, adipose tissue, liver and skin [169]. Compared to ESCs, ASCs proliferate more slowly and have limited expan

sion capacity *in vitro*. Like primary cells, they can enter in senescence [171]. With age, their regenerative potential, growth and divisions are affected [172]. The most commonly used type of ASCs is mesenchymal stem cells (MSCs). These cells can differentiate into musculoskeletal cells, marrow and other cells of connective tissue, and they can provide trophic support and modulate the immune response [173]. They can migrate to a damaged region and promote healing by secreting molecules involved in angiogenesis and cell proliferation and inhibit oxidative stress and

be used. Stem cells are present in most if not all tissues and, according to their origin, they can be classified into embryonic and adult stem cells. Stem cells are able to both duplicate (self-renew) and differentiate in one or more

**6**


**2**). However, primary cells are dif-

 *Examples of commercially available cell-based implants for drug delivery.* *Biomaterials*

**Manufacture**

Encapsulated human cells producing

CNTF into the back of the eye.

PTFE porous membrane device filled

with cells.

Pouch made of medical-grade

materials.

**16**

**Company** Neurotech

VIaCyte Sernova PharmaCyte

Beta-O2

Sigilon Encapsulife

Encapsulation system for

Diabetes

the immunoisolation of

living cells

Organogenesis

GINTUIT

Mucogingival

Keratinocytes and fibroblasts produce cytokines and growth

factors that promote healing and regeneration of the tissue.

conditions

incorporated

**Table 5.** *Examples of commercially available cell-based implants for drug delivery.*

Afibromer™

Diabetes

βAir® bioartificial pancreas

Diabetes, adrenal

Device using alginate—high guluronic acid and high mannuronic

acid—to encapsulate cells and impregnate a PTFE porous

membrane, respectively. Also comprises an oxygen-providing

chamber, which needs refilling.

Human stem cells differentiated to β islets encapsulated in

modified alginate spheres, which suppress immune system

response and FBR.

Cellulose-based polymer encapsulation of cells.

Pancreatic islets encapsulated are

stimulated to produce insulin.

Allogeneic keratinocytes and

fibroblast in bovine collagen.

insufficiency

Cell-in-a-box®

Pancreatic cancer/breast

cancer/diabetes

Cell PouchTM with

SertolinTM

Encapsulated cell therapy

(ECT)

Encaptra®

**Product**

**Application** Ophthalmology

Stem cell delivery for

treatment of diabetes

mellitus

Diabetes/haemophilia/

thyroid disease

photoreceptors.

**Method of action**

Ciliary neurotrophic factor (CNTF) has neuroprotective effects on

Human stem cells are isolated and differentiated into β islet cells

contained into a pouch, which is implanted.

Therapeutic cells are inserted into a pouch made of medical-grade

materials inserted subcutaneously; Sertolin® is a patented immune

protection system.

Uses cotton cellulose to encapsulate cells.

Single cell encapsulation in

proprietary polymer, freeze-drying

process to keep cells viable in the long

term.

Single cell encapsulation in

proprietary polymer, freeze-drying

process to keep cells viable in the long

term.

### **4.3 Bioactive cellular implants as tissue replacements**

When damages due to disease, injury or trauma lead to the degeneration of tissues, it is necessary to provide support for their repair, replacement or regeneration. Common approaches include tissue transplantation, both from the patient's own body (autograft) and from a donor (allograft). However, harvesting autografts is expensive and invasive and the patient may experience infections and hematomas. While for the allografts, there are risks of rejection along with the infections due to the surgery or the transplanted tissue [158]. With tissue engineering, biological implants are developed that restore, maintain and improve the tissue function [159]. Implants provide the environment for cell adhesion and proliferation to grow new tissues. They can also include active substances like growth factors and drugs as well as cells to aid tissue regeneration [11]. Cell-based scaffolds are either cultured *in vitro* with the aim of synthetizing tissues that can be implanted, or to be implanted directly in the damaged region [158]. **Table 6** summarises some of the recent studies about cell-based implants tested on *in vivo* models.

### *4.3.1 Primary cells versus stem cells*

The advantage of using cell-based scaffolds is the possibility to customise the construct using cells derived from the patient (primary cells). In this way, there is no risk of rejection due to immunological incompatibility. Cells can be isolated from biopsies and then seeded on the scaffold (**Figure 2**). However, primary cells are differentiated, post-mitotic cells. This leads to a limited lifespan, where after a limited number of cell doubling, they will enter in senescence and stop dividing, but are still viable [166, 167]. Moreover, primary cell types are difficult to culture, because they have difficulties adhering and proliferating *in vitro* [168].

To overcome problems associated with primary cells, stem cells have been be used. Stem cells are present in most if not all tissues and, according to their origin, they can be classified into embryonic and adult stem cells. Stem cells are able to both duplicate (self-renew) and differentiate in one or more cell types [167].

Embryonic stem cells (ESCs) are isolated from inner cell mass of embryo at the blastocyst stage. They can differentiate in any cell type (pluripotency) and have a high rate of self-renewal. Unfortunately, they can cause an immune response, as they are derived from a different body, so immunosuppression is necessary to avoid rejection. Moreover, the injection of undifferentiated ESC can lead to the formation of teratoma [169].

Adult stem cells (ASCs) are multipotent cells that can differentiate in a limited number of cell types, which reside in a specific microenvironment, the stem cell niche. Their role is to replace damaged and dead cells in the tissue to maintain homeostasis [170].

ASCs can be isolated from bone marrow, blood, adipose tissue, liver and skin [169]. Compared to ESCs, ASCs proliferate more slowly and have limited expansion capacity *in vitro*. Like primary cells, they can enter in senescence [171]. With age, their regenerative potential, growth and divisions are affected [172]. The most commonly used type of ASCs is mesenchymal stem cells (MSCs). These cells can differentiate into musculoskeletal cells, marrow and other cells of connective tissue, and they can provide trophic support and modulate the immune response [173]. They can migrate to a damaged region and promote healing by secreting molecules involved in angiogenesis and cell proliferation and inhibit oxidative stress and apoptosis [174, 175].


**19**

**Figure 2.**

*Source of cells used for cell-based implants. Image adapted from [168].*

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

are also associated with tumour development [177].

Induced pluripotent stem cells (iPSCs) originate from fully differentiated somatic cells, which are dedifferentiated to form iPSCs by a process called reprogramming. The methodology was developed in 2006 [176] and involves the stimulation of genes that are active during the embryogenesis. Thanks to the cell derivation, the implantation of these cells does not lead to rejection. However, as with ESCs, iPSCs can form teratoma. Moreover, some of the genes that are activated

**Table 6.** *Examples of recent studies on cell-based implants.*

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

*Biomaterials*

Tendon regeneration

Neural tissue engineering

Wound healing and skin regeneration

Mandible defects repair

Acute kidney injury

Spinal cord regeneration Rat tendon stem/progenitor

Schwann cells, human bone marrow mesenchymal stem cells (BMSCs)

Wharton's jelly mesenchymal stem cells (MSCs)

Endothelial progenitor cells (EPCs), BMSCs

Human placenta-derived mesenchymal stem cells (hP-MSCs)

*Examples of recent studies on cell-based implants.*

Neural stem cells (NSCs)

cells

**Application Cell type Implant Outcome Reference**

• Tenogenic specific genes expression and protein production *in vitro* and *in vivo*. • Formation of aligned collagen fibres *in vivo*.

• Metabolic active cells adhered to scaffold. • Mesenchymal stem cells differentiate in neuronal cells.

• Nanofibrous biodegradable scaffolds. • Cells were metabolic active and proliferative after 21 days in culture. • MSCs on the scaffolds reduced the presence of denaturised proteins *in vitro,* possible anti-inflammatory response.

• Expression of osteogenesis and angiogenesis markers *in vitro*. • After 9 months postimplantation *in vivo*, the defects were nearly completely recovered, and angiogenesis was

promoted.

*in vivo*.

• hP-MSCs niche, cell survival and angiogenesis were promoted in

• Renal functions were ameliorated.

• Graft-host integration in spinal cord *in vivo*. • NSCs exhibited neuronal differentiation. • Inflammatory cells infiltrated the lesion site, functional recovery after 4 weeks. • Degradation products of PSeD-IKVAVS promoted NSCs differentiation, inhibited neuronal apoptosis and alleviated inflammation.

[160]

[161]

[162]

[163]

[164]

[165]

Asymmetric chitosan-based sponges

Polyvinyl alcohol (PVA)/sulphate alginate nanofibers

Poly(εcaprolactone) (PCL)/gelatin nanofibers

Biodegradable bioactive glass ceramic scaffold

Self-assembling peptide hydrogel

Elastic poly(sebacoyl diglyceride) (PSeD) scaffolds coated with poly(sebacoyl diglyceride) isoleucinelysinevalinealaninevaline-serine (PSeD-IKVAVS)

**18**

**Table 6.**

Induced pluripotent stem cells (iPSCs) originate from fully differentiated somatic cells, which are dedifferentiated to form iPSCs by a process called reprogramming. The methodology was developed in 2006 [176] and involves the stimulation of genes that are active during the embryogenesis. Thanks to the cell derivation, the implantation of these cells does not lead to rejection. However, as with ESCs, iPSCs can form teratoma. Moreover, some of the genes that are activated are also associated with tumour development [177].

**Figure 2.**

*Source of cells used for cell-based implants. Image adapted from [168].*

### **5. Implant manufacture**

To generate tissue replacements, it is essential to resemble the native extracellular matrix (ECM). Therefore, the matrix composition, shape and physical properties are crucial. Nanofibers, sponges or gels have been fabricated using numerous different techniques or combinations of techniques to mimic the native ECMs. Some of these techniques and their biomedical applications are presented in **Table 7**.

### **5.1 Solvent casting particulate leaching**

Solvent casting particulate leaching is a technique developed in 1993 by Mikos et al., where a polymer is dissolved in an organic solvent and the polymer solution is mixed with an insoluble porogen. The solvent is evaporated by solvent casting or freeze-drying techniques. The evaporation leads to a porogen-polymer compound, which is washed to remove the porogen leaving a porous polymer matrix behind [187, 188]. This method is relatively easy to use and inexpensive [189]. Pore size, porosity and interconnectivity can be controlled selecting the right polymer, porogen and their concentration [190].

### **5.2 Phase separation**

Phase separation employs temperature changes that separate the polymeric solution in two phases: the lean phase (low polymer concentration) and the rich phase (high polymer concentration). Briefly, the polymer is dissolved in a solvent, then, the temperature is rapidly decreased to have a liquid-liquid separation and twophase solid is formed [191]. Finally, the liquid is removed by extraction, evaporation or sublimation [192].

#### **5.3 Freeze-drying**

Freeze-drying technique or lyophilisation [193] is based on a sublimation process that will produce a porous scaffold. A polymer is added to a mixture of water and organic solvent and moved into a mould. The mixture is quickly frozen and, by lowering the pressure to few millibars, the water and the organic solvent sublimate. The complete removal of the liquid phase takes place under vacuum [189, 194, 195]. To control porosity and pore size, polymer/water ratio, ionic concentration, viscosity and pH, together with freezing rate and temperature, can be changed [194, 195].

### **5.4 Electrospinning**

Electrospinning is used to produce micro- and nanofibers. It is widely used as it can produce matrix that can resemble the native ECMs. Nanofiber scaffolds offer mechanical support and a nanoscale environment for the cells [196, 197]. A polymer solution is added to a syringe. Then, high voltage is applied, and the solution accelerates to a collector of opposite charge. The solution-air interface changes from rounded to conical, due to the repulsive electrostatic forces between the polymer molecules in solution and the attractive force between the polymer solution and the collector. The polymer solution is ejected from the syringe when the electrostatic forces are higher than the surface tension of the solution. Then, the solvent evaporates, and the solid polymer is deposited

**21**

**Table 7.**

E-jet 3D printing

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

> Poly(l-lactic acid) (PLLA) and matrilin-3 (MATN3)

Poly(lactic acid) (PLA)

caprolactone) (PCL) and zein

fibroin-chitosan

caprolactone) (PCL)/poly(d, l-lactide-coglycolide) (PLGA)/gelatin

Electrospinning SiO2CaO Wound

(4-carboxyphenyl) porphyrin/βtricalcium phosphate (Cu-TCPP-TCP)

Poly(lactic-coglycolic acid) and drugs (5-fluorouracil and NVP-BEZ235)

*Techniques used for the fabrication of bioactive implants.*

3D printing Copper/tetrakis

Collagen Tissue

Solvent casting particulate leaching

Phase separation particulate leaching

Freezedrying and self-assembly

Freeze-drying Poly(ε-

Freeze-drying Silk

Electrospinning Poly(ε-

**Technique Material Application Outcome References**

*in vivo*.

• Porous scaffold.

14 days in culture.

• Porous scaffold.

21 days in culture.

porous scaffold.

nanosheets.

HUVEC *in vitro*. • MSCs differentiated in osteocytes.

markers *in vitro*.

tumour site.

*vivo*.

• Nanofibrous porous scaffold. • Cell hypertrophy and endochondral ossification prevented *in vivo*. • Chondrogenesis is promoted

• Osteosarcoma cells (MG63) were metabolic active and viable after

• Porous and degradable scaffold. • Degradation rate increases with the concentration of zein.

• Aligned collagen scaffolds. • Rat fibroblasts and neurons elongate along aligned fibres.

• MSCs were metabolic active, viable and differentiate after

• Dual-oriented/bilayer hydrophilic nanofibers.

• Smooth muscle cells and endothelial cells were viable after 7 days; orientation along the fibres.

• Cotton wool-like, fibrous and

• Human fibroblast seeded on top were metabolic active and proliferative after 7 days in culture, and produced vascular endothelial growth factor.

• Metal-organic photothermal

• Promoted osteosarcoma cell death *in vitro,* ablation of subcutaneous bone tumour tissue *in vivo*. • Adhesion of bone marrow MSCs

• HUVEC expressed angiogenesis

• Enhanced bone regeneration *in* 

• Long-term drug release near the

• Less risk for normal tissue. • No need for several administrations.

[178]

[179]

[180]

[181]

[182]

[183]

[184]

[185]

[186]

Articular cartilage regeneration

Bone tissue engineering

Drug delivery

engineering

Cartilage regeneration

Vascular tissue engineering

healing

Bone tumour ablation and osteogenesis

Drug delivery in orthotopic breast cancer *Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

*Biomaterials*

in **Table 7**.

**5. Implant manufacture**

**5.1 Solvent casting particulate leaching**

porogen and their concentration [190].

**5.2 Phase separation**

tion or sublimation [192].

**5.3 Freeze-drying**

[194, 195].

