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Journal ArticleDOI

Peptide-biofunctionalization of biomaterials for osteochondral tissue regeneration in early stage osteoarthritis: challenges and opportunities

13 Feb 2019-Journal of Materials Chemistry B (The Royal Society of Chemistry)-Vol. 7, Iss: 7, pp 1027-1044
TL;DR: A tissue engineering strategy comprising the use of biomaterials can provide support for neo-tissue osteochondral repair/regeneration whilst conferring proper mechanical and functional features as well as protecting biomolecular agents from premature degradation.
Abstract: Osteoarthritis is a degenerative joint disease characterized by the progressive deterioration of articular cartilage, synovial inflammation and changes in periarticular and subchondral bone, being a leading cause of disability. Conventional treatments present several side effects and can involve the use of painkillers and non-steroidal anti-inflammatory drugs. In this sense, researchers have shifted the focus of new therapeutics to biomolecular agents and/or their combination with cells. However, the efficacy of these molecules is dependent on their metabolization which can differ according to the administration route and delivery approach. Consequently, a tissue engineering strategy comprising the use of biomaterials can provide support for neo-tissue osteochondral repair/regeneration whilst conferring proper mechanical and functional features as well as protecting biomolecular agents from premature degradation. The current strategies and challenges used in biomaterials functionalization with peptides that can mimic ECM proteins or other natural soluble biomolecules, important to induce the complex interactions between cells and the ECM, are discussed herein. Many opportunities for treating OA are being explored by means of peptide-biofunctionalization of biomaterials which can be designed to be recognizable, induce differentiation, prevent infection, degrade at an intended rate or act as drug delivery systems for controlled release or even as simple triggers of cell behavior.

Summary (2 min read)

Introduction

  • Osteoarthritis is a degenerative joint disease characterized by the progressive deterioration of articular cartilage, synovial inflammation and changes in periarticular and subchondral bone, being a leading cause of disability.
  • 3,4 Several factors secreted by articular chondrocytes and synovial cells in OA can also contribute to increasing the disease severity.
  • The benefits will vary with the volume of PRP, the presence of a 3D scaffold to support cells, number and interval of injections.
  • Biomaterials can become recognizable by the host and promote cell proliferation and migration, expand or degrade at an intended rate, acting as controlled release drug delivery systems or simple triggers of cell behaviour.

3.1 Cellular recognition and adhesion peptides

  • In the last years, it has been demonstrated that the ECM is not only the natural scaffold that holds the cells into the living organisms but also it holds several proteins, proteoglycans and other signaling molecules important to modulate a wide range of cellular behaviors such as adhesion, proliferation, migration, and differentiation.
  • One of the most important motifs for cell recognition and binding to many integrins is RGD (Arginyl-glycyl-aspartic acid) which was identified by Pierschbacher and Rouslahti as an essential cell adhesion peptide sequence in fibronectin.
  • 57 Additionally, other studies have demonstrated the effectiveness of this mimetic peptide on the regulation of the osteogenesis of hMSCs.58,59 Zhu and coworker functionalized HA hydrogels with HAV and RGD peptides and showed an enhancement of osteogenesis, which was attributed to improved cell-cell communication and gene expression through connexin-mediated gap junctions.
  • 64 P-selectins are involved in the rolling and adhesion between endothelial cells and neutrophils and when in deficient number accelerate the development of OA.

3.2 Cellular differentiation peptides

  • The process of cell differentiation is of great importance in tissue regeneration and cell turnover.
  • Therefore, alternatives to the use of the whole proteins have been investigated due to the evidence that using smaller GF fragments or mimetic peptides motivates receptor-mediated signal transduction.
  • On the other hand, osteogenic differentiation has been accomplished by using bone morphogenetic proteins (BMPs), transforming growth factor (TGF-β), ascorbic acid, insulin‐like growth factor 2 (IGF-2), osteogenic growth peptide (OGP), Col-I, parathyroid hormone (PTH), and platelet-derived growth factor (PDGF).
  • On the other hand, TGF-β mimetic peptides are important for chondrogenic differentiation, matrix deposition, and collagen synthesis.

