Advances in Medical and Surgical Engineering

By Waqar Ahmed, David Phoenix and Mark Jackson

Advances in Medical and Surgical Engineering integrates the knowledge and experience of experts from academia and practicing surgeons working with patients. The cutting-edge progress in medical technology applications is making the traditional line between engineering and medical science ever thinner. This is an excellent resource for biomedical engineers working in industry and academia on developing medical technologies. It covers challenges in the application of technology in the clinic with views from an editorial team that is highly experienced in engineering, biomaterials, surgical practice, biomedical science and technology, and that has a proven track record of publishing applied biomedical science and technology.

For medical practitioners, this book covers advances in technology in their domain. For students, this book identifies the opportunities of research based on the reviews of utilization of current technologies. The content in this book can also be of interest to policymakers, research funding agencies, and libraries, that are contributing to development of medical technologies.

• Covers circulatory support, aortic valve implantation and microvascular antestmosis
• Explores arthroplasty of both the knee and the shoulder
• Includes tribology of materials, laser treatment and machining of biomaterial

• Language: English
• Publisher: Academic Press
• Release date: Mar 21, 2020
• ISBN: 9780128226032

Book preview

Advances in Medical and Surgical Engineering

Edited by

Waqar Ahmed

School of Mathematics and Physics & Lincoln School of Medicine, College of Science, University of Lincoln, Lincoln, United Kingdom

David A. Phoenix

Office of the Vice Chancellor, London South Bank University, London, United Kingdom

Mark J. Jackson

Kansas State University, Salina, KS, United States

Charalambos P. Charalambous

Department of Trauma and Orthopaedics, Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Trust, Blackpool, United Kingdom

School of Medicine, University of Central Lancashire, Preston, United Kingdom

Contents

Cover

Title page

Copyright

Contributors

Chapter 1: Introduction to advances in medical and surgical engineering

Abstract

Chapter 2: Engineering advances in promoting bone union

Abstract

1. Introduction

2. Principles of bone union

3. Biological factors in bone union

4. Mechanical factors in bone union

5. Future advances to facilitate bone to bone union

Chapter 3: Engineering advances in promoting tendon to bone healing

Abstract

1. Introduction

2. Principles of tendon to bone healing

3. Factors affecting tendon-to-bone healing

4. Future advances to facilitate tendon to bone healing

Chapter 4: Engineering advances in reverse total shoulder arthroplasty

Abstract

1. Background of shoulder arthroplasty

2. Design systems and their development

3. Clinical outcomes of shoulder arthroplasty

4. Advances in implant design and surgical techniques

5. Future challenges

Chapter 5: Engineering advances in knee arthroplasty

Abstract

1. Introduction

2. Prosthetic joint infection

3. Strategies to improve implant longevity

4. Metal hypersensitivity in total knee arthroplasty

5. Conclusion

Chapter 6: Advances in cartilage restoration techniques

Abstract

1. Introduction

Chapter 7: Mechanical circulatory support: an overview

Abstract

1. Introduction

2. Short term mechanical circulatory support

Chapter 8: Advances in transcatheter aortic valve implantation

Abstract

1. Introduction

2. Evidence and current indications for TAVI

3. Imaging work up for TAVI patient

4. Approaches for TAVI access

5. Transcatheter heart valves and delivery systems

6. Future perspectives

7. Conclusion

Chapter 9: Advances in magnetic resonance imaging (MRI)

Abstract

1. Introduction

2. A brief history of development of MRI [4,5]

3. Advantages and disadvantages of MRI

4. Basic physics of MRI [6–10]

5. Commonly used MRI sequences [6,9,12,13]

6. Advances in general MRI [6,12,13,15]

7. Advances in musculoskeletal (MSK) MRI

8. Impact of MRI field strength on imaging

9. Conclusions and future of MRI [88–113]

Chapter 10: Technological advances in breast implants

Abstract

1. Types of breast implants

Chapter 11: Importance of biomaterials in biomedical engineering

Abstract

1. Introduction

2. Chitosan

3. Hyaluronic acid

4. Silk fibroin

5. Conclusions

Chapter 12: Visible light activated antimicrobial silver oxide thin films

Abstract

1. Introduction

2. Theoretical background

3. Materials and methods

4. Major challenges overcome by using silver/silver oxide thin films

5. Further research

6. Conclusion

Chapter 13: Corrosion and Mott-Schottky probe of chromium nitride coatings exposed to saline solution for engineering and biomedical applications

Abstract

1. Introduction

2. Chromium nitride coatings for biomedical implants

3. The films characterization

4. Conclusions

Chapter 14: Characterization of cochleate nanoparticles for delivery of the anti-asthma drug beclomethasone dipropionate

Abstract

1. Introduction

2. Controlling the size of empty and BDP drug-filled SPC liposomes

3. Zeta potential of empty and BDP drug-filled liposomes

4. Structure and morphology of SPC liposomes/cochleates

5. SPS liposome size and zeta potential

6. Size and zeta potential of cochleates

7. Conclusion

Chapter 15: Advances in nasal drug delivery systems

Abstract

1. Historical background

2. Why the nasal route?

3. Anatomy of the nose

4. Nasal delivery

5. Mechanisms of drug transport following intranasal administration

6. Factors affecting nasal drugs delivery

7. Barriers interfering with nasal drug delivery

8. Dosage forms for intranasal administration

9. Factors affecting particle deposition in the nasal cavity

10. Mucoadhesive drug delivery systems

11. Microspheres as a drug delivery system

12. Liposomes

13. Nasal drops

14. Nasal sprays

15. Delivery devices of powdered nasal formulations

16. Conclusions

Chapter 16: Carbon nanotubes drug delivery system for cancer treatment

Abstract

1. Introduction

2. Carbon-based materials

3. Allotropes of carbon

4. CNTs: structures and properties

5. Synthesis of CNTs

6. Functionalization

7. CNTs as carriers for cancer treatment

8. Toxicity of CNTs

9. Conclusions

Chapter 17: Advances in multi-functional superparamagnetic iron oxide nanoparticles in magnetic fluid hyperthermia for medical applications