**5.4 Electrospinning**

To generate tissue replacements, it is essential to resemble the native extracellular matrix (ECM). Therefore, the matrix composition, shape and physical properties are crucial. Nanofibers, sponges or gels have been fabricated using numerous different techniques or combinations of techniques to mimic the native ECMs. Some of these techniques and their biomedical applications are presented

Solvent casting particulate leaching is a technique developed in 1993 by Mikos et al., where a polymer is dissolved in an organic solvent and the polymer solution is mixed with an insoluble porogen. The solvent is evaporated by solvent casting or freeze-drying techniques. The evaporation leads to a porogen-polymer compound, which is washed to remove the porogen leaving a porous polymer matrix behind [187, 188]. This method is relatively easy to use and inexpensive [189]. Pore size, porosity and interconnectivity can be controlled selecting the right polymer,

Phase separation employs temperature changes that separate the polymeric solution in two phases: the lean phase (low polymer concentration) and the rich phase (high polymer concentration). Briefly, the polymer is dissolved in a solvent, then, the temperature is rapidly decreased to have a liquid-liquid separation and twophase solid is formed [191]. Finally, the liquid is removed by extraction, evapora-

Freeze-drying technique or lyophilisation [193] is based on a sublimation process that will produce a porous scaffold. A polymer is added to a mixture of water and organic solvent and moved into a mould. The mixture is quickly frozen and, by lowering the pressure to few millibars, the water and the organic solvent sublimate. The complete removal of the liquid phase takes place under vacuum [189, 194, 195]. To control porosity and pore size, polymer/water ratio, ionic concentration, viscosity and pH, together with freezing rate and temperature, can be changed

Electrospinning is used to produce micro- and nanofibers. It is widely used as it can produce matrix that can resemble the native ECMs. Nanofiber scaffolds offer mechanical support and a nanoscale environment for the cells [196, 197]. A polymer solution is added to a syringe. Then, high voltage is applied, and the solution accelerates to a collector of opposite charge. The solution-air interface changes from rounded to conical, due to the repulsive electrostatic forces between the polymer molecules in solution and the attractive force between the polymer solution and the collector. The polymer solution is ejected from the syringe when the electrostatic forces are higher than the surface tension of the solution. Then, the solvent evaporates, and the solid polymer is deposited

**20**


#### **Table 7.**

*Techniques used for the fabrication of bioactive implants.*

on the collector. By changing the voltage, collector, polymer concentration and solvent, it is possible to control the size of the fibres [196, 198].

### **5.5 Additive manufacturing techniques**

Additive manufacturing (AM) techniques, or solid freeform fabrications (SFFs), are based on the use of computer-aided design (CAD) to fabricate scaffolds. The CAD controls the layer-by-layer deposition of material. The advantage of these methods is the full control of the topography of the construct [196, 198].

Three-dimensional (3D) printing is a commonly used AM technique that was developed at the Massachusetts Institute of Technology in 1990s [198, 199]. The CAD is converted in a stereo lithography (STL) file and exported to the 3D printer to control the movement and deposition of the material.

This technique allows the inclusion of cells within the scaffold, as high temperature or solvents are not required for its production [200]. In recent years, 3D printing has been used to produce scaffolds and anatomically customised implants based on MRI and CT scans. The AM can be classified in three different approaches [201], namely laser-based (stereolithography, selective laser sintering, electron beam melting and binder jetting) [202–204], nozzle-based (fused deposition modelling and melt electrospinning writing) [204–208] and indirect 3D printing [209–211].

### **5.6 Injection moulding**

Injection moulding is one of the most commonly used techniques for largescale production of thermoplastic items. The plastic is melted and injected into a mould of desired shape. When the material solidifies, the mould is removed, and the finished part is extracted [212]. Metal constructs can also be fabricated with this technique. Metal injection moulding uses fine metal powders mixed with a binder and is injected with a conventional thermoplastic moulding machine. The binder is then removed, and the product is formed. This method allows the production of constructs with a sophisticate shape and higher mechanical properties [213].

### **5.7 Self-assembly**

Self-assembly is the spontaneous formation of molecular units in supramolecular structures, without external intervention. These molecules interact through hydrogen bonding, van der Waals and electrostatic forces. Due to their biocompatibility and biodegradability, peptides are commonly used for self-assembly. Specific structure can be created by modifying the amino-acidic composition of the peptides [189, 214]. These nanostructures can be used in drug delivery and tissue engineering [215].

### **5.8 Manufacturing considerations**

The manufacturing of bioactive implants, whether these are for tissue engineering or for drug delivery purposes, includes several common aspects. These include the manufacturing methods that are employed, the biomaterial source, use of solvents, scalability, the need for aseptic facilities or if final product sterilisation is preferred, and if a specifically designed device is needed to administer the implant.

**23**

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

for the different categories.

may be possible.

risks [220].

**6. Summary**

and versatility to the field.

Most importantly, the regulatory strategy for filing needs to be in place soon in product development to define all the data that are needed for submission. It is important to define if the bioactive implant will be considered a drug product, a medical device, or a combination product (drug-device), and in which markets should it be launched, as different markets have different regulations and requisites

Comprehensive reviews and discussions on the regulatory aspects for filing medical devices, and combination products in the biomedical field were reviewed [216–218]. Ragelle et al. provide an excellent perspective for nanoparticle-based biomaterials, its manufacture and regulatory outlook for biomedical engineering [219]. To enable the use in animals and humans, the sterilisation process is important. If the manufacturing method is simplified enough, the use of aseptic technique for manufacturing, using filters and a particulate-free environment, will be possible although costly and complex for significantly large-scale manufacturing. For devices where metals are used, sterilisation by moist or dry heat

However, for implants that involve polymers or heat-sensitive bioactive molecules, the preferred sterilisation method is gamma-irradiation. The drawback of using this technique is the potential risk to polymer and/or bioactive molecule degradation, changing the release rate and potentially compromising the efficacy of the implant [150]. Depending on the biomaterial and bioactive molecule involved, there may be ways to avoid degradation upon gamma-irradiation, such as using an antioxidant mixed with the drug. Apart from aseptic conditions, gamma-irradiation of the final product remains the best solution but exposes one of the disadvantages of developing bioactive implants as it is still a costly technique bringing its own

In this chapter, we reviewed the current literature about bioactive biomedical implants applicable to regenerative therapies and used in drug delivery. To generate new biomedical implants, biomaterials are continuously developed, either through entirely new or by combining advantageous properties of well-known and safe biomaterials to improve the application and effectiveness of implants. Thus, materials that enhance the natural response of the body and simultaneously provide support for cell adhesion and proliferation are required. Another field that has developed in recent years is cell-induced bioactivity, where cells are used in implants for tissue regeneration and disease treatment. While there are several manufacturing techniques to create application-specific bioactive implants, new technologies, such as additive manufacturing, bring advantages

#### *Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

*Biomaterials*

[209–211].

**5.6 Injection moulding**

properties [213].

**5.7 Self-assembly**

tissue engineering [215].

**5.8 Manufacturing considerations**

on the collector. By changing the voltage, collector, polymer concentration and

Additive manufacturing (AM) techniques, or solid freeform fabrications (SFFs), are based on the use of computer-aided design (CAD) to fabricate scaffolds. The CAD controls the layer-by-layer deposition of material. The advantage of these methods is the full control of the topography of the construct [196, 198]. Three-dimensional (3D) printing is a commonly used AM technique that was developed at the Massachusetts Institute of Technology in 1990s [198, 199]. The CAD is converted in a stereo lithography (STL) file and exported to the 3D printer

This technique allows the inclusion of cells within the scaffold, as high temperature or solvents are not required for its production [200]. In recent years, 3D printing has been used to produce scaffolds and anatomically customised implants based on MRI and CT scans. The AM can be classified in three different approaches [201], namely laser-based (stereolithography, selective laser sintering, electron beam melting and binder jetting) [202–204], nozzle-based (fused deposition modelling and melt electrospinning writing) [204–208] and indirect 3D printing

Injection moulding is one of the most commonly used techniques for largescale production of thermoplastic items. The plastic is melted and injected into a mould of desired shape. When the material solidifies, the mould is removed, and the finished part is extracted [212]. Metal constructs can also be fabricated with this technique. Metal injection moulding uses fine metal powders mixed with a binder and is injected with a conventional thermoplastic moulding machine. The binder is then removed, and the product is formed. This method allows the production of constructs with a sophisticate shape and higher mechanical

Self-assembly is the spontaneous formation of molecular units in supramolecular structures, without external intervention. These molecules interact through hydrogen bonding, van der Waals and electrostatic forces. Due to their biocompatibility and biodegradability, peptides are commonly used for self-assembly. Specific structure can be created by modifying the amino-acidic composition of the peptides [189, 214]. These nanostructures can be used in drug delivery and

The manufacturing of bioactive implants, whether these are for tissue engineering or for drug delivery purposes, includes several common aspects. These include the manufacturing methods that are employed, the biomaterial source, use of solvents, scalability, the need for aseptic facilities or if final product sterilisation is preferred, and if a specifically designed device is needed to administer the

solvent, it is possible to control the size of the fibres [196, 198].

to control the movement and deposition of the material.

**5.5 Additive manufacturing techniques**

**22**

implant.

Most importantly, the regulatory strategy for filing needs to be in place soon in product development to define all the data that are needed for submission. It is important to define if the bioactive implant will be considered a drug product, a medical device, or a combination product (drug-device), and in which markets should it be launched, as different markets have different regulations and requisites for the different categories.

Comprehensive reviews and discussions on the regulatory aspects for filing medical devices, and combination products in the biomedical field were reviewed [216–218]. Ragelle et al. provide an excellent perspective for nanoparticle-based biomaterials, its manufacture and regulatory outlook for biomedical engineering [219].

To enable the use in animals and humans, the sterilisation process is important. If the manufacturing method is simplified enough, the use of aseptic technique for manufacturing, using filters and a particulate-free environment, will be possible although costly and complex for significantly large-scale manufacturing. For devices where metals are used, sterilisation by moist or dry heat may be possible.

However, for implants that involve polymers or heat-sensitive bioactive molecules, the preferred sterilisation method is gamma-irradiation. The drawback of using this technique is the potential risk to polymer and/or bioactive molecule degradation, changing the release rate and potentially compromising the efficacy of the implant [150]. Depending on the biomaterial and bioactive molecule involved, there may be ways to avoid degradation upon gamma-irradiation, such as using an antioxidant mixed with the drug. Apart from aseptic conditions, gamma-irradiation of the final product remains the best solution but exposes one of the disadvantages of developing bioactive implants as it is still a costly technique bringing its own risks [220].

### **6. Summary**

In this chapter, we reviewed the current literature about bioactive biomedical implants applicable to regenerative therapies and used in drug delivery. To generate new biomedical implants, biomaterials are continuously developed, either through entirely new or by combining advantageous properties of well-known and safe biomaterials to improve the application and effectiveness of implants. Thus, materials that enhance the natural response of the body and simultaneously provide support for cell adhesion and proliferation are required. Another field that has developed in recent years is cell-induced bioactivity, where cells are used in implants for tissue regeneration and disease treatment. While there are several manufacturing techniques to create application-specific bioactive implants, new technologies, such as additive manufacturing, bring advantages and versatility to the field.

*Biomaterials*

### **Author details**

Andrea Domingues Goncalves1 , Wendy Balestri<sup>2</sup> and Yvonne Reinwald<sup>2</sup> \*

1 Pharmaceutical Development—Oral and Inhaled, Product Development and Supply, GlaxoSmithKline, Ware, United Kingdom

2 Department of Engineering, Nottingham Trent University, Nottingham, United Kingdom

\*Address all correspondence to: yvonne.reinwald@ntu.ac.uk

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**25**

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

[1] Regulation of medical implants. House of Commons—Evidence—HC 163-i. 2019. Available from: http:// www.publications.parliament.uk/pa/ cm201213/cmselect/cmsctech/uc163-i/ success of narrow-diameter dental implants. The International Journal of Oral & Maxillofacial Implants.

Menias CO, Bhalla S, Siegel C, Gayer G, Katz DS. Imaging of cosmetic plastic procedures and implants in the body and their potential complications. American Journal of Roentgenology.

[9] Yahyavi-Firouz-Abadi N,

[10] Silva VV, Domingues RZ, Lameiras FS. Microstructural and mechanical study of zirconiahydroxyapatite (ZH) composite ceramics for biomedical applications. Composites Science and Technology.

[11] Stratton S, Shelke NB, Hoshino K, Rudraiah S, Kumbar SG. Bioactive polymeric scaffolds for tissue engineering. Bioactive Materials.

[12] Dhandayuthapani B, Sakthikumar D. Biomedical Applications of Polymeric Materials and Composites. 1st ed. Weinheim, Germany: Wiley; 2017.

[13] Jones AJ, Denning NT. Polymeric Biomaterials: Bio- and Ecocompatible Polymers, A Perspective for Australia. Department of Industry, Technology

[14] ASM International. Overview of biomaterials and their use in medical devices. Handbook of Materials for Medical Devices. Cleveland, OH, USA:

[15] Zdrahala RJ, Zdrahala IJ. Biomedical applications of polyurethanes: A review of past promises, present realities, and a vibrant future. Journal of Biomaterials

and Commerce; 1988. ISBN: 0642134618, 9780642134615

ASM International, Inc; 2003

Applications. 1999;**14**(1):67-90

2014;**29**:43-54

2015;**204**:707-715

2001;**61**:301-310

2016;**1**(2):93-108

pp. 1-20

[2] Huang Y, Van Dessel J, Martens W, Lambrichts I, Zhong WJ, Ma GW, et al. Sensory innervation around immediately vs. delayed loaded implants: A pilot study. International Journal of Oral Science. 2015;**7**:49

[3] Arsiwala A, Desai P, Patravale V.

[4] Takmakov P, Ruda K, Phillips KS, Isayeva IS, Krauthamer V, Welle CG. Rapid evaluation of the durability of cortical neural implants using accelerated aging with reactive oxygen species. Journal of Neural Engineering. 2015;**12**:026003

[5] Guo R, Merkel AR, Sterling JA, Davidson JM, Guelcher SA. Substrate modulus of 3D-printed scaffolds regulates the regenerative response in subcutaneous implants through the macrophage phenotype and Wnt signaling. Biomaterials. 2015;**73**:85-95

[6] Li J, Stachowski M, Zhang Z. Application of responsive polymers in implantable medical devices and biosensors. In: Switchable and Responsive Surfaces and Materials for Biomedical Applications. Cambridge, UK: Elsevier; 2015. pp. 259-298

[7] Bagga C, Erbe EM, Murphy JP, Freid JM, Pomrink GJ. Bioactive Spinal Implants and Method of Manufacture Thereof. U.S. Patent 8,715,353; 2014

[8] Klein MO, Schiegnitz E, Al-Nawas B. Systematic review on

Recent advances in micro/ nanoscale biomedical implants. Journal of Controlled Release.

2014;**189**(2014):25-45

**References**

uc16301.htm

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

### **References**

*Biomaterials*

**24**

**Author details**

United Kingdom

Andrea Domingues Goncalves1

Supply, GlaxoSmithKline, Ware, United Kingdom

provided the original work is properly cited.