3.3 Antimicrobial peptides

  • Medical devices and biomaterials to be implanted inside the body should be able to promote adsorption of a layer of adhesion proteins (e.g. FN, VN, fibrinogen, albumin, and immunoglobulins) to its surface, favoring unwanted effects namely, microbial colonization.
  • 24 Inhibits proteases such MMP-2 and MMP-9 and prevents the formation of reactive oxygen species (ROS) in fungus and bacteria.
  • The unique feature of antimicrobial peptides is that the molecular mechanism of antimicrobial action does not rely on specific interactions with receptors or enzymes in bacteria.
  • Positive correlations were observed between IL-37 and the pro-inflammatory cytokines TNF-α, IL-1β and IL-6.

4.4 Immune system improvement: anti-inflammatory peptides

  • After an injury, the tissue-resident macrophages produce DAMP (damage-associated molecular patterns) that are passively released from necrotic cells initiating inflammation.
  • As referred, increased quantities of M2 macrophages within the remodelling site has been associated with better outcomes after the implantation of biomaterials improving the regeneration process.

4.5 Degradation enzymes

  • Natural ECM provides the structural framework to allow the homeostasis between the formation and maintenance of the tissues.
  • They observed that the rate of cell spreading and elongation in these cell-degradable gels depends on two factors, the MMP-mediated degradation, and the hydrogel stiffness.
  • Either way, the liberation of these mimetic peptides will depend on the strategy used to entrap the peptide into the biomaterial, which is of utmost importance (Table 4).

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Peptide-biofunctionalization of biomaterials for osteochondral tissue regeneration in early
stage osteoarthritis: Challenges and opportunities
D. Bicho
1,2,4, *
, S. Ajami
4
, C. Liu
4
, R. L. Reis
1,2, 3
and J. M. Oliveira
1,2,3
1
3B's Research Group, I3Bs Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho,
Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência
e Tecnologia, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal;
2
ICVS/3B’s–PT Government Associate Laboratory,
Braga/Guimarães, Portugal;
3
The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho,
Avepark, 4805-017 Barco, Guimarães, Portugal;
4
Institute of Orthopaedics and Musculo-Skeletal Sci, University College London,
Royal National Orthopaedic Hospital, Stanmore, Middlesex, HA7 4LP, UK.
*
Corresponding author: diana.bicho.db@gmail.com
Abstract
Osteoarthritis is a degenerative joint disease characterized by the progressive deterioration
of articular cartilage, synovial inflammation and changes in periarticular and subchondral bone,
being a leading cause of disability. Conventional treatments present several side effects and can
involve the use of painkillers and non-steroidal anti-inflammatory drugs. In this sense, researchers
have shifted the focus of new therapeutics to biomolecular agents and/or their combination with
cells. However, the efficacy of these molecules is dependent on their metabolization which can
differ according to the administration route and delivery approach. Consequently, tissue
engineering strategy comprising the use of biomaterials can provide support for neo-tissue
osteochondral repair/regeneration whilst conferring proper mechanical and functional features as
well as protecting biomolecular agents from premature degradation. The current strategies and
challenges used in biomaterials functionalization with peptides that can mimic ECM proteins or
other natural soluble biomolecules, important to induce the complex interactions between cells
and the ECM, are discussed herein. Many opportunities for treating OA are being explored by
means of peptide-biofunctionalization of biomaterials which can be designed to be recognizable,
induce differentiation, prevent infection, degrade at an intended rate or act as drug delivery
systems for controlled release or even as simple triggers of cell behavior.
Keywords: biomaterials, osteoarthritis, osteochondral, mimetic peptides, immunomodulation.
Page 2 of 29Journal of Materials Chemistry B
Journal of Materials Chemistry B Accepted Manuscript
Published on 25 January 2019. Downloaded by Universidade do Porto (UP) on 1/25/2019 11:24:48 AM.
View Article Online
DOI: 10.1039/C8TB03173H