Abstract

1. Introduction

2. Physics of IONPs

3. Magnetic fluid heating

4. Applications of SPIONs for hyperthermia

5. Biocompatibility of SPIONs

6. Techniques for physico-chemical properties of SPION

7. Multipurpose smart system for medical applications

8. In vivo applications of magnetic hyperthermia

9. Conclusions

Chapter 18: Taxane anticancer formulations: challenges and achievements

Abstract

1. Chemical structure and pharmacology of taxanes

2. Traditional taxane formulations

3. Stability of taxane formulations

4. Undesirable effects of taxanes

5. Nanotechnology as an approach to reduce taxane instabilities

6. Lipid nanoemulsions

7. Conclusions

Acknowledgement

Chapter 19: Biomechanics of the mandible and current evidence base for treatment of the fractured mandible

Abstract

1. Structure of the mandible

2. Forces relevant to mono-cortical fixation

3. Rationale for fixation

4. How the fracture heals

5. Discussion

6. Summary

Chapter 20: Dental implants—the preparation of enamel, dentin, and bone by machining

Abstract

1. Introduction

2. Conclusions

Acknowledgments

Index

Copyright

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Contributors

Banu Abdallah,     School of Pharmacy and Biomedical Sciences, University of Central Lancashire, United Kingdom

Hesham K. Abdelaziz,     Lancashire Cardiac Centre, Blackpool Victoria Hospital, Blackpool, United Kingdom; Department of Cardiovascular Medicine: Ain Shams University, Cairo, Egypt

Waqar Ahmed,     School of Mathematics and Physics & Lincoln School of Medicine, College of Science, University of Lincoln, Lincoln, United Kingdom

Sanil H. Ajwani,     Department of Orthopaedics, Blackpool Victoria Hospital, Blackpool, United Kingdom

Ahmed Aljawadi,     Wythenshawe Hospital, Wythenshawe, Manchester, England

Abraham Atta Ogwu,     East Kazakhstan State Technical University, Ust-Kamenogorsk, Republic of Kazakhstan

Paul Callan,     Department of Cardiothoracic Transplantation and Mechanical Circulatory Support, Wythenshawe Hospital, Manchester, United Kingdom

Charalambos Panayiotou Charalambous,     Department of Trauma and Orthopaedics, Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Trust, Blackpool; School of Medicine, University of Central Lancashire, Preston, United Kingdom

Michalis Charalambous,     The Parapet Breast Unit, King Edward VII Hospital, Windsor, United Kingdom

Raouf Daoud,     Breast Unit, Frimley Park Hospital, Firmley, United Kingdom

Ioannis Dimarakis,     Department of Cardiothoracic Transplantation and Mechanical Circulatory Support, Wythenshawe Hospital, Manchester; Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom

Abdelbary M.A. Elhissi,     College of Pharmacy and Office of the Vice President (Research and Graduate Studies), Qatar University, Doha, Qatar

Aisha Ghauri,     School of Mathematics and Physics & Lincoln School of Medicine, College of Science, University of Lincoln, United Kingdom; College of Pharmacy and Office of VP (Research and Graduate Studies), Qatar University, Doha, Qatar

Imran Ghauri,     School of Mathematics and Physics & Lincoln School of Medicine, College of Science, University of Lincoln, United Kingdom; College of Pharmacy and Office of VP (Research and Graduate Studies), Qatar University, Doha, Qatar

Douglas Hammond,     School of Dentistry and School of Engineering, University of Central Lancashire, Preston, United Kingdom

Israr U. Hassan,     Dhofar University, Salalah, Oman

Chahinez Houacine,     School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, United Kingdom

Luke Hughes,     Department of Trauma and Orthopaedics, Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Trust, Blackpool, United Kingdom

Nozad Rashid Hussein,     College of Pharmacy, Hawler Medical University, Iraq

Luke J. Hyde,     Purdue University, West Lafayette, IN, United States

Mark J. Jackson,     Kansas State University, Salina, KS, United States

Christopher Jump,     ST3 Trauma and Orthopaedics, North Western Deanery, United Kingdom

Isabella Karat,     Breast Unit, Frimley Park Hospital, Firmley, United Kingdom

Iftikhar Khan,     School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom

Maire-Clare Killen,     Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom

Rukhsana Mahmood,     School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, United Kingdom

Abdul Majid,     Department of Biochemistry, Shah Abdul Latif University, Khairpur, Pakistan

Wael Mati,     Department of Radiology, Blackpool Victoria Hospital, Blackpool, United Kingdom

Mohammad Najlah,     Pharmaceutical Research Group, School of Allied Health, Faculty of Health, Education, Medicine and Social Care, Anglia Ruskin University, United Kingdom

Farah Naz,     Department of Biochemistry, Shah Abdul Latif University, Khairpur, Pakistan

Abraham A. Ogwu,     East Kazakhstan State Technical University, Ust-Kamenogorsk, Republic of Kazakhstan