\*Address all correspondence to: yvonne.reinwald@ntu.ac.uk

, Wendy Balestri<sup>2</sup>

1 Pharmaceutical Development—Oral and Inhaled, Product Development and

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Department of Engineering, Nottingham Trent University, Nottingham,

and Yvonne Reinwald<sup>2</sup>

\*

[1] Regulation of medical implants. House of Commons—Evidence—HC 163-i. 2019. Available from: http:// www.publications.parliament.uk/pa/ cm201213/cmselect/cmsctech/uc163-i/ uc16301.htm

[2] Huang Y, Van Dessel J, Martens W, Lambrichts I, Zhong WJ, Ma GW, et al. Sensory innervation around immediately vs. delayed loaded implants: A pilot study. International Journal of Oral Science. 2015;**7**:49

[3] Arsiwala A, Desai P, Patravale V. Recent advances in micro/ nanoscale biomedical implants. Journal of Controlled Release. 2014;**189**(2014):25-45

[4] Takmakov P, Ruda K, Phillips KS, Isayeva IS, Krauthamer V, Welle CG. Rapid evaluation of the durability of cortical neural implants using accelerated aging with reactive oxygen species. Journal of Neural Engineering. 2015;**12**:026003

[5] Guo R, Merkel AR, Sterling JA, Davidson JM, Guelcher SA. Substrate modulus of 3D-printed scaffolds regulates the regenerative response in subcutaneous implants through the macrophage phenotype and Wnt signaling. Biomaterials. 2015;**73**:85-95

[6] Li J, Stachowski M, Zhang Z. Application of responsive polymers in implantable medical devices and biosensors. In: Switchable and Responsive Surfaces and Materials for Biomedical Applications. Cambridge, UK: Elsevier; 2015. pp. 259-298

[7] Bagga C, Erbe EM, Murphy JP, Freid JM, Pomrink GJ. Bioactive Spinal Implants and Method of Manufacture Thereof. U.S. Patent 8,715,353; 2014

[8] Klein MO, Schiegnitz E, Al-Nawas B. Systematic review on success of narrow-diameter dental implants. The International Journal of Oral & Maxillofacial Implants. 2014;**29**:43-54

[9] Yahyavi-Firouz-Abadi N, Menias CO, Bhalla S, Siegel C, Gayer G, Katz DS. Imaging of cosmetic plastic procedures and implants in the body and their potential complications. American Journal of Roentgenology. 2015;**204**:707-715

[10] Silva VV, Domingues RZ, Lameiras FS. Microstructural and mechanical study of zirconiahydroxyapatite (ZH) composite ceramics for biomedical applications. Composites Science and Technology. 2001;**61**:301-310

[11] Stratton S, Shelke NB, Hoshino K, Rudraiah S, Kumbar SG. Bioactive polymeric scaffolds for tissue engineering. Bioactive Materials. 2016;**1**(2):93-108

[12] Dhandayuthapani B, Sakthikumar D. Biomedical Applications of Polymeric Materials and Composites. 1st ed. Weinheim, Germany: Wiley; 2017. pp. 1-20

[13] Jones AJ, Denning NT. Polymeric Biomaterials: Bio- and Ecocompatible Polymers, A Perspective for Australia. Department of Industry, Technology and Commerce; 1988. ISBN: 0642134618, 9780642134615

[14] ASM International. Overview of biomaterials and their use in medical devices. Handbook of Materials for Medical Devices. Cleveland, OH, USA: ASM International, Inc; 2003

[15] Zdrahala RJ, Zdrahala IJ. Biomedical applications of polyurethanes: A review of past promises, present realities, and a vibrant future. Journal of Biomaterials Applications. 1999;**14**(1):67-90

#### *Biomaterials*

[16] Daebritz SH, Fausten B, Hermanns B, Schroeder J, Groetzner J, Autschbach R, et al. Introduction of a flexible polymeric heart valve prosthesis with special design for the aortic position. Circulation. 2003;**108**(10- Suppl. 1):II-135-II-139

[17] Zhu Y, Gao C, He T, Shen J. Endothelium regeneration on luminal surface of polyurethane vascular scaffold modified with diamine and covalently grafted with gelatin. Biomaterials. 2004;**25**(3):423-430

[18] Yuan Y, Ai F, Zang X, Zhuang W, Shen J, Lin S. Polyurethane vascular catheter surface grafted with zwitterionic sulfobetaine monomer activated by ozone. Colloids and Surfaces B. 2004;**35**(1):1-5

[19] Lin W-C, Tseng C-H, Yang M-C. In-vitro hemocompatibility evaluation of a thermoplastic polyurethane membrane with surfaceimmobilized water-soluble chitosan and heparin. Macromolecular Bioscience. 2005;**5**:1013-1021

[20] Topol EJ, Serruys PW. Frontiers in interventional cardiology. Circulation. 1802-1820;**1998**:98

[21] Whelan DM, van der Giessen WJ, Krabbendam SC, van Vliet EA, Verdouw PD, Serruys PW, et al. Biocompatibility of phosphorylcholine coated stents in normal porcine coronary arteries. Heart. 2000;**83**:338-345

[22] Horner PJ, Gage FH. Regenerating the damaged central nervous system. Nature. 2000;**407**:963-970

[23] Scheib J, Hoke A. Advances in peripheral nerve regeneration. Nature Reviews. Neurology. 2013;**9**:668-676

[24] Cao J, Xiao Z, Jin W, Chen B, Meng D, Ding W, et al. Induction of rat facial nerve regeneration by functional collagen scaffolds. Biomaterials. 2013;**34**:1302-1310

[25] White JD, Wang S, Weiss AS, Kaplan DL. Silke-tropoelastin protein films for nerve guidance. Acta Biomaterialia. 2015;**14**:1-10

[26] Xie J, MacEwan MR, Liu W, Jesuraj N, Li X, Hunter D, et al. Nerve guidance conduits based on doublelayered scaffolds of electrospun nanofibers for repairing the peripheral nervous system. ACS Applied Materials & Interfaces. 2014;**6**:9472-9480

[27] Prakasam M, Locs J, Salma-Ancane K, Dagnija Loca D, Largeteau A, Berzina-Cimdina L. Biodegradable materials and metallic implants—A review. Journal of Functional Biomaterials. 2017;**8**:44

[28] Zimmerli W. Clinical presentation and treatment of orthopaedic implantassociated infection. Journal of Internal Medicine. 2014;**276**:111-119

[29] Bellini H, Moyano J, Gil J, Puigdollers A. Comparison of the superelasticity of different nickel– titanium orthodontic archwires and the loss of their properties by heat treatment. Journal of Materials Science. Materials in Medicine. 2016;**27**:158

[30] Hutmacher DW, Garcia AJ. Scaffold-based bone engineering by using genetically modified cells. Gene. 2005;**347**(1):1-10

[31] Liu YD, Hu J, Zhuang XL, et al. Synthesis and characterization of novel biodegradable and electroactive hydrogel based on aniline oligomer and gelatin. Macromolecular Bioscience. 2011;**12**:241-250

[32] Guo BL, Glavas L, Albertsson AC. Biodegradable and electrically

**27**

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

The Journal of Oral Implantology.

[42] Teramoto H, Kawai A, Sugihara S, Yoshida A, Inoue H. Resorption of apatite-wollastonite containing glassceramic and beta-tricalcium phosphate

[43] Boanini E, Gazzano M, Bigi A. Ionic substitutions in calcium phosphates synthesized at low temperature. Acta Biomaterialia. 2010;**6**:1882-1894

[44] Thian ES, Konishi T, Kawanobe Y, Lim PN, Choong C, Ho B, et al. Zinc-substituted hydroxyapatite: A biomaterial with enhanced bioactivity and antibacterial properties. Journal of Materials Science. Materials in Medicine. 2013;**24**:437-445

[45] Mayer I, Jacobsohn O,

2003:1445-1451

1969;**22**:371-380

Niazov T, Werckmann J, Iliescu M, Richard-Plouet M, et al. Manganese in precipitated hydroxyapatites. European

Journal of Inorganic Chemistry.

[46] Tamimi F, Le Nihouannen D, Eimar H, Sheikh Z, Komarova S, Barralet J. The effect of autoclaving on the physical and biological properties of dicalcium phosphate dihydrate bioceramics: Brushite vs. monetite. Acta

Biomaterialia. 2012;**8**:3161-3169

[47] Hodosh M, Povar M, Shklar G. The dental polymer implant concept. The Journal of Prosthetic Dentistry.

in vivo. Acta Medica Okayama.

2005;**59**:201-207

[41] Chiapasco M, Casentini P, Zaniboni M, Corsi E, Anello T. Titanium-zirconium alloy narrowdiameter implants (Straumann Roxolid(®)) for the rehabilitation of horizontally deficient edentulous ridges: Prospective study on 18 consecutive patients. Clinical Oral Implants Research. 2012;**23**:1136-1141

2011;**37**:367-376

conducting polymers for biomedical applications. Progress in Polymer Science. 2013;**38**:1263-1286

[33] Guo BL, Finne-Wistrand A, Albertsson AC. Versatile functionalization of polyester hydrogels with electroactive aniline oligomers. Journal of Polymer Science Part A: Polymer Chemistry. 2011;**49**:2097-2105

[34] Saini M, Singh Y, Arora P,

[35] Sykaras N, Iacopino AM, Marker VA, Triplett RG, Woody RD. Implant materials, designs, and surface topographies: Their effect on osseointegration. A literature review. The International Journal of Oral & Maxillofacial Implants. 2000;**15**:

52-57

675-690

1993;**19**:363-366

2008;**23**:691-695

Arora V, Jain K. Implant biomaterials: A comprehensive review. World Journal of Clinical Cases. 2015;**3**(1):

[36] LeGeros RZ, Lin S, Rohanizadeh R, Mijares D, LeGeros JP. Biphasic calcium phosphate bioceramics: Preparation, properties and applications. Journal of Materials Science. Materials in Medicine. 2003;**14**:201-209

[37] DeGroot K. Clinical applications of calcium phosphate biomaterials: A review. Ceramics International.

[38] Wennerberg A, Albrektsson T. On implant surfaces: A review of current

knowledge and opinions. The International Journal of Oral & Maxillofacial Implants. 2010;**25**:63-74

[39] Hoffmann O, Angelov N, Gallez F, Jung RE, Weber FE. The zirconia implant-bone interface: A preliminary histologic evaluation in rabbits. The International Journal of Oral & Maxillofacial Implants.

[40] Özkurt Z, Kazazoğlu E. Zirconia dental implants: A literature review.

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

conducting polymers for biomedical applications. Progress in Polymer Science. 2013;**38**:1263-1286

*Biomaterials*

[16] Daebritz SH, Fausten B,

Suppl. 1):II-135-II-139

with special design for the aortic position. Circulation. 2003;**108**(10-

[17] Zhu Y, Gao C, He T, Shen J. Endothelium regeneration on luminal surface of polyurethane vascular scaffold modified with diamine and covalently grafted with gelatin. Biomaterials. 2004;**25**(3):423-430

[18] Yuan Y, Ai F, Zang X, Zhuang W, Shen J, Lin S. Polyurethane vascular catheter surface grafted with zwitterionic sulfobetaine monomer activated by ozone. Colloids and Surfaces B. 2004;**35**(1):1-5

[19] Lin W-C, Tseng C-H, Yang M-C. In-vitro hemocompatibility evaluation of a thermoplastic polyurethane membrane with surfaceimmobilized water-soluble chitosan and heparin.

[20] Topol EJ, Serruys PW. Frontiers in interventional cardiology. Circulation.

[21] Whelan DM, van der Giessen WJ, Krabbendam SC, van Vliet EA, Verdouw PD, Serruys PW, et al. Biocompatibility of phosphorylcholine coated stents in normal porcine coronary arteries. Heart.

[22] Horner PJ, Gage FH. Regenerating the damaged central nervous system.

[23] Scheib J, Hoke A. Advances in peripheral nerve regeneration. Nature Reviews. Neurology. 2013;**9**:668-676

[24] Cao J, Xiao Z, Jin W, Chen B, Meng D, Ding W, et al. Induction of rat

Nature. 2000;**407**:963-970

Macromolecular Bioscience.

2005;**5**:1013-1021

1802-1820;**1998**:98

2000;**83**:338-345

Hermanns B, Schroeder J, Groetzner J, Autschbach R, et al. Introduction of a flexible polymeric heart valve prosthesis facial nerve regeneration by functional collagen scaffolds. Biomaterials.

[25] White JD, Wang S, Weiss AS, Kaplan DL. Silke-tropoelastin protein

[26] Xie J, MacEwan MR, Liu W, Jesuraj N, Li X, Hunter D, et al. Nerve guidance conduits based on doublelayered scaffolds of electrospun nanofibers for repairing the peripheral nervous system. ACS Applied Materials & Interfaces.

[27] Prakasam M, Locs J, Salma-

Ancane K, Dagnija Loca D, Largeteau A, Berzina-Cimdina L. Biodegradable materials and metallic implants—A review. Journal of Functional Biomaterials. 2017;**8**:44

[28] Zimmerli W. Clinical presentation and treatment of orthopaedic implantassociated infection. Journal of Internal

Medicine. 2014;**276**:111-119

2016;**27**:158

2005;**347**(1):1-10

2011;**12**:241-250

[29] Bellini H, Moyano J, Gil J, Puigdollers A. Comparison of the superelasticity of different nickel– titanium orthodontic archwires and the loss of their properties by heat treatment. Journal of Materials Science. Materials in Medicine.

[30] Hutmacher DW, Garcia AJ. Scaffold-based bone engineering by using genetically modified cells. Gene.

[31] Liu YD, Hu J, Zhuang XL, et al. Synthesis and characterization of novel biodegradable and electroactive hydrogel based on aniline oligomer and gelatin. Macromolecular Bioscience.

[32] Guo BL, Glavas L, Albertsson AC.

Biodegradable and electrically

films for nerve guidance. Acta Biomaterialia. 2015;**14**:1-10

2013;**34**:1302-1310

2014;**6**:9472-9480

**26**

[33] Guo BL, Finne-Wistrand A, Albertsson AC. Versatile functionalization of polyester hydrogels with electroactive aniline oligomers. Journal of Polymer Science Part A: Polymer Chemistry. 2011;**49**:2097-2105

[34] Saini M, Singh Y, Arora P, Arora V, Jain K. Implant biomaterials: A comprehensive review. World Journal of Clinical Cases. 2015;**3**(1): 52-57

[35] Sykaras N, Iacopino AM, Marker VA, Triplett RG, Woody RD. Implant materials, designs, and surface topographies: Their effect on osseointegration. A literature review. The International Journal of Oral & Maxillofacial Implants. 2000;**15**: 675-690

[36] LeGeros RZ, Lin S, Rohanizadeh R, Mijares D, LeGeros JP. Biphasic calcium phosphate bioceramics: Preparation, properties and applications. Journal of Materials Science. Materials in Medicine. 2003;**14**:201-209

[37] DeGroot K. Clinical applications of calcium phosphate biomaterials: A review. Ceramics International. 1993;**19**:363-366

[38] Wennerberg A, Albrektsson T. On implant surfaces: A review of current knowledge and opinions. The International Journal of Oral & Maxillofacial Implants. 2010;**25**:63-74

[39] Hoffmann O, Angelov N, Gallez F, Jung RE, Weber FE. The zirconia implant-bone interface: A preliminary histologic evaluation in rabbits. The International Journal of Oral & Maxillofacial Implants. 2008;**23**:691-695

[40] Özkurt Z, Kazazoğlu E. Zirconia dental implants: A literature review.