1. The osteoarthritic process.
Osteoarthritis (OA) is a degenerative and inflammatory disease that especially affects weight-
bearing joints, typically knees, hips, hands, spine, and feet. OA is characterized by the progressive
loss of articular cartilage, subchondral sclerosis, and proliferation of periosteal cells, leading to
osteophyte formation and abnormal subchondral bone.
1,2
In its advanced stage, OA is manifested
by the complete loss of cartilage causing eburnation, stiffness, and swelling.
3,4
Several factors secreted by articular chondrocytes and synovial cells in OA can also
contribute to increasing the disease severity. These include type-X collagen (Col-X), alkaline
phosphatase (ALP), and RUNX2 (runt-related transcription factor 2), NOS-2 (nitric oxide
synthase 2) and COX-2 (cyclooxygenase-2). Some catabolic enzymes are also expressed: matrix
metalloproteinases (MMPs) 1, 2, 3, 8, 9 and 13; a disintegrin and metalloproteinase with
thrombospondin motifs 4 and 5 (ADAMTS4 and ADAMTS5).
5,6
During OA the infiltration of
mononuclear cells and the production of pro-inflammatory mediators, such as interleukins -1β
and -6 (IL-1β, IL-6, respectively), tumor necrosis factor (TNF-α), and several chemokines also
occurs. Additionally, degradation of type II collagen (Col-II) determines the irreversible
progression of OA.
7
Similarly, osteoclasts also increase the levels of cathepsin K
8
and activate of
the RANK/RANKL (Receptor-activator of Nuclear Factor kappa-β)
9,10
and other osteoclast-
related molecules such as Colony-stimulating factor-1 receptor (c-fms), macrophage colony-
stimulating factor (M-CSF), and osteocalcin (OCN).
11
Consequently, as OA progresses all the
components of the osteochondral (OC) joint suffer chemical and cellular changes, which means
that alterations/injuries in one single tissue will influence the entire joint, complicating the
development of therapies that aim to treat a single phenomenon of OA (Figure 1). Therefore, the
proper understanding of the biological and cellular processes associated with the pathophysiology
of OA is of great importance to deep understand the progression of the disease and in order to
develop more effective and targeted approaches.
12
Herein, we intend to provide an overview
concerning the current cellular therapies used in OA. It is also summarized the existing
methodologies that mimic and can improve OC tissue environment by means of using
biomaterials functionalized with immunomodulatory and chemical cues.
Page 3 of 29 Journal of Materials Chemistry B
Journal of Materials Chemistry B Accepted Manuscript
Published on 25 January 2019. Downloaded by Universidade do Porto (UP) on 1/25/2019 11:24:48 AM.
View Article Online
DOI: 10.1039/C8TB03173H

Figure 1: Sagittal section of the knee. A. Progression of OA: conditions and treatments in each stage. B. Schematic
representation of cartilage structural and signaling changes between healthy (I) and osteoarthritic (II) scenarios.
(Adapted with permission from
13
). IL=interleukin. ADAMTS=desintegrin and metalloproteinase with
thrombospondin-like motifs. MMP=matrix metalloproteinase. TNF=tumour necrosis factor. IFN=interferon.
IGF=insulin-like growth factor. TGF=transforming growth factor. VEGF=vascular endothelial growth factor.
2. Up-to-date cellular therapies
Page 4 of 29Journal of Materials Chemistry B
Journal of Materials Chemistry B Accepted Manuscript
Published on 25 January 2019. Downloaded by Universidade do Porto (UP) on 1/25/2019 11:24:48 AM.
View Article Online
DOI: 10.1039/C8TB03173H