Huner Kamal Omer,     College of Pharmacy, Hawler Medical University, Iraq

Ishrat Parveen,     School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, United Kingdom

Yogita Patil-Sen,     School of Physical Sciences and Computing, University of Central Lancashire, Preston, United Kingdom

Paul Sutton,     Department of Orthopaedics, Northern General Hospital, Sheffield, United Kingdom

David A. Phoenix,     Office of the Vice Chancellor, London South Bank University, London, United Kingdom

Abdul Rahman Phull,     Department of Biochemistry, Shah Abdul Latif University, Khairpur, Pakistan

Saeed Ur Rahman,     Institute of Thin films, Sensors and Imaging, School of Engineering and Computing, University of the West of Scotland, Scotland

David H. Roberts,     Department of Cardiovascular Medicine: Ain Shams University, Cairo, Egypt

Grant M. Robinson,     Purdue University, West Lafayette, IN, United States

Htet Sein,     University of Lincoln, Lincoln, United Kingdom

Tapas Sen,     School of Physical Sciences and Computing, University of Central Lancashire, Preston, United Kingdom

Khurram Shahzad,     Department of Radiology, Blackpool Victoria Hospital, Blackpool, United Kingdom

Nathaniel T. Tsendzughul,     School of Computing, Engineering and Physical Sciences, University of the West of Scotland, High Street, Paisley Campus, Paisley, Scotland

Asma Vali,     School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, United Kingdom

Justin Whitty,     School of Dentistry and School of Engineering, University of Central Lancashire, Preston, United Kingdom

Sakib S. Yousaf,     School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, United Kingdom

Chapter 1

Introduction to advances in medical and surgical engineering

Waqar Ahmeda

David A. Phoenixb

Mark J. Jacksonc

Charalambos Panayiotou Charalambousd,e

a    School of Mathematics and Physics & Lincoln School of Medicine, College of Science, University of Lincoln, Lincoln, United Kingdom

b    Office of the Vice Chancellor, London South Bank University, London, United Kingdom

c    Kansas State University, Salina, KS

d    Department of Trauma and Orthopaedics, Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Trust, Blackpool, United Kingdom

e    School of Medicine, University of Central Lancashire, Preston, United Kingdom

Abstract

Clinicians and Engineers work together to apply current technologies and develop new technologies to improve patient care. This book aims to inform engineers as to clinical needs and clinicians as to available technologies in various areas of Medicine and Surgery.

Keywords

medical and surgical engineering

medicine

surgery

radiology

radiological diagnostics

Clinicians aim to do an accurate and speedy diagnosis based on clinical symptoms, clinical signs and relevant investigations that will allow them to instate the appropriate treatment. In intervening to tackle medical or surgical conditions one aims to an effective and long lasting treatment, minimizing harm and facilitating early recovery. The aims of medical and surgical interventions are not only to prolong life but also improve quality of life. Hence, there is a constant drive to develop minimally invasive interventions, with fewer side effects, develop implants that will outlive the patient. Central do what Physicians and Surgeons do is First do no harm [1,2].

Close co-operation between clinicians and engineers is essential to allow the former express their needs and the latter to improve awareness as to what technology is available to meet those clinical needs. Working together, new horizons are explored and new opportunities are unleashed.

This book aims to describe engineering advances in various areas of medicine and surgery both with regards to interventions but also radiological diagnostics. Potential targets of future engineering advances are also discussed.

With an increasing aging but at the same time active population, musculoskeletal conditions, traumatic and degenerative, are on the rise [3–7]. The orthopedic surgeon strives to ease patients’ pain, facilitate, and speed healing and maintain high function. The initial chapters are devoted to engineering advances in various aspects of orthopedic surgery, the management of fractures and soft tissue injuries, the biomechanical improvements of shoulder and knee arthroplasty implants, and the role of joint preserving procedures in the management of chondral disruption of the knee.

The subsequent two chapters address two of the latest engineering developments in the management of heart conditions—mechanical circulatory support devices for patients with heart failure and transcatheter aortic valve implantation, a minimally invasive procedure that avoids more extensive open heart surgery.

Choosing an appropriate and effective treatment relies on accurate diagnosis. The working diagnosis based on clinical symptoms and signs is often further investigated using, among others, radiological modalities. The next chapter explores engineering advances in magnetic resonance imaging that allow the clinician to view the body structures in both static and dynamic ways.

Reconstructive surgery of the breast for malignant and benign conditions is on the rise [8,9]. The development of reliable and durable breast implants that can closely match the native tissues is essential, and the next chapter addresses engineering advances in this area.

The subsequent chapters discuss the use of biomaterials in biomedical applications with particular reference to naturally occurring polymers, as well as basic engineering advances in making implants more infection resistant using antimicrobial silver oxide films. Advances in chromium-based coatings for artificial joint replacements with particular reference to corrosion resistance and biocompatibility are discussed.

Despite having effective treatments for certain chronic conditions such as asthma or migraine, engineering advances have aimed to improve the availability and duration of action of therapeutic agents, to help improve the quality of life of sufferers. There has been extensive interest in using nanotechnology for drug delivery with nanocarriers providing specific tissue or cell targeting. In line with this there has been wide exploration of alternative routes of introducing agents into the body. The next two chapters discuss advances in the use of cochleates, a new class of nanocarriers derived from multilamellar liposomes for the pulmonary drug delivery of steroids in the treatment of asthma, and explore drug introduction into the body via the nasal route.