The Journal of Oral Implantology. 2011;**37**:367-376

[41] Chiapasco M, Casentini P, Zaniboni M, Corsi E, Anello T. Titanium-zirconium alloy narrowdiameter implants (Straumann Roxolid(®)) for the rehabilitation of horizontally deficient edentulous ridges: Prospective study on 18 consecutive patients. Clinical Oral Implants Research. 2012;**23**:1136-1141

[42] Teramoto H, Kawai A, Sugihara S, Yoshida A, Inoue H. Resorption of apatite-wollastonite containing glassceramic and beta-tricalcium phosphate in vivo. Acta Medica Okayama. 2005;**59**:201-207

[43] Boanini E, Gazzano M, Bigi A. Ionic substitutions in calcium phosphates synthesized at low temperature. Acta Biomaterialia. 2010;**6**:1882-1894

[44] Thian ES, Konishi T, Kawanobe Y, Lim PN, Choong C, Ho B, et al. Zinc-substituted hydroxyapatite: A biomaterial with enhanced bioactivity and antibacterial properties. Journal of Materials Science. Materials in Medicine. 2013;**24**:437-445

[45] Mayer I, Jacobsohn O, Niazov T, Werckmann J, Iliescu M, Richard-Plouet M, et al. Manganese in precipitated hydroxyapatites. European Journal of Inorganic Chemistry. 2003:1445-1451

[46] Tamimi F, Le Nihouannen D, Eimar H, Sheikh Z, Komarova S, Barralet J. The effect of autoclaving on the physical and biological properties of dicalcium phosphate dihydrate bioceramics: Brushite vs. monetite. Acta Biomaterialia. 2012;**8**:3161-3169

[47] Hodosh M, Povar M, Shklar G. The dental polymer implant concept. The Journal of Prosthetic Dentistry. 1969;**22**:371-380

[48] Wang Y, Blasioli DJ, Kim H-J, Kim HS, Kaplan DL. Cartilage tissue engineering with silk scaffolds and human articular chondrocytes. Biomaterials. 2006;**27**:4434-4442

[49] Vepari C, Kaplan DL. Silk as a biomaterial. Progress in Polymer Science. 2007;**32**:991-1007

[50] Yang Y, Ding F, Wu J, Hu W, Liu W, Liu J, et al. Development and evaluation of silk fibroin-based nerve grafts used for peripheral nerve regeneration. Biomaterials. 2007;**28**:5526-5535

[51] Hakimi O, Knight DP, Vollrath F, Vadgama P. Spider and mulberry silkworm silks as compatible biomaterials. Composites. Part B, Engineering. 2007;**38**:324-337

[52] Etienne O, Schneider A, Kluge JA, Bellemin-Laponnaz C, Polidori C, Leisk GG, et al. Soft tissue augmentation using silk gels: An in vitro and in vivo study. Journal of Periodontology. 2009;**80**:1852-1858

[53] Kardestuncer T, McCarthy M, Karageorgiou V, Kaplan DL, Gronowicz G. RGD-tethered silk substrate stimulates the differentiation of human tendon cells. Clinical Orthopaedics and Related Research. 2006;**448**:234-239

[54] Cai Z-X, Mo X-M, Zhang K-H, Fan L-P, Yin A-L, He C-L, et al. Fabrication of chitosan/silk fibroin composite nanofibers for wounddressing applications. International Journal of Molecular Sciences. 2010;**11**:3529-3539

[55] Okabayashi R, Nakamura M, Okabayashi T, Tanaka Y, Nagai A, Yamashita K. Efficacy of polarized hydroxyapatite and silk fibroin composite dressing gel on epidermal recovery from full-thickness skin wounds. Journal of Biomedical

Materials Research Part B: Applied Biomaterials. 2009;**90B**:641-646

[56] Necas J, Bartosikova L, Brauner P, Kolar J. Hyaluronic acid (hyaluronan): A review. Veterinární Medicína. 2008;**53**:397-411

[57] Laurencin CT, Jiang T, Kumbar SG, Nair LS. Biologically active chitosan systems for tissue engineering and regenerative medicine. Current Topics in Medicinal Chemistry. 2008;**8**:354-364

[58] He S, Yaszemski MJ, Yasko AW, Engel PS, Mikos AG. Injectable biodegradable polymer composites based on poly (propylene fumarate) crosslinked with poly (ethylene glycol)-dimethacrylate. Biomaterials. 2000;**21**:2389-2394

[59] Shelke NB, Anderson M, Idrees S, Nip MJ, Donde S, Yu X, et al. Handbook of Polyester Drug Delivery Systems. Singapore: Pan Stanford; 2016. pp. 595-649

[60] Narayanan G, Gupta BS, Tonelli AE. Enhanced mechanical properties of poly(ε-caprolactone) nanofibers produced by the addition of nonstoichiometric inclusion complexes of poly(ε-caprolactone) and a-cyclodextrin. Polymer. 2015;**76**:321-330

[61] Karst D, Yang Y. Molecular modeling study of the resistance of PLA to hydrolysis based on the blending of PLLA and PDLA. Polymer. 2006;**47**:4845-4850

[62] Gentile P, Chiono V, Carmagnola I, Hatton PV. An overview of poly (lactic co-glycolic) acid (PLGA)-based biomaterials for bone tissue engineering. International Journal of Molecular Sciences. 2014;**15**:3640-3659

[63] Woodruff MA, Hutmacher DW. The return of a forgotten polymer

**29**

2013;**15**(5):1-5

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

> [70] Zhou J, Huang X, Zheng D, Li H, Herrler T, Li Q. Oriental nose elongation using an L-shaped polyethylene sheet implant for combined septal spreading and extension. Aesthetic Plastic Surgery.

2014;**38**(2):295-302

[71] Teo AJT, Mishra A, Park I, Kim YJ, Park WT, Yoon YJ. Polymeric biomaterials for medical implants and devices. ACS Biomaterials Science &

Engineering. 2016;**2**:454-472

2013;**54**(4):2654-2661

[72] Pérez-Merino P, Dorronsoro C, Llorente L, Durán S, Jiménez-Alfaro I, Marcos S. In vivo chromatic aberration in eyes implanted with intraocular lenses. Investigative Ophthalmology & Visual Science.

[73] Terrada C, Julian K, Cassoux N, Prieur A-M, Debre M, Quartier P, et al. Cataract surgery with primary intraocular lens implantation in children with uveitis: Long-term outcomes. Journal of Cataract & Refractive Surgery. 2011;**37**(11):1977-1983

[74] Kim B-J, Hong K-S, Park K-J, Park D-H, Chung Y-G, Kang S-H. Customized cranioplasty implants using three-dimensional printers and polymethyl-methacrylate casting. Journal of Korean Neurosurgical Association. 2012;**52**(6):541-546

[75] Rivkin A. A prospective study of non-surgical primary rhinoplasty using a polymethylmethacrylate injectable implant. Dermatologic Surgery.

[76] Shklar G, Hodosh M, Povar M. Tissue reactions to polymer-coated vitallium pin implants. Journal of Prosthetic Dentistry. 1970;**24**:636-645

[77] Qin Y, Howlader MM, Deen MJ, Haddara YM, Selvaganapathy PR. Polymer integration for packaging of implantable sensors. Sensors and Actuators, B: Chemical. 2014;**202**:758

2014;**40**(3):305-313

polycaprolactone in the 21st century.

[64] Nada AA, James R, Shelke NB, Harmon MD, Awad HM, Nagarale RK, et al. A smart methodology to fabricate

electrospun chitosan nanofiber matrices for regenerative engineering applications. Polymers for Advanced Technologies. 2014;**25**:507-515

[65] Chang KY, Hung LH, Chu I, Ko CS, Lee YD. The application of type II collagen and chondroitin sulfate grafted PCL porous scaffold in

cartilage tissue engineering. Journal of Biomedial Materials Research Part A.

Yang K. Biodegradable materials for bone repairs: A review. Journal of Materials Science and Technology.

Alberda GO, Zavaglia CA, Ten Brinke G, Duek EA. Poly (para-dioxanone) and poly (L-lactic acid) blends: Thermal, mechanical, and morphological properties. Journal of Applied Polymer

Progress in Polymer Science.

2010;**35**:1217-1256

2010;**92**:712-723

2013;**29**:503-513

2011;**26**(6):72-77

[66] Tan L, Yu X, Wan P,

[67] Pezzin AP, Ekenstein V,

Science. 2003;**88**:2744-2755

[68] Amanatullah DF, Landa J, Strauss EJ, Garino JP, Kim SH, Di Cesare PE. Comparison of surgical outcomes and implant wear between ceramic-ceramic and ceramic-

polyethylene articulations in total hip arthroplasty. Journal of Arthroplasty.

[69] Green JM, Hallab NJ, Liao Y-S, Narayan V, Schwarz EM, Xie C. Antioxidation treatment of ultra high molecular weight polyethylene

components to decrease periprosthetic osteolysis: Evaluation of osteolytic and osteogenic properties of wear debris particles in a murine calvaria model. Current Rheumatology Reports. *Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

polycaprolactone in the 21st century. Progress in Polymer Science. 2010;**35**:1217-1256

*Biomaterials*

[48] Wang Y, Blasioli DJ, Kim H-J, Kim HS, Kaplan DL. Cartilage tissue engineering with silk scaffolds and human articular chondrocytes. Biomaterials. 2006;**27**:4434-4442

Materials Research Part B: Applied Biomaterials. 2009;**90B**:641-646

[56] Necas J, Bartosikova L, Brauner P, Kolar J. Hyaluronic acid (hyaluronan): A review. Veterinární Medicína.

[57] Laurencin CT, Jiang T, Kumbar SG, Nair LS. Biologically active chitosan systems for tissue engineering and regenerative medicine. Current Topics in Medicinal Chemistry.

2008;**53**:397-411

2008;**8**:354-364

[58] He S, Yaszemski MJ,

Yasko AW, Engel PS, Mikos AG. Injectable biodegradable polymer composites based on poly (propylene fumarate) crosslinked with poly (ethylene glycol)-dimethacrylate. Biomaterials. 2000;**21**:2389-2394

[59] Shelke NB, Anderson M,

[60] Narayanan G, Gupta BS, Tonelli AE. Enhanced mechanical properties of poly(ε-caprolactone) nanofibers produced by the addition of nonstoichiometric inclusion complexes of poly(ε-caprolactone) and a-cyclodextrin. Polymer.

[61] Karst D, Yang Y. Molecular modeling study of the resistance of PLA to hydrolysis based on the blending of PLLA and PDLA. Polymer.

[62] Gentile P, Chiono V, Carmagnola I, Hatton PV. An overview of poly (lactic co-glycolic) acid (PLGA)-based

biomaterials for bone tissue engineering. International Journal of Molecular Sciences. 2014;**15**:3640-3659

[63] Woodruff MA, Hutmacher DW. The

return of a forgotten polymer

2016. pp. 595-649

2015;**76**:321-330

2006;**47**:4845-4850

Idrees S, Nip MJ, Donde S, Yu X, et al. Handbook of Polyester Drug Delivery Systems. Singapore: Pan Stanford;

[49] Vepari C, Kaplan DL. Silk as a biomaterial. Progress in Polymer Science. 2007;**32**:991-1007

[51] Hakimi O, Knight DP,

[52] Etienne O, Schneider A, Kluge JA, Bellemin-Laponnaz C, Polidori C, Leisk GG, et al. Soft tissue augmentation using silk gels: An in vitro and in vivo study. Journal of Periodontology. 2009;**80**:1852-1858

[53] Kardestuncer T, McCarthy M, Karageorgiou V, Kaplan DL, Gronowicz G. RGD-tethered silk substrate stimulates the differentiation

of human tendon cells. Clinical Orthopaedics and Related Research.

[54] Cai Z-X, Mo X-M, Zhang K-H, Fan L-P, Yin A-L, He C-L, et al. Fabrication of chitosan/silk fibroin composite nanofibers for wounddressing applications. International Journal of Molecular Sciences.

[55] Okabayashi R, Nakamura M, Okabayashi T, Tanaka Y, Nagai A, Yamashita K. Efficacy of polarized hydroxyapatite and silk fibroin composite dressing gel on epidermal recovery from full-thickness skin wounds. Journal of Biomedical

2006;**448**:234-239

2010;**11**:3529-3539

Vollrath F, Vadgama P. Spider and mulberry silkworm silks as compatible biomaterials. Composites. Part B, Engineering. 2007;**38**:324-337

[50] Yang Y, Ding F, Wu J, Hu W, Liu W, Liu J, et al. Development and evaluation of silk fibroin-based nerve grafts used for peripheral nerve regeneration. Biomaterials. 2007;**28**:5526-5535

**28**

[64] Nada AA, James R, Shelke NB, Harmon MD, Awad HM, Nagarale RK, et al. A smart methodology to fabricate electrospun chitosan nanofiber matrices for regenerative engineering applications. Polymers for Advanced Technologies. 2014;**25**:507-515

[65] Chang KY, Hung LH, Chu I, Ko CS, Lee YD. The application of type II collagen and chondroitin sulfate grafted PCL porous scaffold in cartilage tissue engineering. Journal of Biomedial Materials Research Part A. 2010;**92**:712-723

[66] Tan L, Yu X, Wan P, Yang K. Biodegradable materials for bone repairs: A review. Journal of Materials Science and Technology. 2013;**29**:503-513

[67] Pezzin AP, Ekenstein V, Alberda GO, Zavaglia CA, Ten Brinke G, Duek EA. Poly (para-dioxanone) and poly (L-lactic acid) blends: Thermal, mechanical, and morphological properties. Journal of Applied Polymer Science. 2003;**88**:2744-2755

[68] Amanatullah DF, Landa J, Strauss EJ, Garino JP, Kim SH, Di Cesare PE. Comparison of surgical outcomes and implant wear between ceramic-ceramic and ceramicpolyethylene articulations in total hip arthroplasty. Journal of Arthroplasty. 2011;**26**(6):72-77

[69] Green JM, Hallab NJ, Liao Y-S, Narayan V, Schwarz EM, Xie C. Antioxidation treatment of ultra high molecular weight polyethylene components to decrease periprosthetic osteolysis: Evaluation of osteolytic and osteogenic properties of wear debris particles in a murine calvaria model. Current Rheumatology Reports. 2013;**15**(5):1-5

[70] Zhou J, Huang X, Zheng D, Li H, Herrler T, Li Q. Oriental nose elongation using an L-shaped polyethylene sheet implant for combined septal spreading and extension. Aesthetic Plastic Surgery. 2014;**38**(2):295-302

[71] Teo AJT, Mishra A, Park I, Kim YJ, Park WT, Yoon YJ. Polymeric biomaterials for medical implants and devices. ACS Biomaterials Science & Engineering. 2016;**2**:454-472

[72] Pérez-Merino P, Dorronsoro C, Llorente L, Durán S, Jiménez-Alfaro I, Marcos S. In vivo chromatic aberration in eyes implanted with intraocular lenses. Investigative Ophthalmology & Visual Science. 2013;**54**(4):2654-2661

[73] Terrada C, Julian K, Cassoux N, Prieur A-M, Debre M, Quartier P, et al. Cataract surgery with primary intraocular lens implantation in children with uveitis: Long-term outcomes. Journal of Cataract & Refractive Surgery. 2011;**37**(11):1977-1983

[74] Kim B-J, Hong K-S, Park K-J, Park D-H, Chung Y-G, Kang S-H. Customized cranioplasty implants using three-dimensional printers and polymethyl-methacrylate casting. Journal of Korean Neurosurgical Association. 2012;**52**(6):541-546

[75] Rivkin A. A prospective study of non-surgical primary rhinoplasty using a polymethylmethacrylate injectable implant. Dermatologic Surgery. 2014;**40**(3):305-313

[76] Shklar G, Hodosh M, Povar M. Tissue reactions to polymer-coated vitallium pin implants. Journal of Prosthetic Dentistry. 1970;**24**:636-645

[77] Qin Y, Howlader MM, Deen MJ, Haddara YM, Selvaganapathy PR. Polymer integration for packaging of implantable sensors. Sensors and Actuators, B: Chemical. 2014;**202**:758 [78] Lachhman S, Zorman C, Ko W. Multi-layered polydimethylsiloxane as a non-hermetic packaging material for medical MEMS. In: 2012 Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). Piscataway, NJ: IEEE; 2012. pp. 1655-1658

[79] Rahimi A, Mashak A. Review on rubbers in medicine: Natural, silicone and polyurethane rubbers. Plastics Rubber and Composites. 2013;**42**(6):223-230

[80] Kappel RM, Klunder AJ, Pruijn GJ. Silicon chemistry and silicone breast implants. European Journal of Plastic Surgery. 2014;**37**(3):123-128

[81] Kubyshkina G, Zupančič B, Štukelj M, GroŠelj D, Marion L, Emri I. Sterilization effect on structure, thermal and timedependent properties of polyamides. In: Mechanics of Time-Dependent Materials and Processes in Conventional and Multifunctional Materials. Vol. 3. New York: Springer; 2011. pp. 11-19

[82] Cruz F. Fabrication of HA/ PLLA composite scaffolds for bone tissue engineering using additive manufacturing technologies. In: Elnashar M, editor. Biopolymers. Rijeka, Croatia: INTECH Open Access; 2010. pp. 227-242. (Chapter 11)

[83] Li X, Liu X, Huang J, Fan Y, Cui, F.-z. Biomedical investigation of CNT based coatings. Surface and Coating Technology. 2011;**206**(4):759-766

[84] Li N, Zheng Y. Novel magnesium alloys developed for biomedical application: A review. Journal of Materials Science and Technology. 2013;**29**:489-502