Cellular therapies have emerged due to the non-satisfactory results to repair articular cartilage and
restore full joint function obtained using conventional FDA-approved therapies. Autologous
chondrocyte implantation (ACI) was the method of selection for many years.
14
It consists of
harvesting a piece of cartilage from a non-bearing weight area, isolating the cells, their in vitro
expansion and re-implantation of the cell suspension on the damaged area. Nevertheless, this
frequently resulted in uneven distribution of the cells, and as a result, matrix-induced autologous
chondrocyte implantation (MACI), intending to implant these cells on biodegradable membranes,
was proposed.
15,16
However, other issues like availability, donor site morbidity and
dedifferentiation represent ongoing challenges.
17,18
In this sense, mesenchymal stem cells (MSCs)
started being used for local delivery to treat OA joints, due to their ability of self-renewal and
differentiation into chondrocytes.
19
However, besides the loss of phenotype, there is a risk of
pathogen contamination in cell expansion and MSC can induce teratoma formation.
20
Microfracture (MF) represents an option to treat small cartilage defects (< 2 3 cm
2
). MF removes
the calcified cartilage layer and drills into the surface of the underlying bone until the
extravasation of blood, which releases bone marrow and MSCs that can contribute to the repair
of the OC defect. However, the regenerated tissue is mainly fibrocartilaginous with a disorganized
matrix .
21
Mosaicplasty (MP) is based on the extraction of OC autographs from non-weight
bearing joints and re-implantation on the injured side. This process is limited bydonor cartilage
reserves.
22
FDA guidelines impose that when working with cells minimum manipulation must be
applied. In this sense, platelet-rich plasma (PRP) prepared from autologous blood has been
applied in several repairs and regenerative processes including angiogenesis, anti-inflammation,
chondrogenesis and bone remodeling.
23,24
PRP excludes the concerns of immunologic reactions
and disease transmission due to its autologous origin. It also represents an economic procedure
with high recovery potential, easy handling and offers natural growth factors (GF), cytokines,
chemokines, ECM proteins, ascorbic acid, MMP inhibitors, and nucleotides.
24
The clinical use of
PRP-based therapies can decrease joint pain and stiffness and improve the quality of life of
patients with OA. However, the benefits will vary with the volume of PRP, the presence of a 3D
scaffold to support cells, number and interval of injections.
25
Exosomes (Exos) and microvesicles/microparticles (MPs) derived from MSCs have paracrine
effects associated to a chondroprotective effect in collagenase-induced OA models.
26
Exos (30-
100 nm) are generated from the cell membrane during endocytic internalization, before being
released, while MPs (0.05–1.0µm) are released from cell membranes upon activation and/or
apoptosis, expressing markers from the parental cell.
27
Cosenza and co-workers demonstrated
that Exos and MPs from murine BM-MSCs were able to re-establish chondrocyte homeostatic
state, protect chondrocytes from apoptosis and stimulate macrophage polarization towards an
anti-inflammatory phenotype. RT-qPCR quantification showed that Exos and MPs could recover
Page 5 of 29 Journal of Materials Chemistry B
Journal of Materials Chemistry B Accepted Manuscript
Published on 25 January 2019. Downloaded by Universidade do Porto (UP) on 1/25/2019 11:24:48 AM.
View Article Online
DOI: 10.1039/C8TB03173H