Along with advances in the management of chronic conditions, recent years have seen the development of novel strategies for targeting cancer. The next three chapters explore some of these advances, in particular the use of carbon nanotubes and magnetic nanoparticles in malignant tissue and cell targeting as well as the development of novel nanocarrier systems (based on lipid and polymeric materials) for the delivery of taxane agents, a promising group of naturally occurring cancer fighting substances.

The final two chapters explore engineering advances in managing mandibular conditions, namely the use of intermaxillary fixation for mandibular fractures and dental implants for the treatment of conditions such as temporomandibular joint dysfunction [10].

This book will hopefully increase awareness both among clinicians as well as engineers of what is achievable and stimulate further collaboration between clinicians and industry to further improve patient care.

References

[1] Sokol DK. First do no harm revisited. BMJ. 2013;347:f6426.

[2] Charalambous CP. Career skills for surgeons. Springer; 2017.

[3] Prieto-Alhambra D, Judge A, Javaid MK, Cooper C, Diez-Perez A, Arden NK. Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. Ann Rheum Dis. 2014;73(9):1659–1664.

[4] Deshpande BR, Katz JN, Solomon DH, et al. Number of persons with symptomatic knee osteoarthritis in the US: impact of race and ethnicity, age, sex, and obesity. Arthritis Care Res (Hoboken). 2016;68:1743–1750.

[5] Johnson VL, Hunter DJ. The epidemiology of osteoarthritis. Best Pract Res Clin Rheumatol. 2014;28:5.

[6] Friedman S Mendelson F D.A. SM. Epidemiology of fragility fractures. Clin Geriatr Med. 2014;30(2):175–181.

[7] Mall NA, Chalmers PN, Moric M, Tanaka MJ, Cole BJ, Bach Jr BR, Paletta Jr GA. Incidence and trends of anterior cruciate ligament reconstruction in the United States. Am J Sports Med. 2014;42(10):2363–2370.

[8] Nègre G, Balcaen T, Dast S, Sinna R, Chazard E. Breast reconstruction in France, observational study of 140,904 cases of mastectomy for breast cancer. Ann Chir Plast Esthet. 2019;: pii: S0294–1260(19)30128–1.

[9] Yang RL, Newman AS, Lin IC, Reinke CE, Karakousis GC, Czerniecki BJ, Wu LC, Kelz RR. Trends in immediate breast reconstruction across insurance groups after enactment of breast cancer legislation. Cancer. 2013;119(13):2462–2468.

[10] Lomas J, Gurgenci T, Jackson C, Campbell D. Temporomandibular dysfunction. Aust J Gen Pract. 2018;47(4):212–215.

Chapter 2

Engineering advances in promoting bone union

Luke Hughesa

Ahmed Aljawadic

Charalambos Panayiotou Charalambousa,b

a    Department of Trauma and Orthopaedics, Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Trust, Blackpool, United Kingdom

b    School of Medicine, University of Central Lancashire, Preston, United Kingdom

c    Wythenshawe Hospital, Wythenshawe, Manchester, England

Abstract

This chapter outlines the processes of primary and secondary bone healing, providing examples of these in clinical practice. With descriptions of the various biological and mechanical factors involved in the processes of bone healing, novel methods of delivering, and manipulating these factors are detailed. The aim is to give the reader an idea of current and future research into facilitating bone healing.

Keywords

bone

union

biological

mechanical

advances

1. Introduction

Fast and complete bone healing (union) is essential in allowing quick recovery and rehabilitation following bone fractures or surgical osteotomies. Patient local and systemic factors as well as exogenous factors (such as mechanism of injury, magnitude of force applied, or surgical procedure), may predispose certain bone disruptions to delayed union or even non-union. High rates of non-union are recognized in fractures of the scaphoid and the femoral neck (intra-capsular hip fractures).

Chapter 3 discusses the pathways of bone to bone and tendon to bone union, and describes engineering advances that aim to facilitate these processes.

2. Principles of bone union

Bone union may occur via secondary or primary union and these are discussed next. Before moving on it is important to understand the following terms:

1. Osteoinduction refers to the stimulation of osteogenesis through the recruitment of osteogenic cells to the site of injury.

2. Osteoconduction refers to the process by which bone grows onto a surface or into a structure (scaffold or implant). The exact structure of the surface or structure at a nano-level may facilitate or hinder such growth.

3. Osteointegration refers to the incorporation of an exogenous material within bone—so that it is firmly attached to the surrounding bone or even replaced with time by bone.

2.1. Secondary bone union

Secondary or indirect bone union (Fig. 2.1) describes the process of bone union that occurs following most untreated fractures or fractures treated without absolute stability upon fixation, for example, compression hip screw for fractured neck of femur; intramedullary nailing for diaphyseal fractures (Figs. 2.2 and 2.3).

Figure 2.1   Secondary bone healing.

Figure 2.2   Radiograph of mid-diaphyseal humeral fracture.

Figure 2.3   Radiograph of mid-diaphyseal humeral fracture, treated with intra-medullary nail.

Evidence of secondary bone healing with callous formation.

Immediately following fracture, bone and soft tissue trauma results in bleeding and hematoma formation. This hematoma connects the bony ends and creates a template for subsequent callus formation. The hematoma contains macrophages and other inflammatory cells, which initiate an acute inflammatory response by secreting various molecules, including interleukin (IL)-1, IL-6, IL-11, IL-18, and tumor necrosis factor alpha (TNF-α) among others [1]. The inflammatory response peaks within 24 hours and is complete after 7 days [2]. During this time phagocytes remove debris, while fibroblasts and mesenchymal cells migrate to the fracture site. Fibroblasts proliferate and a fibrin rich granulation tissue forms [3].

