Injectable scaffolds: Preparation and application in dental and craniofacial regeneration

https://doi.org/10.1016/j.mser.2016.11.001Get rights and content

Abstract

Injectable scaffolds are appealing for tissue regeneration because they offer many advantages over pre-formed scaffolds. This article provides a comprehensive review of the injectable scaffolds currently being investigated for dental and craniofacial tissue regeneration. First, we provide an overview of injectable scaffolding materials, including natural, synthetic, and composite biomaterials. Next, we discuss a variety of characteristic parameters and gelation mechanisms of the injectable scaffolds. The advanced injectable scaffolding systems developed in recent years are then illustrated. Furthermore, we summarize the applications of the injectable scaffolds for the regeneration of dental and craniofacial tissues that include pulp, dentin, periodontal ligament, temporomandibular joint, and alveolar bone. Finally, our perspectives on the injectable scaffolds for dental and craniofacial tissue regeneration are offered as signposts for the future advancement of this field.

Introduction

Tooth is an important organ for our daily life. However, a tooth is susceptible to losing part or even all of its structures due to bacterial invasion, trauma, or congenital anomalies. From a report of the Centers for Disease Control and Prevention, dental caries or cavities, is one of the most common chronic diseases of young children and adolescents (6–19 years old) [1]. Dental caries also affects adults, with more than 90% of all the population over the age of 20 having some degree of tooth decay. Meanwhile, nearly half of the U.S. adult population aged 30 years and older has mild, moderate or severe periodontitis, and 64% of adults over the age of 65 have moderate to severe forms of periodontal disease, which is the major cause for tooth loss [2]. The loss of tooth can cause immediate problems with eating and speech and subsequent bone resorption, leading to physical and mental suffering that compromises an individual’s self-esteem and quality of life.

Clinically, if dental caries progresses and severely inflames the pulp tissues inside the tooth, a root canal procedure is often performed to remove the necrotic dental tissues, clean the pulp chamber, and seal it with bio-inert materials. While this therapy has been used for many years with high success rates, the repaired tooth is not a living organ and loses a significant amount of the tooth structure, which weakens the strength of the tooth. Similarly, an artificial prosthetic dental implant is used to replace the lost tooth. Despite its clinical success, dental implant failure is also well documented in the literature including peri-implant bone loss, infections, and allergic reactions [3]. Another example is temporomandibular joint disorders (TMDs), which are a heterogeneous group of diseases that cause orofacial pain, affecting a patient population of more than 10 million in the United States [4]. Treatment options for TMDs are few and have limited success rates. For patients with severe TMDs, a surgical procedure called a “discectomy” is often performed to remove the diseased temporomandibular joint (TMJ) disc that compromises the normal physiological function. Therefore, there is a need to develop an alternative to traditional dental and craniofacial clinical treatments.