the expression of chondrocyte markers (Col-II, aggrecan) and inhibit the catabolic (MMP-13,
ADAMTS5) and inflammatory (iNOS) markers.
28
In a more recent study, Consenza and
coworkers showed that Exos and MPs have similar immunosuppressive effect, decrease T and B
cells and induce Regulatory T cell (Treg).
29
The authors observed that Exos, but not MPs,
significantly decrease arthritis in an in vivo model for collagenase-induced OA (CIOA).
30
In brief,
the potent immunosuppressive effect of Exos can open up novel therapeutic possibilities for
managing the treatment of OA patients.
3. Biofunctionalization strategies to improve the efficacy of biomaterials
Administration of simple cell transplantation originates low survival rates, phenotypic
instability, regulatory issues, and high costs. Therefore, tissue engineering (TE) uses biomaterials
to provide support and guide neo-tissue development whilst conferring proper mechanical and
functional features. The rationale is that biomaterials can stimulate tissue repair without the
hurdles of using cell-based therapies. However, clinical translation can be hampered by some
degree of immune response or foreign-body response, associated with infection or allergic
reaction, which end in the rejection of the biomaterial. Other limitations include mechanical
failure and teratoma formation. Even though the choice of the biomaterial is essential, we must
bear in mind that the cell-biomaterial interface must mimic the environment in which it will be
used in order to allow to precisely control cell fate. Biomaterials must behave as bioactive
instructive scaffolds with the capacity to dictate cell behavior. In this sense, biomaterials can be
modified through physicochemical modification and functionalized using mimetic peptides to
promote desirable features. Biomaterials can become recognizable by the host and promote cell
proliferation and migration, expand or degrade at an intended rate, acting as controlled release
drug delivery systems or simple triggers of cell behaviour.
31,32
3.1 Cellular recognition and adhesion peptides
In the last years, it has been demonstrated that the ECM is not only the natural scaffold that
holds the cells into the living organisms but also it holds several proteins, proteoglycans and other
signaling molecules important to modulate a wide range of cellular behaviors such as adhesion,
proliferation, migration, and differentiation.
33
One of the most important motifs for cell
recognition and binding to many integrins is RGD (Arginyl-glycyl-aspartic acid) which was
identified by Pierschbacher and Rouslahti as an essential cell adhesion peptide sequence in
fibronectin.
34,35
The RGD immobilization into scaffolds has shown to enhance cell
recognition.
36,37
Therefore, the use of cell-adhesive molecules (CAM) in conjunction with RGD
has been employed to mimic cell interactions and to enhance cell adhesion. CAMs are grouped
into several families, namely, immunoglobulins, cadherins, integrins, selectins and ECM proteins
Page 6 of 29Journal of Materials Chemistry B
Journal of Materials Chemistry B Accepted Manuscript
Published on 25 January 2019. Downloaded by Universidade do Porto (UP) on 1/25/2019 11:24:48 AM.
View Article Online
DOI: 10.1039/C8TB03173H

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Cites background from "Peptide-biofunctionalization of bio..."

  • ...Osteochondral defects can lead to mechanical instability of the joint and loss of joint function and can proceed to the generation of osteoarthritis (OA), which is one of the most prevalent joint diseases and a major cause of disability in the adult population [1]....

    [...]

DOI
14 Sep 2021
TL;DR: A bioink consisting of decellularized extracellular matrix and silk fibroin is developed to print the bilayered scaffold that mimics the natural osteochondral tissue by controlling the composition, mechanical properties, and growth factor release in each layer of the scaffold.
Abstract: Recently, three-dimensional (3D) bioprinting technology is becoming an appealing approach for osteochondral repair. However, it is challenging to develop a bilayered scaffold with anisotropic structural properties to mimic a native osteochondral tissue. Herein, we developed a bioink consisting of decellularized extracellular matrix and silk fibroin to print the bilayered scaffold. The bilayered scaffold mimics the natural osteochondral tissue by controlling the composition, mechanical properties, and growth factor release in each layer of the scaffold. The in vitro results show that each layer of scaffolds had a suitable mechanical strength and degradation rate. Furthermore, the scaffolds encapsulating transforming growth factor-beta (TGF-β) and bone morphogenetic protein-2 (BMP-2) can act as a controlled release system and promote directed differentiation of bone marrow-derived mesenchymal stem cells. Furthermore, the in vivo experiments suggested that the scaffolds loaded with growth factors promoted osteochondral regeneration in the rabbit knee joint model. Consequently, the biomimetic bilayered scaffold loaded with TGF-β and BMP-2 would be a promising strategy for osteochondral repair.