It is the mechanical environment, which drives the differentiation of mesenchymal cells along chondroblastic and later osteoblastic lineages [4,5]. Initially there is instability and hence movement at the fracture site. Chondrocytes produce type 2 collagen and soft callus forms after 2 weeks. As soft callus forms and connects the fracture ends some stability is conferred [6]. Ossification of the soft callus and bridging of the defect by hard callus further increases stability and rigidity such to permit weight bearing [7]. Chondrocyte apoptosis and re-absorption of the cartilaginous callus allows for angiogenesis and vessel ingrowth [8].

Although the hard callus is a rigid structure it does not replicate the biomechanical properties of normal bone. In order to achieve this the hard callus under goes remodeling in accordance with Wolffs’ law, wherein cyclic loading induces cells to modify the internal architecture of the bone trabeculae, such to best resist the mechanical stresses acting upon it [9]. This process involves osteoclastic resorption of hard callus and osteoblastic deposition of laminar bone and persists long after clinical union.

2.2. Primary bone union

When surgical fixation ensures direct bone on bone contact and absolute stability, primary rather than secondary bone union predominates (Figs. 2.4–2.6). Under these conditions cutting cones are formed at the end of the osteons closest to the fracture site (Fig. 2.7) [10]. The osteon is the fundamental unit of cortical bone. They are cylindrical structures about 0.2 mm in diameter [11]. Cutting cones consist of osteoclasts, which act to create a microscopic cavity that crosses the fracture site. Osteoblasts follow the osteoclasts and lay down new bone in these cavities resulting in bone union and restoration of the Haversian systems. The Haversian systems comprise a central canal surrounded by concentrically arranged lamellae of bone matrix. The central canal carries the bone’s blood supply and delivers osteoblastic factors [12]. The bridging osteons subsequently undergo remodeling. This process allows for fracture union without callus formation.

Figure 2.4   Radiograph of radial diaphyseal fracture.

Figure 2.5   Fluoroscopy image of radial diaphyseal fracture treated with dynamic compression plating.

Figure 2.6   Radiograph of radial diaphyseal fracture undergoing primary bone healing in the absence of callus formation.

Figure 2.7   Primary bone healing.

3. Biological factors in bone union

Biological factors are important for osteoinduction. Platelets are involved in clotting and initial hematoma formation. When activated they release a number of growth factors. These include platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and transforming growth factor beta (TGFβ) [13]. PDGF acts to recruit various inflammatory and progenitor cells to the fracture site [14]. FGF stimulates proliferation of mesenchymal cells [15]. VEGF promotes neovascularization of the callus with new blood vessels delivering cells and nutrients to the site of bone formation [16]. Bone morphogenetic proteins (BMP) are members of the transforming growth factor beta (TGFβ) superfamily and have been shown to have a diverse role in bone development and repair. Of the 15 BMPs in humans BMP-2 and 7 have been most studied in the context of bone union. These act by binding to osteoprogenitor cells, increasing the transcription of osteoinductive genes such as RUNX2 to enhance osteoblast differentiation [17].

Bone union relies upon the delivery of nutrients, growth factors and cells to the site of injury. This necessitates a connection with the systemic circulation. However, some bones have a tenuous blood supply. Examples include the scaphoid (Fig. 2.8), femoral neck (Fig. 2.9) and talus. At these sites a fracture can disrupt the blood supply to the proximal segment of bone. If this does occur there is a lack of factors necessary to promote bone union and non-union or avascular necrosis will result. If fracture union is compromised by the anatomy then it is important to consider ways to locally increase the concentration of growth factors. This can be achieved through the use of autologous bone marrow, which contains progenitor cells with both osteogenic and angiogenic properties. These cells are self-regenerating and are able to produce both VEGF and BMPs [18]. For larger defects autologous bone graft is preferred, as this also provides structural support. Other advantages of using autologous grafts include their low cost, low risk of disease transmission or immunological rejection. However, these must be balanced against the risk of donor site morbidity. Platelet rich plasma (PRP) is obtained from a sample of the patient’s blood drawn at the time of treatment. This is subsequently mixed with an anticoagulant and cold centrifuged by adjusting the acceleration force platelets sediment from solution [19]. In vitro studies have shown the local injection of PRP can stimulate osteoprogenitor cell proliferation, increase extracellular matrix formation, and promote angiogenesis [13].

Figure 2.8   Radiograph of a fracture through the waist of the scaphoid.

Figure 2.9   Radiograph demonstrating an intracapsular fracture through the neck of a femur.

3.1. Engineering advances influencing the local environment of growth factors in bone union

Another method of achieving local growth factor delivery includes engineering processes, which achieve the incorporation of growth factors to a synthetic graft or fixation implant (Figs. 2.10–2.12). Recent work has explored these processes. One study investigated the use of recombinant human PDGF incorporated in a beta-tricalcium phosphate scaffold, in patients requiring hindfoot or ankle arthrodesis. It demonstrated comparable outcomes to autograft in promoting fusion at 52 weeks [20]. VEGF-loaded nanographene coated internal fixation screws have been used to treat canine femoral neck fractures. These were prepared by way of direct liquid phase exfoliation of the graphite and VEFG loading by physical adsorption. Subsequent ELISA, X-ray, microangiography, and histological evaluation revealed sustained release of VEGF, without burst release, increased speed of fracture union, new bone formation areas and revascularization [21].

Figure 2.10   Radiograph demonstrating compression screw used to trad scaphoid fracture.

Figure 2.11   AP fluoroscopy of fractured neck of femur treated with cannulated screws.