[85] Witte F, Fischer J, Nellesen J, Crostack HA, Kaese V, Pisch A, et al. In vitro and in vivo corrosion

measurements of magnesium alloys. Biomaterials. 2006;**27**:1013-1018

[86] Tang A, Pan F, Yang M, Cheng R. Mechanical properties and microstructure of magnesiumaluminum based alloys containing strontium. Materials Transactions. 2008;**49**:1203-1211

[87] Tekumalla S, Seetharaman S, Almajid A, Gupta M. Mechanical properties of magnesium-rare earth alloy systems: A review. Metals. 2015;**5**:1-39

[88] Taïr K, Kharoubi O, Taïr OA, Hellal N, Benyettou I, Aoues A. Aluminium-induced acute neurotoxicity in rats: Treatment with aqueous extract of Arthrophytum (*Hammada scoparia*). Journal of Acute Disease. 2016;**5**:470-482

[89] Gu X-N, Zheng Y-F. A review on magnesium alloys as biodegradable materials. Frontiers of Materials Science in China. 2010;**4**:111-115

[90] Zhang E, Yang L, Xu J, Chen H. Microstructure, mechanical properties and bio-corrosion properties of Mg–Si(–Ca, Zn) alloy for biomedical application. Acta Biomaterialia. 2010;**6**:1756-1762

[91] Kulkarni M, Mazare A, Gongadze E, Perutkova Š, Kralj-Igli V, Milošev I, et al. Titanium nanostructures for biomedical applications. Nanotechnology. 2015;**26**:062002

[92] Kopova I, Stráský J, Harcuba P, Landa M, Janeček M, Bačákova L. Newly developed Ti–Nb–Zr–Ta–Si–Fe biomedical beta titanium alloys with increased strength and enhanced biocompatibility. Materials Science and Engineering: C. 2016;**60**: 230-238

[93] Wang S, Liu Y, Zhang C, Liao Z, Liu W. The improvement of wettability,

**31**

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

biotribological behavior and corrosion resistance of titanium alloy pre-treated by thermal oxidation. Tribology International. 2014;**79**:174-182

[103] Lee JW, Han HS, Han KJ, Park J, Jeon H, Ok MR, et al. Long-term clinical study and multiscale analysis of in vivo biodegradation mechanism of Mg alloy. Proceedings of the National Academy of Sciences of the United States of

America. 2016;**113**:716-721

2010;**6**:626-640

[104] Zhang S, Zhang X, Zhao C, Li J, Song Y, Xie C, et al. Research on an Mg–Zn alloy as a degradable biomaterial. Acta Biomaterialia.

[105] Wang J, Zhang J, Zong X, Xu C, You Z, Nie K. Effects of Ca on the formation of LPSO phase and mechanical properties of Mg-Zn-Y-Mn alloy. Materials Science and Engineering A. 2015;**648**:37-40

[106] He Y, Tao H, Zhang Y, Jiang Y, Zhang S, Zhao C, et al. Biocompatibility of bio-Mg-Zn alloy within bone with heart, liver, kidney and spleen. Chinese Science Bulletin. 2009;**54**:484-491

biodegradation of polymers: Recent results. Macromolecular Materials and

Biodegradation of polymers. Indian

[109] Hule RA, Pochan DJ. Polymer nanocomposites for biomedical applications. MRS Bulletin. 2007;**32**:

[110] Lasprilla AJ, Martinez GA, Lunelli BH, Jardini AL, Maciel Filho R. Polylactic acid synthesis for application in biomedical devices: A review. Biotechnology Advances.

[111] Fukushima K, Kimura Y. An efficient solid-state polycondensation

method for synthesizing

[107] David C, De Kesel C, Lefebvre F, Weiland M. The

Engineering. 1994;**216**:21-35

[108] Premraj R, Doble M.

Journal of Biotechnology.

2005;**4**:186-193

2012;**30**:321-328

354-358

[94] Li Y, Yang C, Zhao H, Qu S, Li X, Li Y. New developments of Ti-based alloys for biomedical applications. Materials. 2014;**7**:1709-1800

Biocompatibility of Ti-alloys for longterm implantation. Journal of the Mechanical Behavior of Biomedical

[95] Gepreel MA, Niinomi M.

Materials. 2013;**20**:407-415

Research. 1987;**95**:356-363

WB Saunders; 1982

2010;**2**:40-54

[96] Arvidson K, Cottler-Fox M, Hammarlund E, Friberg U. Cytotoxic effects of cobalt-chromium alloys on fibroblasts derived from human gingiva. Scandinavian Journal of Dental

[97] Phillips RW. Skinner's Science of Dental Materials. 8th ed. Philadelphia:

[98] Manivasagam G, Dhinasekaran D, Rajamanickam A. Biomedical implants: Corrosion and its prevention—A review. Recent Patents on Corrosion Science.

[99] Chaturvedi TP. An overview of the corrosion aspect of dental implants (titanium and its alloys). Indian Journal of Dental Research. 2009;**20**:91-98

[100] Adya N, Alam M, Ravindranath T, Mubeen A, Saluja B. Corrosion in titanium dental implants: Literature review. Journal of Indian Prosthodontic

[101] Song GL, Atrens A. Corrosion mechanisms of magnesium alloys. Advanced Engineering Materials.

[102] Lee YC, Dahle AK, StJohn DH. Grain refinement of magnesium. In: Essential Readings in Magnesium Technology. Berlin, Germany: Springer;

Society. 2005;**5**:126-131

1999;**1**:11-33

2016. pp. 247-254

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

*Biomaterials*

[78] Lachhman S, Zorman C, Ko W. Multi-layered polydimethylsiloxane as a non-hermetic packaging material for medical MEMS. In: 2012 Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). Piscataway, NJ:

measurements of magnesium alloys. Biomaterials. 2006;**27**:1013-1018

Cheng R. Mechanical properties and microstructure of magnesiumaluminum based alloys containing strontium. Materials Transactions.

[87] Tekumalla S, Seetharaman S, Almajid A, Gupta M. Mechanical properties of magnesium-rare earth alloy systems: A review. Metals.

[88] Taïr K, Kharoubi O, Taïr OA, Hellal N, Benyettou I, Aoues A.

in rats: Treatment with aqueous extract of Arthrophytum (*Hammada scoparia*). Journal of Acute Disease.

[89] Gu X-N, Zheng Y-F. A review on magnesium alloys as biodegradable materials. Frontiers of Materials Science

Chen H. Microstructure, mechanical properties and bio-corrosion properties of Mg–Si(–Ca, Zn) alloy for biomedical

[91] Kulkarni M, Mazare A, Gongadze E, Perutkova Š, Kralj-Igli V, Milošev I, et al. Titanium nanostructures for biomedical

application. Acta Biomaterialia.

applications. Nanotechnology.

[92] Kopova I, Stráský J, Harcuba P, Landa M, Janeček M, Bačákova L. Newly developed Ti–Nb–Zr–Ta–Si–Fe biomedical beta titanium alloys with increased strength and

enhanced biocompatibility. Materials Science and Engineering: C. 2016;**60**:

[93] Wang S, Liu Y, Zhang C, Liao Z, Liu W. The improvement of wettability,

Aluminium-induced acute neurotoxicity

[86] Tang A, Pan F, Yang M,

2008;**49**:1203-1211

2015;**5**:1-39

2016;**5**:470-482

in China. 2010;**4**:111-115

2010;**6**:1756-1762

2015;**26**:062002

230-238

[90] Zhang E, Yang L, Xu J,

IEEE; 2012. pp. 1655-1658

2013;**42**(6):223-230

[80] Kappel RM, Klunder AJ,

[81] Kubyshkina G, Zupančič B, Štukelj M, GroŠelj D, Marion L, Emri I. Sterilization effect on structure, thermal and time-

Materials and Processes in

[82] Cruz F. Fabrication of HA/ PLLA composite scaffolds for bone tissue engineering using additive manufacturing technologies. In:

pp. 227-242. (Chapter 11)

2013;**29**:489-502

2011. pp. 11-19

dependent properties of polyamides. In: Mechanics of Time-Dependent

Conventional and Multifunctional Materials. Vol. 3. New York: Springer;

Elnashar M, editor. Biopolymers. Rijeka, Croatia: INTECH Open Access; 2010.

[83] Li X, Liu X, Huang J, Fan Y, Cui, F.-z. Biomedical investigation of CNT based coatings. Surface and Coating Technology. 2011;**206**(4):759-766

[84] Li N, Zheng Y. Novel magnesium alloys developed for biomedical application: A review. Journal of Materials Science and Technology.

[85] Witte F, Fischer J, Nellesen J, Crostack HA, Kaese V, Pisch A, et al. In vitro and in vivo corrosion

Pruijn GJ. Silicon chemistry and silicone breast implants. European Journal of Plastic Surgery. 2014;**37**(3):123-128

[79] Rahimi A, Mashak A. Review on rubbers in medicine: Natural, silicone and polyurethane rubbers. Plastics Rubber and Composites.

**30**

biotribological behavior and corrosion resistance of titanium alloy pre-treated by thermal oxidation. Tribology International. 2014;**79**:174-182

[94] Li Y, Yang C, Zhao H, Qu S, Li X, Li Y. New developments of Ti-based alloys for biomedical applications. Materials. 2014;**7**:1709-1800

[95] Gepreel MA, Niinomi M. Biocompatibility of Ti-alloys for longterm implantation. Journal of the Mechanical Behavior of Biomedical Materials. 2013;**20**:407-415

[96] Arvidson K, Cottler-Fox M, Hammarlund E, Friberg U. Cytotoxic effects of cobalt-chromium alloys on fibroblasts derived from human gingiva. Scandinavian Journal of Dental Research. 1987;**95**:356-363

[97] Phillips RW. Skinner's Science of Dental Materials. 8th ed. Philadelphia: WB Saunders; 1982

[98] Manivasagam G, Dhinasekaran D, Rajamanickam A. Biomedical implants: Corrosion and its prevention—A review. Recent Patents on Corrosion Science. 2010;**2**:40-54

[99] Chaturvedi TP. An overview of the corrosion aspect of dental implants (titanium and its alloys). Indian Journal of Dental Research. 2009;**20**:91-98

[100] Adya N, Alam M, Ravindranath T, Mubeen A, Saluja B. Corrosion in titanium dental implants: Literature review. Journal of Indian Prosthodontic Society. 2005;**5**:126-131

[101] Song GL, Atrens A. Corrosion mechanisms of magnesium alloys. Advanced Engineering Materials. 1999;**1**:11-33

[102] Lee YC, Dahle AK, StJohn DH. Grain refinement of magnesium. In: Essential Readings in Magnesium Technology. Berlin, Germany: Springer; 2016. pp. 247-254

[103] Lee JW, Han HS, Han KJ, Park J, Jeon H, Ok MR, et al. Long-term clinical study and multiscale analysis of in vivo biodegradation mechanism of Mg alloy. Proceedings of the National Academy of Sciences of the United States of America. 2016;**113**:716-721

[104] Zhang S, Zhang X, Zhao C, Li J, Song Y, Xie C, et al. Research on an Mg–Zn alloy as a degradable biomaterial. Acta Biomaterialia. 2010;**6**:626-640

[105] Wang J, Zhang J, Zong X, Xu C, You Z, Nie K. Effects of Ca on the formation of LPSO phase and mechanical properties of Mg-Zn-Y-Mn alloy. Materials Science and Engineering A. 2015;**648**:37-40

[106] He Y, Tao H, Zhang Y, Jiang Y, Zhang S, Zhao C, et al. Biocompatibility of bio-Mg-Zn alloy within bone with heart, liver, kidney and spleen. Chinese Science Bulletin. 2009;**54**:484-491

[107] David C, De Kesel C, Lefebvre F, Weiland M. The biodegradation of polymers: Recent results. Macromolecular Materials and Engineering. 1994;**216**:21-35

[108] Premraj R, Doble M. Biodegradation of polymers. Indian Journal of Biotechnology. 2005;**4**:186-193

[109] Hule RA, Pochan DJ. Polymer nanocomposites for biomedical applications. MRS Bulletin. 2007;**32**: 354-358

[110] Lasprilla AJ, Martinez GA, Lunelli BH, Jardini AL, Maciel Filho R. Polylactic acid synthesis for application in biomedical devices: A review. Biotechnology Advances. 2012;**30**:321-328

[111] Fukushima K, Kimura Y. An efficient solid-state polycondensation method for synthesizing

stereo-complexed poly (lactic acid) s with high molecular weight. Journal of Polymer Science Part A: Polymer Chemistry. 2008;**46**:3714-3722

[112] Sastri VR. Plastics in Medical Devices: Properties, Requirements, and Applications. Cambridge, UK: William Andrew; 2013

[113] Joung Y-H. Development of implantable medical devices: From an engineering perspective. International Neurourology Journal. 2013;**17**(3):98-106

[114] Anderson J. Inflammatory response to implants. ASAIO Transactions. 1988;**34**(2):101-107

[115] Kenneth Ward W. A review of the foreign-body response to subcutaneously-implanted devices: The role of macrophages and cytokines in biofouling and fibrosis. Journal of Diabetes Science and Technology. 2008;**2**(5):768-777

[116] Luttikhuizen D, Harmsen M, Luyn M. Cellular and molecular dynamics in the foreign body reaction. Tissue Engineering. 2006;**12**(7):1955-1970

[117] Anderson J, Rodriguez A, Chang D. Foreign body reaction to biomaterials. Seminars in Immunology. 2008;**20**(2):86-100

[118] Wilson C, Clegg R, Leavesley D, Pearcy M. Mediation of biomaterialcell interactions by adsorbed proteins: A review. Tissue Engineering. 2005;**11**(1-2):1-18

[119] Kuhn A, Singh S, Smit P, Ko F, Falcone R, Lyle W, et al. Periprosthetic breast capsules contain the fibrogenic cytokines TGF-beta1 and TGF-beta2, suggesting possible new treatment approaches. Annals of Plastic Surgery. 2000;**44**(4):387-391

[120] Mazaheri M, Schultz G, Blalock T, Caffee H, Chin G, Lineaweaver W. Role of connective tissue growth factor in breast implant elastomer capsular formation. Annals of Plastic Surgery. 2003;**50**(3):263-268

[121] Mariani E, Lisignoli G, Borzì R, Pulsatelli L. Biomaterials: Foreign bodies or tuners for the immune response? International Journal of Molecular Sciences. 2019;**20**(3):636-678

[122] Orive G, De Castro M, Kong H, Hernández R, Ponce S, Mooney D, et al. Bioactive cell-hydrogel microcapsules for cell-based drug delivery. Journal of Controlled Release. 2009;**135**(3):203-210

[123] Orive G, Santos E, Poncelet D, Hernández R, Pedraz J, Wahlberg L, et al. Cell encapsulation: Technical and clinical advances. Trends in Pharmacological Sciences. 2015;**36**(8):537-546

[124] Major M, Wong V, Nelson E, Longaker M, Gurtner G. The foreign body response: At the Interface of surgery and bioengineering. Plastic and Reconstructive Surgery. 2015;**135**(5):1489-1498

[125] Vishwakarma A, Bhise N, Evangelista M, Rouwkema J, Dokmeci M, Ghaemmaghami A, et al. Engineering immunomodulatory biomaterials to tune the inflammatory response. Trends in Biotechnology. 2016;**34**(6):470-482

[126] Drury J, Mooney D. Hydrogels for tissue engineering: Scaffold design variables and applications. Biomaterials. 2003;**24**(24):4337-4351

[127] Kakizawa Y, Lee J, Bell B, Fahmy T. Precise manipulation of biophysical particle parameters enables control of proinflammatory cytokine production in presence of TLR 3

**33**

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

muscle restoration. Biomaterials.