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References
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Journal ArticleDOI
TL;DR: This report provides the best available prevalence estimates for the US for osteoarthritis, polymyalgia rheumatica, gout, fibromyalgia, and carpal tunnel syndrome as well as the symptoms of neck and back pain.
Abstract: Objective To provide a single source for the best available estimates of the US prevalence of and number of individuals affected by osteoarthritis, polymyalgia rheumatica and giant cell arteritis, gout, fibromyalgia, and carpal tunnel syndrome, as well as the symptoms of neck and back pain. A companion article (part I) addresses additional conditions.

4,813 citations

22 Jan 2008
TL;DR: In this paper, the best available estimates of the US prevalence of and number of individuals affected by osteoarthritis, polymyalgia rheumatica and giant cell arteritis, gout, fibromyalgia, and carpal tunnel syndrome, as well as the symptoms of neck and back pain are provided.
Abstract: OBJECTIVE To provide a single source for the best available estimates of the US prevalence of and number of individuals affected by osteoarthritis, polymyalgia rheumatica and giant cell arteritis, gout, fibromyalgia, and carpal tunnel syndrome, as well as the symptoms of neck and back pain. A companion article (part I) addresses additional conditions. METHODS The National Arthritis Data Workgroup reviewed published analyses from available national surveys, such as the National Health and Nutrition Examination Survey and the National Health Interview Survey. Because data based on national population samples are unavailable for most specific rheumatic conditions, we derived estimates from published studies of smaller, defined populations. For specific conditions, the best available prevalence estimates were applied to the corresponding 2005 US population estimates from the Census Bureau, to estimate the number affected with each condition. RESULTS We estimated that among US adults, nearly 27 million have clinical osteoarthritis (up from the estimate of 21 million for 1995), 711,000 have polymyalgia rheumatica, 228,000 have giant cell arteritis, up to 3.0 million have had self-reported gout in the past year (up from the estimate of 2.1 million for 1995), 5.0 million have fibromyalgia, 4-10 million have carpal tunnel syndrome, 59 million have had low back pain in the past 3 months, and 30.1 million have had neck pain in the past 3 months. CONCLUSION Estimates for many specific rheumatic conditions rely on a few, small studies of uncertain generalizability to the US population. This report provides the best available prevalence estimates for the US, but for most specific conditions more studies generalizable to the US or addressing understudied populations are needed.

4,355 citations

Journal ArticleDOI
17 Jul 2014-Immunity
TL;DR: A set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation are described with the goal of unifying experimental standards for diverse experimental scenarios.

4,287 citations

Journal ArticleDOI
TL;DR: The key features of the life of a neutrophil are discussed, from its release from bone marrow to its death, and the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites are explained.
Abstract: Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.

3,898 citations

Journal ArticleDOI
03 May 1984-Nature
TL;DR: The ability of fibronectin to bind cells can be accounted for by the tetrapeptide L-arginyl-glycyl- L-aspartyl-L-serine, a sequence which is part of the cell attachment domain of fibronsectin and present in at least five other proteins.
Abstract: The ability of fibronectin to bind cells can be accounted for by the tetrapeptide L-arginyl-glycyl-L-aspartyl-L-serine, a sequence which is part of the cell attachment domain of fibronectin and present in at least five other proteins. This tetrapeptide may constitute a cellular recognition determinant common to several proteins.

3,574 citations

Frequently Asked Questions (1)
Q1. What are the contributions mentioned in the paper "Peptide-biofunctionalization of biomaterials for osteochondral tissue regeneration in early stage osteoarthritis: challenges and opportunities" ?

In this sense, researchers have shifted the focus of new therapeutics to biomolecular agents and/or their combination with cells. Consequently, tissue engineering strategy comprising the use of biomaterials can provide support for neo-tissue osteochondral repair/regeneration whilst conferring proper mechanical and functional features as well as protecting biomolecular agents from premature degradation. The current strategies and challenges used in biomaterials functionalization with peptides that can mimic ECM proteins or other natural soluble biomolecules, important to induce the complex interactions between cells and the ECM, are discussed herein.