Figure 2.12   Lateral fluoroscopy of fractured neck of femur treated with cannulated screws.

Sustained local release of VEGF with improved revascularization of canine femoral heads has also been achieved using a poly-lactic acid/glycolic acid delivery system, with formation of microspheres suspended within fibrin glue [22]. When BMP-2 was incorporated into a silica xerogel-chitosan hybrid coating of a porous hydroxyapitate scaffold, this demonstrated superior osteoblastic cell responses and increased bone formation, when compared to a control group wherein the hydroxyapitate scaffold was coated in the hybrid without incorporation of BMP-2 [23]. The addition of 50 micrograms of BMP-2 and its slow release from poly d, l-lactide coated titanium intramedullary implants has been demonstrated to facilitate callus consolidation and improve biomechanical properties (maximal load to failure and torsional stiffness) compared to uncoated implants at 28 and 42 weeks in a rat model [24].

An alternative method is to use stem cells, which when attached to implants can differentiate in vivo and locally produce the desired growth factors. One study isolated and cultured mesenchymal stem cells from bone marrow, suspended them in fibrin glue and then sprayed these on the surface of implants prior to implantation. Subsequent radiological and histological analysis of the ovine model demonstrated increased bone mass and increased bone contact when compared to controls [25].

4. Mechanical factors in bone union

Mechanical factors influencing bone union include pressure, stability, strain, and fluid/solid velocity. All forms of fixation work to provide stability and reduce movement at the fracture site. The type of bone union depends upon the degree of stability achieved.

When using compression plating, rigid stability may be achieved, with zero strain and velocity. The result is primary bone union with Haversian remodeling. This necessitates bone contact and compression and hence can only be used in simple fracture configurations that permit this. In the absence of bone contact rigid stability may impair bone union, as the cutting cones cannot cross the gap and callus does not form.

Other methods of orthopedic stabilization include external fixation and intramedullary nailing. These provide relative stability and bone union is secondary by way of endochondral ossification. In the early stages of secondary bone union, the hematoma provides little structural support and there is significant movement at the fracture site (i.e., high strain and velocity). Recruitment of fibroblasts allows fibrous tissue to form. When fibrous tissue connects the boney ends, it acts to increased stability, such that strain and velocity decrease. With moderate strain and velocity, we then have chondrocyte differentiation, cartilaginous tissue formation, and soft callus forms. This soft callous gradually crystallizes and its stiffness increases. Strain and velocity are further reduced allowing for osteoblastic differentiation, which leads to hard callus and eventually bone formation [26].

Without stabilization and sufficient immobilization bone cannot advance through the stages of union and non-union may occur. However, some movement is important for the bone remodeling process. Wolff’s law dictates that upon cyclic loading, a bone with gradually remodel such that it becomes more resistant to that load [27]. Studies have shown that there is a positive correlation between compression rate and bone union [28]. If a bone is subject to reduced loading or strain over a prolonged period it becomes less dense and weaker due to the lack of stimulus required for remodeling [29]. This is the case in disuse osteopenia or bone loss as a result of implant stress shielding of bone.

The remodeling response of bone to loading is via mechanotransduction, a process through which forces are converted to biochemical cell signals. With the role of mechanical stimuli on bone heading and remodeling described that it is clear to see how we must achieve a balance whereby sufficient stability is conferred to allow for union while subsequent rehabilitation to load the bone is necessary to restore its full strength by remodeling along lines of force transmission.

4.1. Engineering advances influencing the mechanical environment in bone union

Bone loss poses a problem. Large defects do not permit direct bone on bone contact without significant shortening or deformity. Furthermore, gross instability can inhibit progression through the stages of secondary bone union. Traditionally defects were filled with autologous bone graft, to provide structural support. Scaffolds have been designed as an alternative to bone grafting. More recent advances in scaffold design have allowed for improved osteoconduction. To achieve this, scaffolds must be highly porous with interconnected pores of a diameter of at least 100 μm to allow ingrowth of cells and vessels [30]. Studies have looked at modifying the surface properties of scaffolds to further facilitate osteoconduction. One study immobilized gelatin to the surface of poly alpha-hydroxy acid films and porous scaffolds. Subsequent cell culture demonstrated significantly improved cell attachment and proliferation [31]. Likewise, the immobilization of Arg-Gly-Asp peptide of polycaprolactone films has been shown to significantly improve bone marrow stromal cell adhesion [32]. It is important that the kinetics of scaffold degradation match tissue regeneration. In this way the scaffold will provide sufficient support to allow for progression through the stages of bone union, while allowing for appropriate loading of the newly formed bone, necessary for remodeling.

The process of mechanotransduction may be influenced with the use of locally applied ultrasound (Figs. 2.13 and 2.14). Ultrasound applied at specific frequency and intensity may distort and stimulate osteoprogenitor cells, impacting on gene regulation and chondrocyte differentiation with increased production of mRNA levels for Cbfa1/Rnx2 and osteocalcin necessary for osteogenesis [33]. Ultrasound also increases prostaglandin and nitric oxide production by osteoblasts [34]. Prostaglandins have been demonstrated to stimulate bone union and accelerate union [35], while nitric oxide facilitates bone remodeling [36]. Engineering advances have allowed the development of portable ultrasound devices that may be utilized at home by patients.

Figure 2.13   Exogen kit—charger, power pack, transducer, strap, and gel.

Figure 2.14   Diagram of exogen mechanism of action.