[135] Toyoda H, Terai H, Sasaoka R, Oda K, Takaoka K. Augmentation of bone morphogenetic protein-induced bone mass by local delivery of a prostaglandin E EP4 receptor agonist.

[136] Wynn T, Vannella K. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;**44**(3):450-462

Barczyk K, Bode G, Nippe N, Kran N, et al. Induction of an anti-inflammatory human monocyte subtype is a unique property of glucocorticoids, but can be modified by IL-6 and IL-10. Immunobiology. 2012;**217**(3):329-335

[138] Swartzlander M, Blakney A, Amer L, Hankenson K, Kyriakides T, Bryant S. Immunomodulation by mesenchymal stem cells combats the foreign body response to cell-laden synthetic hydrogels. Biomaterials.

[139] Dohle E, Bischoff I, Bose T, Marsano A, Banfi A, Unger R, et al. Macrophage-mediated angiogenic activation of outgrowth endothelial cells in co-culture with primary osteoblasts.

European Cells and Materials.

Investigation. 2012;**2**(1):2

[141] Koduri R, Mahalakshmi K, Maheswara Rao U. Implantable drug delivery systems: A review on parenteral implants. International Journal of Innovative Pharmaceutical Sciences and Research. 2015;**3**(9):

[142] Agrawal M, Limbachiya M, Sapariya A, Patel G. A review on

[140] Tiwari G, Tiwari R, Bannerjee S, Bhati L, Pandey S, Pandey P, et al. Drug delivery systems: An updated review. International Journal of Pharmaceutical

2015;**41**:79-88

2014;**27**:149-164

1406-1418

2016;**103**:128-136

Bone. 2005;**37**:555-562

[137] Tsianakas A, Varga G,

and 4 ligands. Acta Biomaterialia.

[128] Bota P, Collie A, Puolakkainen P, Vernon R, Sage E, Ratner B, et al. Biomaterial topography alters healing in vivo and monocyte/macrophage activation in vitro. Journal of Biomedical Materials Research.

Hung Y, Huang G. Control of growth and inflammatory response of macrophages and foam cells with nanotopography. Nanoscale Research

[130] Scopelliti P, Borgonovo A, Indrieri M, Giorgetti L, Bongiorno G, Carbone R, et al. The effect of surface nanometre-scale morphology on protein adsorption. PLoS One.

[131] Mrksich M, Whitesides G. Using self-assembled monolayers to understand the interactions of man-made surfaces with proteins and cells. Annual Review of Biophysics and Biomolecular Structures.

[132] Bartneck M, Keul H, Singh S, Czaja K, Bornemann J, Bockstaller M, et al. Rapid uptake of gold nanorods by primary human blood phagocytes and immunomodulatory effects of surface chemistry. ACS Nano.

[133] Veiseh O, Doloff J, Ma M, Vegas A, Tam H, Bader A, et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and nonhuman primates. Nature Materials.

[134] Badylak S, Dziki J, Sicari B, Ambrosio F, Boninger M. Mechanisms by which acellular biologic scaffolds

promote functional skeletal

2017;**15**(57):136-145

2010;**95**(2):649-657

Letters. 2012;**7**:394

2010;**5**(7):e11862

1996;**25**:55-78

2010;**4**(6):3073-3086

2015;**14**:643-651

[129] Mohiuddin M, Pan H,

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

and 4 ligands. Acta Biomaterialia. 2017;**15**(57):136-145

*Biomaterials*

Andrew; 2013

2013;**17**(3):98-106

1988;**34**(2):101-107

2008;**2**(5):768-777

2006;**12**(7):1955-1970

2008;**20**(2):86-100

2005;**11**(1-2):1-18

2000;**44**(4):387-391

stereo-complexed poly (lactic acid) s with high molecular weight. Journal of Polymer Science Part A: Polymer Chemistry. 2008;**46**:3714-3722

[120] Mazaheri M, Schultz G, Blalock T, Caffee H, Chin G, Lineaweaver W. Role of connective tissue growth factor in breast implant elastomer capsular formation. Annals of Plastic Surgery.

[121] Mariani E, Lisignoli G, Borzì R, Pulsatelli L. Biomaterials: Foreign bodies or tuners for the immune response? International Journal of Molecular Sciences. 2019;**20**(3):636-678

Mooney D, et al. Bioactive cell-hydrogel microcapsules for cell-based drug delivery. Journal of Controlled Release.

[123] Orive G, Santos E, Poncelet D, Hernández R, Pedraz J, Wahlberg L, et al. Cell encapsulation: Technical and clinical advances. Trends in Pharmacological Sciences.

[124] Major M, Wong V, Nelson E, Longaker M, Gurtner G. The foreign body response: At the Interface of surgery and bioengineering. Plastic and Reconstructive Surgery.

[125] Vishwakarma A, Bhise N, Evangelista M, Rouwkema J,

Dokmeci M, Ghaemmaghami A, et al. Engineering immunomodulatory biomaterials to tune the inflammatory response. Trends in Biotechnology.

[126] Drury J, Mooney D. Hydrogels for tissue engineering: Scaffold design variables and applications. Biomaterials.

[122] Orive G, De Castro M, Kong H, Hernández R, Ponce S,

2009;**135**(3):203-210

2015;**36**(8):537-546

2015;**135**(5):1489-1498

2016;**34**(6):470-482

2003;**24**(24):4337-4351

[127] Kakizawa Y, Lee J, Bell B, Fahmy T. Precise manipulation of biophysical particle parameters enables control of proinflammatory cytokine production in presence of TLR 3

2003;**50**(3):263-268

[112] Sastri VR. Plastics in Medical Devices: Properties, Requirements, and Applications. Cambridge, UK: William

[113] Joung Y-H. Development of implantable medical devices: From an engineering perspective. International Neurourology Journal.

[114] Anderson J. Inflammatory response to implants. ASAIO Transactions.

[115] Kenneth Ward W. A review of the foreign-body response to subcutaneously-implanted devices: The role of macrophages and cytokines in biofouling and fibrosis. Journal of Diabetes Science and Technology.

[116] Luttikhuizen D, Harmsen M, Luyn M. Cellular and molecular dynamics in the foreign body reaction. Tissue Engineering.

[117] Anderson J, Rodriguez A, Chang D. Foreign body reaction to biomaterials. Seminars in Immunology.

A review. Tissue Engineering.

[118] Wilson C, Clegg R, Leavesley D, Pearcy M. Mediation of biomaterialcell interactions by adsorbed proteins:

[119] Kuhn A, Singh S, Smit P, Ko F, Falcone R, Lyle W, et al. Periprosthetic breast capsules contain the fibrogenic cytokines TGF-beta1 and TGF-beta2, suggesting possible new treatment approaches. Annals of Plastic Surgery.

**32**

[128] Bota P, Collie A, Puolakkainen P, Vernon R, Sage E, Ratner B, et al. Biomaterial topography alters healing in vivo and monocyte/macrophage activation in vitro. Journal of Biomedical Materials Research. 2010;**95**(2):649-657

[129] Mohiuddin M, Pan H, Hung Y, Huang G. Control of growth and inflammatory response of macrophages and foam cells with nanotopography. Nanoscale Research Letters. 2012;**7**:394

[130] Scopelliti P, Borgonovo A, Indrieri M, Giorgetti L, Bongiorno G, Carbone R, et al. The effect of surface nanometre-scale morphology on protein adsorption. PLoS One. 2010;**5**(7):e11862

[131] Mrksich M, Whitesides G. Using self-assembled monolayers to understand the interactions of man-made surfaces with proteins and cells. Annual Review of Biophysics and Biomolecular Structures. 1996;**25**:55-78

[132] Bartneck M, Keul H, Singh S, Czaja K, Bornemann J, Bockstaller M, et al. Rapid uptake of gold nanorods by primary human blood phagocytes and immunomodulatory effects of surface chemistry. ACS Nano. 2010;**4**(6):3073-3086

[133] Veiseh O, Doloff J, Ma M, Vegas A, Tam H, Bader A, et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and nonhuman primates. Nature Materials. 2015;**14**:643-651

[134] Badylak S, Dziki J, Sicari B, Ambrosio F, Boninger M. Mechanisms by which acellular biologic scaffolds promote functional skeletal

muscle restoration. Biomaterials. 2016;**103**:128-136

[135] Toyoda H, Terai H, Sasaoka R, Oda K, Takaoka K. Augmentation of bone morphogenetic protein-induced bone mass by local delivery of a prostaglandin E EP4 receptor agonist. Bone. 2005;**37**:555-562

[136] Wynn T, Vannella K. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;**44**(3):450-462

[137] Tsianakas A, Varga G, Barczyk K, Bode G, Nippe N, Kran N, et al. Induction of an anti-inflammatory human monocyte subtype is a unique property of glucocorticoids, but can be modified by IL-6 and IL-10. Immunobiology. 2012;**217**(3):329-335

[138] Swartzlander M, Blakney A, Amer L, Hankenson K, Kyriakides T, Bryant S. Immunomodulation by mesenchymal stem cells combats the foreign body response to cell-laden synthetic hydrogels. Biomaterials. 2015;**41**:79-88

[139] Dohle E, Bischoff I, Bose T, Marsano A, Banfi A, Unger R, et al. Macrophage-mediated angiogenic activation of outgrowth endothelial cells in co-culture with primary osteoblasts. European Cells and Materials. 2014;**27**:149-164

[140] Tiwari G, Tiwari R, Bannerjee S, Bhati L, Pandey S, Pandey P, et al. Drug delivery systems: An updated review. International Journal of Pharmaceutical Investigation. 2012;**2**(1):2

[141] Koduri R, Mahalakshmi K, Maheswara Rao U. Implantable drug delivery systems: A review on parenteral implants. International Journal of Innovative Pharmaceutical Sciences and Research. 2015;**3**(9): 1406-1418

[142] Agrawal M, Limbachiya M, Sapariya A, Patel G. A review on parenteral controlled drug delivery system. IJPSR. 2012;**3**(10):3657-3669

[143] Citrin D, Resnick M, Guinan P, Al-Bussam N, Scott M, Gau T, et al. A comparison of Zoladex@ and DES in the treatment of advanced prostate cancer: Results of a randomized multicenter trial. The Prostate. 1991;**18**:139-146

[144] Royer P, Jones K. Progestins for contraception: Modern delivery systems and novel formulations. Clinical Obstetrics and Gynecology. 2014;**57**(4):644-658

[145] Mommers E, Blum G, Gent T, Peters K, Sordal T, Marintcheva-Petrova M. Nexplanon, a radiopaque etonogestrel implant in combination with a next-generation applicator: 3-year results of a noncomparative multicenter trial. American Journal of Obstetrics and Gynecology. 2012;**207**(5): 388.e1-388.e6

[146] Intarcia. n.d. Available from: https://www.intarcia.com/media.html

[147] Rohloff C, Alessi T, Yang B, Dahms J, Carr J, Lautenbach S. DUROS ® technology delivers peptides and proteins at consistent rate continuously for 3 to 12 months. Journal of Diabetes Science and Technology. 2008;**2**(3):461-467

[148] Barrett S, Teller R, Forster S, Li L, Mackey M, Skomski D, et al. Extendedduration MK-8591-eluting implant as a candidate for HIV treatment and prevention. Antimicrobial Agents and Chemotherapy. 2018;**62**:1058-1076

[149] Zaki M, Patil S, Baviskar D, Jain D. Implantable drug delivery system: A review. International Journal of Pharm Tech Research. 2012;**4**(1):280-292

[150] Hu L, Zhang H, Song W. An overview of preparation

and evaluation sustainedrelease injectable microspheres. Journal of Microencapsulation. 2013;**30**(4):369-382

[151] Park E, Amatya S, Kim M, Park J, Seol E, Lee H, et al. Long-acting injectable formulations of antipsychotic drugs for the treatment of schizophrenia. Archives of Pharmacal Research. 2013;**36**(6):651-659

[152] Hoffman A. Hydrogels for biomedical applications. Advanced Drug Delivery Reviews. 2012;**64**:18-23

[153] Kempe S, Mäder K. In situ forming implants—An attractive formulation principle for parenteral depot formulations. Journal of Controlled Release. 2012;**161**(2):668-679

[154] Flexner C. Antiretroviral implants for treatment and prevention of HIV infection. Current Opinion in HIV and AIDS. 2018;**13**(4):374-380

[155] Ruel-Gariépy E, Leroux J. In situ-forming hydrogels—Review of temperature-sensitive systems. European Journal of Pharmaceutics and Biopharmaceutics. 2004;**58**(2):409-426

[156] Available from: https://www. fda.gov/advisory-committees/ blood-vaccines-and-other-biologics/ cellular-tissue-and-gene-therapiesadvisory-committee [Accessed: 28 November 2019]

[157] Fliervoet LAL, Mastrobattista E. Drug delivery with living cells. Advanced Drug Delivery Reviews. 2016;**106**(part A):63-72

[158] O'Brien FJ. Biomaterials & scaffolds for tissue engineering. Materials Today. 2011;**14**(3):88-95

[159] Atala A. Tissue engineering and regenerative medicine: Concepts for clinical application. In: Rejuvenation

**35**

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

Research. Vol. 7. Mary Ann Liebert Inc.;

Pathogenic Viruses. Cambridge, UK:

Introduction to tissue engineering. In: Biomaterials, Artificial Organs and Tissue Engineering. Cambridge, UK: Elsevier Inc.; 2005. pp. 193-200

[168] Kengla C, Kidiyoor A, Murphy SV. Bioprinting complex 3D tissue and organs. In: Kidney Transplantation, Bioengineering, and Regeneration: Kidney Transplantation in the

Regenerative Medicine Era. Cambridge, UK: Elsevier Inc.; 2017. pp. 957-971

[169] Rippon HJ, Bishop AE. Embryonic stem cells. Cell Proliferation in Basic and Clinical Sciences. Feb 2004;**37**(1):23-34

[170] Seo BJ, Hong YJ, Do JT. Cellular reprogramming using protein and cell-penetrating peptides [Internet]. International Journal of Molecular

[171] Carpenedo RL, McDevitt TC. Stem Cells: Key Concepts. In: Biomaterials Science: An Introduction to Materials. 3rd ed. Cambridge, UK: Elsevier Inc.;

[172] Ahmed ASI, Sheng MH, Wasnik S, Baylink DJ, Lau K-HW. Effect of aging

[174] Los MJ, Skubis A, Ghavami S. Stem cells. In: Stem Cells and Biomaterials for Regenerative Medicine. Cambridge, UK:

[175] Atala A, Lanza R, Thomson JA, Nerem RM. Principles of Regenerative Medicine. Cambridge, UK: Academic

Press (Elsevier); 2018. p. 1454

on stem cells. World Journal of Experimental Medicine. 2017;**7**(1):1

[173] Beyer Nardi N, Da Silva Meirelles L. Mesenchymal stem cells: Isolation, in vitro expansion and characterization. Handbook of Experimental Pharmacology.

Sciences. 2017;**18**:552

2013. pp. 487-495

2006;**174**:249-282

Elsevier; 2019. pp. 5-16

Elsevier; 2017. pp. 47-62

[167] Buttery LDK, Bishop AE.

[160] Chen E, Yang L, Ye C, Zhang W, Ran J, Xue D, et al. An asymmetric chitosan scaffold for tendon tissue engineering: In vitro and in vivo evaluation with rat tendon stem/ progenitor cells. Acta Biomaterialia.

[161] Hazeri Y, Irani S, Zandi M,

Pezeshki-Modaress M. Polyvinyl alcohol/ sulfated alginate nanofibers induced the neuronal differentiation of human bone marrow stem cells. International Journal of Biological Macromolecules.

Narayanan S, Mahuvawalla F. Fabrication of electrospun polycaprolactone/gelatin composite nanofibrous scaffolds with cellular responses. American Journal of Nano Research and Applications.