Tissue engineering is a promising approach to replacing damaged/missing dental and craniofacial structures and restoring their biological functions; a number of publications have shown the success of regenerating dental and craniofacial tissues using this strategy [5], [6], [7], [8], [9], [10], [11]. Typically, the tissue engineering strategy involves three critical elements: stem cells or progenitor cells, signaling molecules (e.g., growth factors), and scaffolds. The scaffold is an artificial extracellular matrix (ECM) and serves as a template for cell growth and tissue regeneration. Ideally, the scaffold should be biocompatible and biodegradable, possess proper mechanical and physical properties, and mimic the in vivo microenvironment (niche) to facilitate cell adhesion, proliferation, differentiation, and neo tissue formation [12]. Based on when a scaffold is shaped, it can be considered a pre-formed or an injectable scaffold. A pre-formed scaffold has a definite shape prior to its application, while an injectable scaffold forms the shape in situ. Compared to the pre-formed scaffold, the injectable scaffold has several advantages, including (1) it is performed in a minimally invasive manner, therefore decreasing the risk of infection and improving comfort; (2) it can easily fill any irregularly-shaped defects; and (3) it overcomes the difficulties of cell seeding and adhesion, and the delivery of bioactive molecules, as these factors can be simply mixed with the material solution before being injected in situ. Considering the size, morphology, and complicated structure of dental and craniofacial tissues, an injectable scaffold is more appealing than a pre-formed one. For example, the root canal is a long, narrow channel with an average total volume of approximately 20 μl [13]. With such a small volume and unique anatomical structure, it is a challenge to implant a pre-formed scaffold into the root canal and seamlessly cover the entire space of the canal; however, an injectable scaffold can easily achieve this. Another example is the maxillary sinus lift, which is a surgical procedure in which natural or synthetic bone graft materials are added to the upper jaw to induce bone formation. During the surgery, a surgeon cuts the gum and bone tissues and opens a small oval window to introduce bone-graft materials into the sinus space. Obviously, the adoption of injectable materials is a better choice to reduce the surgical wound size and decrease the risk of infection. Because of the above reasons, injectable scaffolds have received more and more attention in recent years. However, there is no comprehensive summary on the recent advancement of injectable scaffolds for dental and craniofacial tissue regeneration.

In this paper, we first present an overview of various injectable scaffolding materials, including natural and synthetic polymers, inorganic and composite materials, and self-assembled materials. Next, we discuss the characteristic parameters and mechanisms for injectable scaffold formation. Among the various fabrication techniques, we highlight the development of advanced injectable scaffolding systems that have appeared in recent years. These systems include new approaches to incorporating bioactive molecules in injectable scaffolds, the development of cell-instructive biomaterials, novel self-assembly peptides, and bio-inspired nanofibrous microspheres. Finally, we summarize the clinical applications of the injectable scaffolds for the regeneration of dental and craniofacial tissues, including pulp, dentin, periodontal ligament (PDL), TMJ, and alveolar bone. We expect that this review article will give a full perspective vision of the injectable biomaterials to our readers, and further stimulate the increasing interest in the development of better injectable biomaterials for dental and craniofacial tissue regeneration as well as for other applications of translational medicine.

Section snippets

Biomaterials used as injectable scaffolds

A variety of biomaterials have been proposed for use as injectable scaffolds. According to the source of origins, they can be classified as natural and synthetic biomaterials. Natural biomaterials are derived from natural resources and have the advantage of biological recognition that may positively support cell adhesion and growth. These materials usually are biocompatible and biodegradable, and do not cause inflammatory or immune responses. However, there are concerns with natural materials

Injectability

Compared to pre-formed scaffolds, the major advantage of injectable scaffolds is injectability, which means that the scaffold can be injected into the defect area using a syringe needle and then solidified in situ. Injectability is an essential requirement for a biomaterial when it is performed in a minimally invasive manner. Ideally, the material should remain flowable before injection and rapidly become immobile after the material diffuses within the defect. As for hydrogels, the transition

Dentin and pulp regeneration

Dental pulp is a highly specialized connective tissue that maintains the biological and physiological vitality of a tooth. Under certain conditions, the pulp forms tertiary or reparative dentin in response to external agents [167], [168]. Direct and indirect pulp capping with calcium hydroxide cement or mineral trioxide aggregate (MTA) forms a dentinal bridge at the exposure site. For complete necrosis of pulp tissues, a root canal treatment is often performed in the clinic. However, the tooth,

Future directions

Due to their capability to deliver in a minimally invasive manner and other advantageous properties, injectable scaffolds are appealing for dental and craniofacial tissue engineering. A number of synthetic and natural biomaterials have been tested for those applications. However, most conventional injectable biomaterials are not bio-inductive and cannot elicit desirable cell-material interactions. A few approaches such as the development of cell-instructive biomaterials, preparation of novel

Acknowledgements

This work was supported by NIH/NIDCR grants R01DE024979, R03 DE22838 (X. L.) and we would like to thank Jeanne Santa Cruz for her assistance with the editing of this article.