A meta-analysis of 13 clinical studies, including 737 patients, compared pulsed electromagnetic fields (PEMF) or low intensity pulsed ultrasound (LIPUS) to placebo for the management of acute fractures. It concluded that PEMF and LIPUS accelerates time to radiological and clinical union of acute fractures, when these are treated non-operatively or fractures of the upper limb [37]. A meta-analysis of 24 unique randomized controlled trials and 429 patients demonstrated that LIPUS treatment resulted in a mean reduction in radiographic union of 39.8 days, with the greatest reduction in union time seen in fractures with a long natural union tendency. However, this analysis was unable to determine if LIPUS was useful in the prevention of delayed unions or if it led to quicker functional recovery, evaluated by return to work or active duty [38].

5. Future advances to facilitate bone to bone union

Ongoing research aims to determine the optimum environment for facilitating bone union in terms of concentration, proportion, and temporal expression of various growth factors. Furthermore, ongoing work aims to facilitate the local availability of such growth factors by optimizing their incorporation within or on the surface of synthetic grafts and fixation implants and fine-tuning their release profiles to provide optimum bioavailability. This may lead to the development and widespread use in clinical practice of biological fixation implants that may help promote bone union, especially in those fractures predisposed to non-union (such as biological hip and scaphoid fixation screws).

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Chapter 3

Engineering advances in promoting tendon to bone healing

Luke Hughesa

Charalambos Panayiotou Charalambousa,b

a    Department of Trauma and Orthopaedics, Blackpool Victoria Hospital, Blackpool Teaching Hospitals NHS Trust, Blackpool, United Kingdom

b    School of Medicine, University of Central Lancashire, Preston, United Kingdom

Abstract

This chapter outlines the anatomy of the enthesis (tendon-bone junction). Subsequent descriptions of the various biological and mechanical factors involved in tendon to bone healing are provided. Novel methods of delivering and manipulating these factors are detailed. The aim is to give the reader an idea of current and future research into facilitating tendon to bone healing.

Keywords

tendon

bone

enthesis

healing

biological

mechanical

advances

1. Introduction

Tendon disruptions may be described as traumatic occurring secondary to a substantial force or degenerative occurring secondary to the application of no or minimal force. Tendon tears are quite common with over 9000 rotator cuff repairs completed in the United Kingdom between 2016 and 2017 [1]. Tendon tears are often avulsions from the bony insertion rather than mid-substance tears. Hence, surgery often aims to restore this bony attachment by reattaching the avulsed tendon to its native site of insertion.

Similarly, ligamentous tears are very common. In 2017, 2,122 anterior cruciate ligament (ACL) reconstructions were recorded on the UK’s national ligament registry [2]. Ligaments contribute to joint stability and their loss may lead to symptomatic joint instability that hinders day-to-day activities or impairs occupational and recreational function. Ligamentous injuries may be mid-substance tears or bony avulsions. Although in some cases, surgery may attempt to repair the torn ligament or reattach the avulsed ligament to its bony insertion, in many cases the damaged native ligament cannot be restored and needs to be substituted (reconstructed) using a tendinous graft (autograft or allograft). Although primary repairs of acute ACLs tears are becoming more popular, ACL reconstruction using a tendon graft remains the mainstay of surgical management of such tears. Hamstring, patellar tendon, and quadriceps autografts are among the most commonly used in ACL reconstruction.

Rapid tendon to bone healing is essential in the surgical repair of tendon avulsions from their bony insertion as well as in tendon or ligament reconstructions using autografts or autologous grafts, to facilitate rehabilitation and improvement in function. In highly demanding athletes, speedy tendon healing and fast rehabilitation may allow early return to sport at a highly competitive level.

2. Principles of tendon to bone healing

The enthesis is the connective tissue between tendon or ligament and bone. With a complex structure to accommodate force transmission and dissipation [3], entheses are either described as fibrous or fibrocartilaginous. Fibrous entheses are formed when the tendon gives rise to Sharpey’s fibres. These are mineralized collagen fibers, which perforate and anchor directly into bone or its surrounding periosteum [4].

Fibrous entheses (Fig. 3.1) are found in tendons that attach to the diaphyses of long bones. Fibrocartilaginous entheses (Fig. 3.2) are more common than fibrous. They form where tendon was first attached to primordial cartilage, which is progressively replaced on its inner surface by bone. They are found at epiphyses and apophyses and consist of four distinct zones:

1. Fibrous connective tissue

2. Uncalcified fibrocartilage

3. Calcified fibrocartilage

4. Bone

Figure 3.1   Diagram detailing fibrous enthesis.

Figure 3.2   Diagram detailing fibrocartilaginous enthesis.

These create a structurally continuous gradient from uncalcified tendon to calcified bone [5]. The tidemark is a basophilic line that separates the uncalcified and calcified zones of the enthesis.

Torn entheses heal poorly without surgical intervention. Even when surgically fixed, the healing process cannot re-establish the native tendon-bone insertion site formed during embryological development [6–8]. The healing enthesis tends to be fibrous [9] and forms through a process of:

1. hemostasis (minutes)

2. inflammation (0–7 days)

3. repair (5–14 days)

4. remodeling (>14 days) [3,5,10]

When considering the healing of a tendon graft within an osseous tunnel (as in ACL reconstruction), one can expect to find the tendon-bone interface initially comprised of highly cellular fibrovascular tissue. New bone then begins to fill the tunnel. This new bone starts to invade the fibrous interface and then the tendon. In the final stages of healing, collagen fibers connect the tendon to the surrounding bone and are aligned in the direction of pull of the musculotendinous unit, closely resembling Sharpey’s fibres and a fibrous enthesis [6]. However, histologically there is a lack of the normal transition zones and instead scar tissue between the tendon and bone. The abrupt transition of stiffness between the tendon and bone impacts on force transmission and the fibrovascular scar tissue has been shown to be mechanically weaker and more prone to failure [6,7,11].