[163] Xu F, Ren H, Zheng M, Shao X, Dai T, Wu Y, et al. Development of biodegradable bioactive glass ceramics by DLP printed containing EPCs/ BMSCs for bone tissue engineering of rabbit mandible defects. Journal of the Mechanical Behavior of Biomedical

2004. pp. 15-31

2018;**73**:377-387

2019;**147**:946-953

2019;**7**(2):11

[162] Kannaiyan J, Khare S,

Materials. 2020;**103**:103532

[Epub ahead of print]

[164] Wang H, Shang Y, Cheng X, Wang Z, Zhu D, Liu Y, et al. Delivery of MSCs with a hybrid β-sheet peptide hydrogel consisting IGF-1C domain and D-form peptide for acute kidney injury therapy. SSRN Electronic Journal; 2019;**39**. DOI: 10.2139/ssrn.3485132

[165] Gong Z, Lei D, Yu C, Wang C, Xia K, Shu J, et al. Fast degrading bioactive elastic scaffold loaded with neural stem cells promote rapid spinal cord regeneration. SSRN Electronic Journal. 2019. [Epub ahead of print]

[166] Ryu W-S. Diagnosis and methods. In: Molecular Virology of Human

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

*Biomaterials*

1991;**18**:139-146

2014;**57**(4):644-658

388.e1-388.e6

[145] Mommers E, Blum G, Gent T, Peters K, Sordal T,

Marintcheva-Petrova M. Nexplanon, a radiopaque etonogestrel implant in combination with a next-generation applicator: 3-year results of a noncomparative multicenter trial. American Journal of Obstetrics and Gynecology. 2012;**207**(5):

[146] Intarcia. n.d. Available from: https://www.intarcia.com/media.html

[147] Rohloff C, Alessi T, Yang B, Dahms J, Carr J, Lautenbach S. DUROS ® technology delivers peptides and proteins at consistent rate continuously

for 3 to 12 months. Journal of Diabetes Science and Technology.

[148] Barrett S, Teller R, Forster S, Li L, Mackey M, Skomski D, et al. Extendedduration MK-8591-eluting implant as a candidate for HIV treatment and prevention. Antimicrobial Agents and Chemotherapy. 2018;**62**:1058-1076

[149] Zaki M, Patil S, Baviskar D, Jain D. Implantable drug delivery system: A review. International Journal of Pharm Tech Research. 2012;**4**(1):280-292

[150] Hu L, Zhang H, Song W. An overview of preparation

2008;**2**(3):461-467

parenteral controlled drug delivery system. IJPSR. 2012;**3**(10):3657-3669 and evaluation sustainedrelease injectable microspheres. Journal of Microencapsulation.

[151] Park E, Amatya S, Kim M,

drugs for the treatment of

Research. 2013;**36**(6):651-659

[152] Hoffman A. Hydrogels for biomedical applications. Advanced Drug Delivery Reviews. 2012;**64**:18-23

Park J, Seol E, Lee H, et al. Long-acting injectable formulations of antipsychotic

schizophrenia. Archives of Pharmacal

[153] Kempe S, Mäder K. In situ forming implants—An attractive formulation principle for parenteral depot formulations. Journal of Controlled Release. 2012;**161**(2):668-679

[154] Flexner C. Antiretroviral implants for treatment and prevention of HIV infection. Current Opinion in HIV and

AIDS. 2018;**13**(4):374-380

and Biopharmaceutics. 2004;**58**(2):409-426

November 2019]

2016;**106**(part A):63-72

[158] O'Brien FJ. Biomaterials & scaffolds for tissue engineering. Materials Today. 2011;**14**(3):88-95

[159] Atala A. Tissue engineering and regenerative medicine: Concepts for clinical application. In: Rejuvenation

[155] Ruel-Gariépy E, Leroux J. In situ-forming hydrogels—Review of temperature-sensitive systems. European Journal of Pharmaceutics

[156] Available from: https://www. fda.gov/advisory-committees/ blood-vaccines-and-other-biologics/ cellular-tissue-and-gene-therapiesadvisory-committee [Accessed: 28

[157] Fliervoet LAL, Mastrobattista E. Drug delivery with living cells. Advanced Drug Delivery Reviews.

2013;**30**(4):369-382

[143] Citrin D, Resnick M, Guinan P, Al-Bussam N, Scott M, Gau T, et al. A comparison of Zoladex@ and DES in the treatment of advanced prostate cancer: Results of a randomized multicenter trial. The Prostate.

[144] Royer P, Jones K. Progestins for contraception: Modern delivery systems and novel formulations. Clinical Obstetrics and Gynecology.

**34**

Research. Vol. 7. Mary Ann Liebert Inc.; 2004. pp. 15-31

[160] Chen E, Yang L, Ye C, Zhang W, Ran J, Xue D, et al. An asymmetric chitosan scaffold for tendon tissue engineering: In vitro and in vivo evaluation with rat tendon stem/ progenitor cells. Acta Biomaterialia. 2018;**73**:377-387

[161] Hazeri Y, Irani S, Zandi M, Pezeshki-Modaress M. Polyvinyl alcohol/ sulfated alginate nanofibers induced the neuronal differentiation of human bone marrow stem cells. International Journal of Biological Macromolecules. 2019;**147**:946-953

[162] Kannaiyan J, Khare S, Narayanan S, Mahuvawalla F. Fabrication of electrospun polycaprolactone/gelatin composite nanofibrous scaffolds with cellular responses. American Journal of Nano Research and Applications. 2019;**7**(2):11

[163] Xu F, Ren H, Zheng M, Shao X, Dai T, Wu Y, et al. Development of biodegradable bioactive glass ceramics by DLP printed containing EPCs/ BMSCs for bone tissue engineering of rabbit mandible defects. Journal of the Mechanical Behavior of Biomedical Materials. 2020;**103**:103532

[164] Wang H, Shang Y, Cheng X, Wang Z, Zhu D, Liu Y, et al. Delivery of MSCs with a hybrid β-sheet peptide hydrogel consisting IGF-1C domain and D-form peptide for acute kidney injury therapy. SSRN Electronic Journal; 2019;**39**. DOI: 10.2139/ssrn.3485132 [Epub ahead of print]

[165] Gong Z, Lei D, Yu C, Wang C, Xia K, Shu J, et al. Fast degrading bioactive elastic scaffold loaded with neural stem cells promote rapid spinal cord regeneration. SSRN Electronic Journal. 2019. [Epub ahead of print]

[166] Ryu W-S. Diagnosis and methods. In: Molecular Virology of Human

Pathogenic Viruses. Cambridge, UK: Elsevier; 2017. pp. 47-62

[167] Buttery LDK, Bishop AE. Introduction to tissue engineering. In: Biomaterials, Artificial Organs and Tissue Engineering. Cambridge, UK: Elsevier Inc.; 2005. pp. 193-200

[168] Kengla C, Kidiyoor A, Murphy SV. Bioprinting complex 3D tissue and organs. In: Kidney Transplantation, Bioengineering, and Regeneration: Kidney Transplantation in the Regenerative Medicine Era. Cambridge, UK: Elsevier Inc.; 2017. pp. 957-971

[169] Rippon HJ, Bishop AE. Embryonic stem cells. Cell Proliferation in Basic and Clinical Sciences. Feb 2004;**37**(1):23-34

[170] Seo BJ, Hong YJ, Do JT. Cellular reprogramming using protein and cell-penetrating peptides [Internet]. International Journal of Molecular Sciences. 2017;**18**:552

[171] Carpenedo RL, McDevitt TC. Stem Cells: Key Concepts. In: Biomaterials Science: An Introduction to Materials. 3rd ed. Cambridge, UK: Elsevier Inc.; 2013. pp. 487-495

[172] Ahmed ASI, Sheng MH, Wasnik S, Baylink DJ, Lau K-HW. Effect of aging on stem cells. World Journal of Experimental Medicine. 2017;**7**(1):1

[173] Beyer Nardi N, Da Silva Meirelles L. Mesenchymal stem cells: Isolation, in vitro expansion and characterization. Handbook of Experimental Pharmacology. 2006;**174**:249-282

[174] Los MJ, Skubis A, Ghavami S. Stem cells. In: Stem Cells and Biomaterials for Regenerative Medicine. Cambridge, UK: Elsevier; 2019. pp. 5-16

[175] Atala A, Lanza R, Thomson JA, Nerem RM. Principles of Regenerative Medicine. Cambridge, UK: Academic Press (Elsevier); 2018. p. 1454

[176] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;**126**(4):663-676

[177] Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007;**448**(7151):313-317

[178] Liu Q, Wang J, Chen Y, Zhang Z, Saunders L, Schipani E, et al. Suppressing mesenchymal stem cell hypertrophy and endochondral ossification in 3D cartilage regeneration with nanofibrous poly(L-lactic acid) scaffold and matrilin-3. Acta Biomaterialia. 2018;**76**:29-38

[179] Salerno A, Fernández-Gutiérrez M, San Román Del Barrio J, Domingo C. Bio-safe fabrication of PLA scaffolds for bone tissue engineering by combining phase separation, porogen leaching and scCO2 drying. Journal of Supercritical Fluids. 2015;**97**:238-246

[180] Fereshteh Z, Fathi M, Bagri A, Boccaccini AR. Preparation and characterization of aligned porous PCL/zein scaffolds as drug delivery systems via improved unidirectional freeze-drying method. Materials Science and Engineering: C. 2016;**68**:613-622

[181] Lowe CJ, Reucroft IM, Grota MC, Shreiber DI. Production of highly aligned collagen scaffolds by freezedrying of self-assembled, fibrillar collagen gels. ACS Biomaterials Science & Engineering. 2016;**2**(4):643-651

[182] Vishwanath V, Pramanik K, Biswas A. Optimization and evaluation of silk fibroin-chitosan freezedried porous scaffolds for cartilage tissue engineering application. Journal of Biomaterials Science, Polymer Edition. 2016;**27**(7):657-674

[183] Li X, Huang L, Li L, Tang Y, Liu Q, Xie H, et al. Biomimetic dual-oriented/ bilayered electrospun scaffold for vascular tissue engineering. Journal of Biomaterials Science. Polymer Edition. 2020;**31**(4):1-15

[184] Elizabeth N, Carolina RR, Gowsihan P, Joshua PC, Qun J, Akiko O, et al. Electrospinning 3D bioactive glasses for wound healing. Journal of Biomedical Materials Research. 2020;**15**:015014

[185] Dang W, Ma B, Li B, Huan Z, Ma N, Zhu H, et al. 3D printing of metal-organic framework nanosheetsstructured scaffolds with tumor therapy and bone construction. Biofabrication. 2019;**12**(2):025005

[186] Yang Y, Qiao X, Huang R, Chen H, Shi X, Wang J, et al. E-jet 3D printed drug delivery implants to inhibit growth and metastasis of orthotopic breast cancer. Biomaterials. 2019;**13**:119618

[187] Sola A, Bertacchini J, D'Avella D, Anselmi L, Maraldi T, Marmiroli S, et al. Development of solvent-casting particulate leaching (SCPL) polymer scaffolds as improved three-dimensional supports to mimic the bone marrow niche. Materials Science and Engineering: C. 2019;**96**:153-165

[188] Prasad A, Sankar MR, Katiyar V. State of art on solvent casting particulate leaching method for orthopedic scaffoldsfabrication. In: Materials Today: Proceedings. Cambridge, UK: Elsevier Ltd; 2017. pp. 898-907

[189] Yadegari A, Fahimipour F, Rasoulianboroujeni M, Dashtimoghadarm E, Omidi M, Golzar H, et al. Specific considerations in scaffold design for oral tissue engineering. In: Biomaterials for Oral and Dental Tissue Engineering

**37**

2011:270-286

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

[Internet]. Cambridge, UK: Woodhead

biomedical and dental applications. In: Materials. Vol. 9. Basel, Switzerland:

[198] Hutmacher DW, Woodfield TBF, Dalton PD. Scaffold design and

fabrication. In: Tissue Engineering. 2nd ed. Cambridge, UK: Elsevier Inc.; 2014.

[199] Ma PX, Elisseeff J. Scaffolding in tissue engineering. In: Scaffolding in Tissue Engineering. Boca Raton, FL, USA: CRC Press; 2005. pp. 1-639

[200] Liu J, Yan C. 3D printing of scaffolds for tissue engineering. In: 3D Printing [Internet]. Rijeka: IntechOpen; 2018. Available from: http://www.intechopen. com/books/3d-printing/3d-printing-of-

scaffolds-for-tissue-engineering

[201] Billiet T, Vandenhaute M, Schelfhout J, Van Vlierberghe S, Dubruel P. A review of trends and limitations in hydrogel-rapid prototyping for tissue engineering. Biomaterials. 2012;**33**:6020-6041

[202] Skoog SA, Goering PL,

[204] Ambrosi A, Pumera M. 3D-printing technologies for

2014;**25**:845-856

pp. 307-318

Narayan RJ. Stereolithography in tissue engineering. Journal of Materials Science: Materials in Medicine.

[203] Kumar S. Selective laser sintering: A qualitative and objective approach. Journal of Minerals, Metals and Materials Society. 2003;**55**(10):43-47

electrochemical applications. Chemical Society Reviews and Royal Society of Chemistry. 2016;**45**(10):2740-2755

[205] Yan X, Gu P. A review of rapid prototyping technologies and systems. In: CAD Computer Aided Design. Vol. 28. Cambridge, UK: Elsevier Ltd; 1996.

[206] Masood SH. Advances in fused deposition modeling. In: Comprehensive

MDPI AG; 2016

pp. 311-346

[190] Cannillo V, Chiellini F, Fabbri P, Sola A. Production of Bioglass® 45S5— Polycaprolactone composite scaffolds via salt-leaching. Composite Structures.

[191] Eberli D. Tissue Engineering [Internet]. InTech; 2010. p. 536.

com/books/tissue-engineering

Available from: http://www.intechopen.

[192] Mikos AG, Lu L, Temenoff JS, Tessmar JK. Synthetic bioresorbable polymer scaffolds. In: Biomaterials Science: An Introduction to Materials in Medicine. 2nd ed. Cambridge, UK: Academic Press; 2004. pp. 735-753

[193] Pang WQ, Xu Y. Synthesis and purification at low temperatures. In: Modern Inorganic Synthetic Chemistry. 2nd ed. Cambridge, UK: Elsevier Inc.;

[194] Walker JL, Santoro M. Processing and production of bioresorbable

polymer scaffolds for tissue engineering.

In: Bioresorbable Polymers for Biomedical Applications: From Fundamentals to Translational Medicine. Cambridge, UK: Elsevier;

[195] Wahid F, Khan T, Hussain Z, Ullah H. Nanocomposite scaffolds for tissue engineering; properties, preparation and applications. In: Applications of Nanocomposite

UK: Elsevier; 2018. pp. 701-735

Materials in Drug Delivery. Cambridge,

[196] Girth D, Webster TJ. Matrices for tissue engineering and regenerative medicine [Internet]. Biomaterials for Artificial Organs. Chapter 10. Cambridge, UK: Woodhead Publishing;

[197] Zafar M, Najeeb S, Khurshid Z, Vazirzadeh M, Zohaib S, Najeeb B, et al. Potential of electrospun nanofibers for

2017. pp. 45-71

2016. pp. 181-203

Publishing; 2017. pp. 157-183

2010;**92**(8):1823-1832

*Biomedical Implants for Regenerative Therapies DOI: http://dx.doi.org/10.5772/intechopen.91295*

*Biomaterials*

[176] Takahashi K, Yamanaka S.