References (221)

  • T. Qu et al.

    Acta Biomater.

    (2015)
  • C.H. Park et al.

    Biomaterials

    (2012)
  • L. Galois et al.

    Biomaterials

    (2006)
  • P.A. Parmar et al.

    Biomaterials

    (2015)
  • B.P. Mahadik et al.

    Biomaterials

    (2015)
  • T. Billiet et al.

    Biomaterials

    (2014)
  • S. Walke et al.

    Carbohydr. Polym.

    (2015)
  • A.M. Thomas et al.

    Biomaterials

    (2014)
  • S.N. Pawar et al.

    Biomaterials

    (2012)
  • J. Lam et al.

    Acta Biomater.

    (2014)
  • A.J. Engler et al.

    Cell

    (2006)
  • X. Xu et al.

    Acta Biomater.

    (2011)
  • M. Kisiel et al.

    Biomaterials

    (2013)
  • P. Lei et al.

    Biomaterials

    (2009)
  • S. Herrick et al.

    Int. J. Biochem. Cell Biol.

    (1999)
  • A.J. Rufaihah et al.

    Biomaterials

    (2013)
  • L. Almany et al.

    Biomaterials

    (2005)
  • A. Shekaran et al.

    Biomaterials

    (2014)
  • F. Yang et al.

    Biomaterials

    (2005)
  • R.K. Singh et al.

    Biomaterials

    (2013)
  • J.B. Leach et al.

    Biomaterials

    (2005)
  • J.S. Kwon et al.

    Biomaterials

    (2014)
  • M. Curcio et al.

    Eur. J. Pharm. Biopharm.

    (2010)
  • A. Alexander et al.

    Eur. J. Pharm. Biopharm.

    (2014)
  • B. Jeong et al.

    J. Control. Release

    (2000)
  • E. Ruel-Gariepy et al.

    Eur. J. Pharm. Biopharm.

    (2004)
  • F. Ullah et al.

    Mater. Sci. Eng. C: Mater. Biol. Appl.

    (2015)
  • A. Šturcová et al.

    J. Colloid Interface Sci.

    (2010)
  • C. Liu et al.

    Colloids Surf. A

    (2007)
  • J.S. Temenoff et al.

    Biomaterials

    (2000)
  • M. Bohner et al.

    Biomaterials

    (2005)
  • W. Habraken et al.

    Adv. Drug Deliv. Rev.

    (2007)
  • B. Marelli et al.

    Biomaterials

    (2011)
  • V.F.M. Segers et al.

    Drug Discov. Today

    (2007)
  • J.L. Drury et al.

    Biomaterials

    (2003)
  • S. He et al.

    Biomaterials

    (2000)
  • J. Zhu

    Biomaterials

    (2010)
  • W.E. Hennink et al.

    Adv. Drug. Deliv. Rev.

    (2002)
  • M.D. Timmer et al.

    Biomaterials

    (2003)
  • P. Aslani et al.

    J. Control. Release

    (1996)
  • S.M. Jay et al.

    J. Control. Release

    (2009)
  • K.Y. Lee et al.

    Prog. Polym. Sci.

    (2012)
  • J. Berger et al.

    Eur. J. Pharm. Biopharm.

    (2004)
  • B.A. Dye et al.

    Vital Health Stat.

    (2007)
  • P.I. Eke et al.

    J. Dent. Res.

    (2012)
  • R. Adell et al.

    Int. J. Oral. Maxillofac. Implants

    (1990)
  • K.D. Allen et al.

    Tissue Eng.

    (2006)
  • T. Qu et al.

    Tissue Eng. Part A

    (2014)
  • T.J. Qu et al.

    J. Mater. Chem. B

    (2013)
  • G.T.J. Huang

    Regen. Med.

    (2009)
  • Cited by (0)

    View full text