3. Factors affecting tendon-to-bone healing

As with bone healing, both biological and mechanical factors play a role in the normal structural development of the enthesis and in tendon healing [11]. An understanding of these factors can help determine strategies to encourage tendon-to-bone healing following trauma and surgery.

3.1. Biological factors affecting tendon-to-bone healing

Insulin-like growth factors (IGF) 1 and 2, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) are prominent in the early phases of inflammation and proliferation, stimulating fibroblast migration and proliferation [12–14].

Metalloproteinases (MMPs) are responsible for the degradation of extracellular matrix and are important for angiogenesis and remodeling. Their activity is regulated by tissue inhibitors of matrix metalloproteinases (TIMPs) [15]. Both MMPs and TIMPs have been shown to be of elevated concentration at the site of tendon injury [16,17] and their regulation appears to be an active process. Studies have demonstrated that altering the MMPs verses TIMPS balance can influence tendon-to-bone healing following surgical repair, with the addition of intra-articular MMP inhibitor (α2 macrogobulin) resulting in increased fibrocartilage formation, increased numbers of Sharpey’s fibers and higher loads to failure [18,19].

Transforming growth factor beta (TGFβ) has a key role in tendon development and remodeling. It acts to promote cell migration, collagen production, and fibronectin binding, while at the same time regulating cell proliferation and protease activity [20–22]. The application of exogenous TGFβ has been demonstrated to increase the formation of collagen fibers bridging the tendon-bone interface with improved mechanical properties on pull out testing [23].

Bone morphogenic proteins (BMP), members of the TNF-β super-family, play a role in orchestrating the remodeling of bone at the tendon bone interface. BMP-12, 13, and 14 are expressed at the enthesis during embryogenesis while elevated levels of BMP-2 and 7 have been demonstrated to be elevated during tendo-osseus integration. Application of BMP-2, 12, and 13 at the time of surgical repair has been demonstrated to increase fibrocartilage formation, with more Sharpey’s fibers and higher loads to failure [24–26].

3.1.1. Engineering advances influencing the local environment of growth factors in tendon to bone healing

Increasing the local concentration of growth factors will facilitate tendon to bone healing. Engineering advances aim to accomplish this through local injection of growth factors, cell implantation, gene transfer or incorporation onto implants. Following local injection, there is often rapid clearance of growth factors, with many growth factors having a short half-life, susceptibility to inactivation, dilution and metabolism. If cells can be recruited to produce growth factors or growth factors can be fixed to implants, a more sustained delivery may be achieved.

Surgically anchoring periosteum onto the surface of reattached tendon promotes healing, due to precursor cells within the periosteum [27] and the application of mesenchymal stem cells to tendon grafts encourages fibrocartilage formation [28]. These mesenchymal cells can be genetically modified to produce growth factors (including BMP-2) using viral vectors. In a study of ACL repair, this was demonstrated to increase the formation of cartilage-like cells, reduce the size of the tibial bone tunnel and significantly increase the ultimate load and stiffness levels [29].

Alternatively cells and growth factors can be incorporated into an engineered matrix. Hydrogels comprise a network of polymer chains with a high water. As such they form a gel like substance with excellent handling properties. The addition of cells, growth factors, and drugs is through simple mixing and hydrogel can be injected percutaneously to fill defects [30]. The main disadvantage of hydrogels is their lack of biomechanical strength and inability to re-establish tissue continuity [31]. Scaffolds can be used to provide biomechanical support to the healing tendon, while acting as a vehicle for cells and new tissue formation [32].

The attachment of cells and/or growth factors to hydrogels and scaffolds can accelerate healing and improve the biomechanical properties of the graft. Cells commonly mixed with hydrogels or fixed to scaffolds include mesenchymal cells derived from adipose (ADSCs), bone marrow (BMSCs), and tendon (TSPCs) tissue. ADSCs have the advantage of being in abundance and easy to isolate [33], however, they have a clear preference to adipogenesis in vivo [34]. BMSCs are the most widely used stem cell. They exhibit superior tenogenic differentiation capacity when compared to ADSCs, however, harvesting causes greater donor site morbidity [35], and they are associated with higher rates of ectopic ossification and adhesion formation [36]. Although TSPCs have the greatest tenogenic abilities, they are the most difficult to isolate and confer the greatest risk of donor site morbidity [37]. One strategy to overcome the problems posed by harvesting of TSPCs is to use ADSCs or BMSCs that have been pre-differentiated toward the tendon lineage with the help of growth factors. Growth factors have been demonstrated to influence the rate of proliferation and degree of terminal differentiation of mesenchymal cells [38–40]. When incorporated into hydrogels/scaffolds, growth factors can demonstrate sustained release over time. This has been demonstrated to prolong the survival of stem cells and promote their differentiation [41,42].

Fixation devices for tendon repair can be coated in substrates designed to facilitate tendon to bone healing. When comparing the intubation of a poly-L-lactide acid screw (PLLA), a PLLA/β-tricalciumphospate screw, and a poly-l-liactide-co-glycolic acid/β-tricalciumphospate screw with human osteoblast-like cells, one study demonstrated that cell number and cell contract points were significantly increased on the composite materials when viewed under scanning electron microscope [43]. As such it can be concluded that β-tricalciumphospate offers good