2006;**126**(4):663-676

2007;**448**(7151):313-317

[178] Liu Q, Wang J, Chen Y,

with nanofibrous poly(L-lactic acid) scaffold and matrilin-3. Acta Biomaterialia. 2018;**76**:29-38

[179] Salerno A, Fernández-

Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell.

[183] Li X, Huang L, Li L, Tang Y, Liu Q, Xie H, et al. Biomimetic dual-oriented/ bilayered electrospun scaffold for vascular tissue engineering. Journal of Biomaterials Science. Polymer Edition.

Gowsihan P, Joshua PC, Qun J, Akiko O, et al. Electrospinning 3D bioactive glasses for wound healing. Journal of Biomedical Materials Research.

[184] Elizabeth N, Carolina RR,

[185] Dang W, Ma B, Li B, Huan Z, Ma N, Zhu H, et al. 3D printing of metal-organic framework nanosheetsstructured scaffolds with tumor therapy and bone construction. Biofabrication.

[186] Yang Y, Qiao X, Huang R, Chen H, Shi X, Wang J, et al. E-jet 3D printed drug delivery implants to inhibit growth and metastasis of orthotopic breast cancer. Biomaterials.

[187] Sola A, Bertacchini J, D'Avella D, Anselmi L, Maraldi T, Marmiroli S, et al. Development of solvent-casting particulate leaching (SCPL) polymer scaffolds as improved three-dimensional supports to mimic the bone marrow niche. Materials Science and Engineering: C. 2019;**96**:153-165

[188] Prasad A, Sankar MR, Katiyar V. State of art on solvent casting particulate leaching method for orthopedic scaffoldsfabrication. In: Materials Today: Proceedings. Cambridge, UK: Elsevier Ltd; 2017.

[189] Yadegari A, Fahimipour F,

Dashtimoghadarm E, Omidi M, Golzar H, et al. Specific considerations in scaffold design for oral tissue engineering. In: Biomaterials for Oral and Dental Tissue Engineering

Rasoulianboroujeni M,

pp. 898-907

2020;**31**(4):1-15

2020;**15**:015014

2019;**12**(2):025005

2019;**13**:119618

[177] Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature.

Zhang Z, Saunders L, Schipani E, et al. Suppressing mesenchymal stem cell hypertrophy and endochondral ossification in 3D cartilage regeneration

Gutiérrez M, San Román Del Barrio J, Domingo C. Bio-safe fabrication of PLA scaffolds for bone tissue engineering by combining phase separation, porogen leaching and scCO2 drying. Journal of Supercritical Fluids. 2015;**97**:238-246

[180] Fereshteh Z, Fathi M, Bagri A, Boccaccini AR. Preparation and characterization of aligned porous PCL/zein scaffolds as drug delivery systems via improved unidirectional freeze-drying method. Materials Science and Engineering: C.

[181] Lowe CJ, Reucroft IM, Grota MC, Shreiber DI. Production of highly aligned collagen scaffolds by freezedrying of self-assembled, fibrillar collagen gels. ACS Biomaterials Science & Engineering. 2016;**2**(4):643-651

[182] Vishwanath V, Pramanik K, Biswas A. Optimization and evaluation

application. Journal of Biomaterials

of silk fibroin-chitosan freezedried porous scaffolds for cartilage tissue engineering

Science, Polymer Edition. 2016;**27**(7):657-674

2016;**68**:613-622

**36**

[Internet]. Cambridge, UK: Woodhead Publishing; 2017. pp. 157-183

[190] Cannillo V, Chiellini F, Fabbri P, Sola A. Production of Bioglass® 45S5— Polycaprolactone composite scaffolds via salt-leaching. Composite Structures. 2010;**92**(8):1823-1832

[191] Eberli D. Tissue Engineering [Internet]. InTech; 2010. p. 536. Available from: http://www.intechopen. com/books/tissue-engineering

[192] Mikos AG, Lu L, Temenoff JS, Tessmar JK. Synthetic bioresorbable polymer scaffolds. In: Biomaterials Science: An Introduction to Materials in Medicine. 2nd ed. Cambridge, UK: Academic Press; 2004. pp. 735-753

[193] Pang WQ, Xu Y. Synthesis and purification at low temperatures. In: Modern Inorganic Synthetic Chemistry. 2nd ed. Cambridge, UK: Elsevier Inc.; 2017. pp. 45-71

[194] Walker JL, Santoro M. Processing and production of bioresorbable polymer scaffolds for tissue engineering. In: Bioresorbable Polymers for Biomedical Applications: From Fundamentals to Translational Medicine. Cambridge, UK: Elsevier; 2016. pp. 181-203

[195] Wahid F, Khan T, Hussain Z, Ullah H. Nanocomposite scaffolds for tissue engineering; properties, preparation and applications. In: Applications of Nanocomposite Materials in Drug Delivery. Cambridge, UK: Elsevier; 2018. pp. 701-735

[196] Girth D, Webster TJ. Matrices for tissue engineering and regenerative medicine [Internet]. Biomaterials for Artificial Organs. Chapter 10. Cambridge, UK: Woodhead Publishing; 2011:270-286

[197] Zafar M, Najeeb S, Khurshid Z, Vazirzadeh M, Zohaib S, Najeeb B, et al. Potential of electrospun nanofibers for

biomedical and dental applications. In: Materials. Vol. 9. Basel, Switzerland: MDPI AG; 2016

[198] Hutmacher DW, Woodfield TBF, Dalton PD. Scaffold design and fabrication. In: Tissue Engineering. 2nd ed. Cambridge, UK: Elsevier Inc.; 2014. pp. 311-346

[199] Ma PX, Elisseeff J. Scaffolding in tissue engineering. In: Scaffolding in Tissue Engineering. Boca Raton, FL, USA: CRC Press; 2005. pp. 1-639

[200] Liu J, Yan C. 3D printing of scaffolds for tissue engineering. In: 3D Printing [Internet]. Rijeka: IntechOpen; 2018. Available from: http://www.intechopen. com/books/3d-printing/3d-printing-ofscaffolds-for-tissue-engineering

[201] Billiet T, Vandenhaute M, Schelfhout J, Van Vlierberghe S, Dubruel P. A review of trends and limitations in hydrogel-rapid prototyping for tissue engineering. Biomaterials. 2012;**33**:6020-6041

[202] Skoog SA, Goering PL, Narayan RJ. Stereolithography in tissue engineering. Journal of Materials Science: Materials in Medicine. 2014;**25**:845-856

[203] Kumar S. Selective laser sintering: A qualitative and objective approach. Journal of Minerals, Metals and Materials Society. 2003;**55**(10):43-47

[204] Ambrosi A, Pumera M. 3D-printing technologies for electrochemical applications. Chemical Society Reviews and Royal Society of Chemistry. 2016;**45**(10):2740-2755

[205] Yan X, Gu P. A review of rapid prototyping technologies and systems. In: CAD Computer Aided Design. Vol. 28. Cambridge, UK: Elsevier Ltd; 1996. pp. 307-318

[206] Masood SH. Advances in fused deposition modeling. In: Comprehensive Materials Processing. Cambridge, UK: Elsevier Ltd; 2014. pp. 69-91

[207] Dayan CB, Afghah F, Okan BS, Yıldız M, Menceloglu Y, Culha M, et al. Modeling 3D melt electrospinning writing by response surface methodology. Materials and Design. 2018;**148**:87-95

[208] Tourlomousis F, Ding H, Kalyon DM, Chang RC. Melt electrospinning writing process guided by a "Printability Number". Journal of Manufacturing Science and Engineering, Transactions of the ASME. 2017;**139**(8):081004-1 to 081004-15

[209] Do A-V, Smith R, Acri TM, Geary SM, Salem AK. 3D printing technologies for 3D scaffold engineering. In: Deng Y, Kuiper J, editors. Functional 3D Tissue Engineering Scaffolds. Cambridge, UK: Elsevier; 2018. pp. 203-234

[210] Taboas JM, Maddox RD, Krebsbach PH, Hollister SJ. Indirect solid free form fabrication of local and global porous, biomimetic and composite 3D polymerceramic scaffolds. Biomaterials. 2003;**24**(1):181-194

[211] Hernández-Córdova R, Mathew DA, Balint R, Carrillo-Escalante HJ, Cervantes-Uc JM, Hidalgo-Bastida LA, et al. Indirect three-dimensional printing: A method for fabricating polyurethane-urea based cardiac scaffolds. Journal of Biomedical Materials Research Part A. 2016;**104**(8):1912-1921

[212] Ebnesajjad S. Injection molding. Fluoroplastics. 2015;**2**:236-281

[213] Huang B, Liang S, Qu X. The rheology of metal injection molding. Journal of Materials Processing Technology. 2003;**137**(1-3):132-137

[214] Ghalia MA, Dahman Y. Advanced nanobiomaterials in tissue engineering: Synthesis, properties, and applications. In: Nanobiomaterials in Soft Tissue Engineering: Applications of Nanobiomaterials. Cambridge, UK: Elsevier Inc.; 2016. pp. 141-172

**Chapter 2**

**Abstract**

*and Cem Töre*

literature and research.

**1. Introduction**

**1.1 History of dental implants**

resorption.

**39**

Dental Implants

*İhsan Çağlar Çınar, B. Alper Gültekin, Alper Sağlanmak*

The goal of modern dentistry is to return patients to oral health in a predictable fashion. The partial and complete edentulous patient may be unable to recover normal function, esthetics, comfort, or speech with a traditional removable prosthesis. The patient's function when wearing a denture may be reduced to one sixth of the level formerly experienced with natural dentition; however, an implant prosthesis may return the function to near-normal limits. The esthetics of the edentulous patient is affected as a result of muscle and bone atrophy. In order to replace a missing tooth, the development of materials science and technology improved the materials for implant application. Nowadays, titanium has become the most popular implant material due to its advantages. The first submerged implant placed by Strock was still functioning 40 years later. Recently, zirconia implants and innovative surface designs are being researched and practiced. In this chapter, these materials will be comparatively discussed through contemporary

**Keywords:** implant corrosion, dental implants, oral implantology,

root form implants which mimic the root shape of a tooth.

calcium phosphate ceramics, osseointegration

titanium implants, zirconia implants, oxide layer, zirconium dioxide, Ti-6Al-4V,

Modern dentistry aims to restore a patient's oral esthetics, contour, function, and

Implant dentistry has made predictable success a reality for cases in the more difficult part of this spectrum through research, improvements in diagnostic tools, techniques, implant materials, and designs. Endosteal implants are manufactured materials inserted in edentulous ridges via surgery so they can serve as a foundation for the prosthesis [1]. Most implants that will be discussed in this chapter will be

The desire to restore lost teeth is not a new concept. Dental implant surgery is one of the oldest practices in dentistry second only to tooth extractions. There is archeological evidence that humans have attempted to replace missing teeth with root form implants for thousands of years. Remains from ancient China dating

speech. Depending on the patient's needs, the total treatment may range from treating a single tooth with caries to restoring edentulous arches with severe bone

[215] Habibi N, Kamaly N, Memic A, Shafiee H. Self-assembled peptide-based nanostructures: Smart nanomaterials toward targeted drug delivery. Nano Today. Elsevier B.V. 2016;**11**(1):41-60

[216] Greenbaum J. Regulation of drug– device combination products in the USA. In: Greenbaum J, Lewis A, editors. Drug-Device Combination Products. 1st ed. Cambridge, UK: Woodhead Publishing; 2010. pp. 496-529

[217] Leppard S. Regulation of drug– device combination products in Europe. In: Leppard S, Lewis A, editors. Drug-Device Combination Products. 1st ed. Cambridge, UK: Woodhead Publishing.; 2010. pp. 464-495

[218] Ratner B, Hoffman A, Schoen F, Lemons J, editors. Voluntary standards, regulatory compliance, and nontechnical issues. In: Biomaterials Science. 3rd ed. Cambridge, UK: Elsevier; 2012. pp. 1387-1472

[219] Ragelle H, Danhier F, Préat V, Langer R, Anderson D. Nanoparticlebased drug delivery systems: A commercial and regulatory outlook as the field matures. Expert Opinion on Drug Delivery. 2017;**14**(7):851-864

[220] Lambert B, Martin J. Sterilization of implants and devices. In: Lambert B, Martin J, Ratner B, Hoffman A, Schoen F, Lemons J, editors. Biomaterials Science. 3rd ed. London, UK: Elsevier; 2013. pp. 1339-1353

### **Chapter 2**

*Biomaterials*

2018;**148**:87-95

Materials Processing. Cambridge, UK:

Synthesis, properties, and applications. In: Nanobiomaterials in Soft Tissue Engineering: Applications of Nanobiomaterials. Cambridge, UK: Elsevier Inc.; 2016. pp. 141-172

[215] Habibi N, Kamaly N, Memic A, Shafiee H. Self-assembled peptide-based nanostructures: Smart nanomaterials toward targeted drug delivery. Nano Today. Elsevier B.V. 2016;**11**(1):41-60

[216] Greenbaum J. Regulation of drug– device combination products in the USA. In: Greenbaum J, Lewis A, editors. Drug-Device Combination Products. 1st ed. Cambridge, UK: Woodhead Publishing; 2010. pp. 496-529

[217] Leppard S. Regulation of drug– device combination products in Europe. In: Leppard S, Lewis A, editors. Drug-Device Combination Products. 1st ed. Cambridge, UK: Woodhead Publishing.;

[218] Ratner B, Hoffman A, Schoen F, Lemons J, editors. Voluntary standards, regulatory compliance, and nontechnical issues. In: Biomaterials Science. 3rd ed. Cambridge, UK: Elsevier; 2012. pp. 1387-1472

[219] Ragelle H, Danhier F, Préat V, Langer R, Anderson D. Nanoparticlebased drug delivery systems: A commercial and regulatory outlook as the field matures. Expert Opinion on Drug Delivery. 2017;**14**(7):851-864

[220] Lambert B, Martin J. Sterilization

Hoffman A, Schoen F, Lemons J, editors. Biomaterials Science. 3rd ed. London, UK: Elsevier; 2013. pp. 1339-1353

of implants and devices. In: Lambert B, Martin J, Ratner B,

2010. pp. 464-495

[207] Dayan CB, Afghah F, Okan BS, Yıldız M, Menceloglu Y, Culha M, et al. Modeling 3D melt electrospinning writing by response surface

methodology. Materials and Design.

[208] Tourlomousis F, Ding H, Kalyon DM, Chang RC. Melt electrospinning writing process guided by a "Printability Number". Journal of Manufacturing Science and Engineering, Transactions of the ASME. 2017;**139**(8):081004-1 to 081004-15

[209] Do A-V, Smith R, Acri TM, Geary SM, Salem AK. 3D printing technologies for 3D scaffold engineering. In: Deng Y,

Elsevier; 2018. pp. 203-234

2003;**24**(1):181-194

2016;**104**(8):1912-1921

[212] Ebnesajjad S. Injection molding. Fluoroplastics. 2015;**2**:236-281

[214] Ghalia MA, Dahman Y. Advanced nanobiomaterials in tissue engineering:

[213] Huang B, Liang S, Qu X. The rheology of metal injection molding. Journal of Materials Processing Technology. 2003;**137**(1-3):132-137

[210] Taboas JM, Maddox RD, Krebsbach PH, Hollister SJ. Indirect solid free form fabrication of local and global porous, biomimetic and composite 3D polymerceramic scaffolds. Biomaterials.

[211] Hernández-Córdova R, Mathew DA, Balint R, Carrillo-Escalante HJ, Cervantes-Uc JM, Hidalgo-Bastida LA, et al. Indirect three-dimensional printing: A method for fabricating polyurethane-urea based cardiac scaffolds. Journal of Biomedical Materials Research Part A.

Kuiper J, editors. Functional 3D Tissue Engineering Scaffolds. Cambridge, UK:

Elsevier Ltd; 2014. pp. 69-91

**38**
