Chapter 19

Commercial Products for Osteochondral

Tissue Repair and Regeneration

Diana Bicho, Sandra Pina, Rui L. Reis, and J. Miguel Oliveira

Abstract The osteochondral tissue represents a complex structure composed of

four interconnected structures, namely hyaline cartilage, a thin layer of calcified
cartilage, subchondral bone, and cancellous bone. Due to the several difficulties
associated with its repair and regeneration, researchers have developed several stud-
ies aiming to restore the native tissue, some of which had led to tissue-engineered
commercial products. In this sense, this chapter discusses the good manufacturing
practices, regulatory medical conditions and challenges on clinical translations that
should be fulfilled regarding the safety and efficacy of the new commercialized
products. Furthermore, we review the current osteochondral products that are cur-
rently being marketed and applied in the clinical setting, emphasizing the advan-
tages and difficulties of each one.

Keywords Commercial products · Bone, cartilage, and osteochondral

regeneration

D. Bicho (*) · S. Pina

3B’s Research Group—Biomaterials, Biodegradables and Biomimetics, European Institute
of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho,
Barco GMR, Portugal
ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal
e-mail: dianabicho@dep.uminho.pt
R. L. Reis · J. M. Oliveira
3B’s Research Group—Biomaterials, Biodegradables and Biomimetics, European Institute
of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho,
Barco GMR, Portugal
ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal
The Discoveries Centre for Regenerative and Precision Medicine, University of Minho,
Barco, Guimarães, Portugal

© Springer International Publishing AG, part of Springer Nature 2018 415

J. M. Oliveira et al. (eds.), Osteochondral Tissue Engineering,
Advances in Experimental Medicine and Biology 1058,
https://doi.org/10.1007/978-3-319-76711-6_19
416 D. Bicho et al.

19.1 Introduction

Treatment of bone and cartilage defects represents a current problem that needs to be
solved. Although the present therapies are well established and effective for reduc-
ing pain, thus improving the patients’ quality of life, the hyaline or articular cartilage
has a limited regeneration capacity, demanding new therapeutic options for com-
plete healing of the osteochondral (OC) lesions. In this sense, tissue engineered bio-
materials for OC application present some key challenges regarding their
biocompatibility, bioactivity, biodegradation, and biomechanical properties.
Additionally, the ion release of metallic materials and the reproducibility of the tech-
niques are also fundamental aspects to address [1]. Furthermore, the strategies
applied need to present biodegradable with nontoxic degradation products of easy
metabolization and excretion, well-regulated degradation kinetics and similar rate to
native tissue. Similarly, the expected local or systemic immune responses should be
controlled since it will affect significantly the implant–host integration. Most impor-
tantly, OC biomaterials should be able to mimic the extracellular matrix (ECM) and
the complex mechanisms involved in the surrounding cells where the biomaterial
will be applied [2]. The biomaterial chosen should be able to aid the cells to grow
and proliferate at a similar natural rate, with an efficient gas and nutrients exchange
[3]. Thus, the choice of the biomaterial is extremely important and needs to consider
not only its chemical composition, but also its physical properties [4]. Specifically,
in OC tissue engineering the mechanical properties must be able to bear the daily
stress to which this tissue is subjected, as well as to support integration of the cells
involved. Equally, the microstructure of the scaffold is essential for chondrogenesis
and osteogenesis. Normally, it is believed that a superior cell ingrowth, improved
transport of nutrient and vascular formation is related with high porosity (> 300 μm)
[5] and interconnectivity (>100 μm) of scaffolds to allow a proper cell colonization
[6]. In regards to osteoinductive potential, there has been extensive research with
some good synthetic materials having emerged, for example hydroxyapatite (HA),
octacalcium phosphate (OCP), and β-tricalcium phosphate (β-TCP). However,
regardless of their ability to be integrated into host tissues, they present poor mechan-
ical properties, being therefore necessary to mix them with different materials that
could overcome such limitations, and improve integration in OC lesions [7]. In addi-
tion, different natural and synthetic materials have been employed to engineer OC
repair, presenting advantages and limitations. For instance, natural polymers are nor-
mally biocompatible and allow the interaction with cell receptors. However, safety
concerns are usually an issue. In contrast, synthetic materials are more easily con-
trollable and reproducible but lack the cell-­recognition signals [8]. Researchers have
suggested these materials to be especially used in the regeneration of large OC
defects and sometimes combined with cells, growth factors, and tissue grafts [9].
Beside these scientific advances, when trying to launch new medical products and
technologies to the market, several regulatory medical conditions should be fulfilled
regarding their safety and efficacy. Moreover, regulatory hurdles associated with the
commercialization of new products are critical. Therefore, laboratory facilities,
manufacturing practices and documentation related to products development should
19 Commercial Products for Osteochondral Tissue Repair and Regeneration 417

follow strict requirements to ensure both the welfare of the individuals involved in
the process and the reproducibility of the procedures. It is important to stress that all
the directives involved in the manufacture and propagation of medical products and
devices, can cause disagreements depending on the governmental administration
involved. Among the multitude of options, Federal Food and Drug Administration
(FDA) in the USA, and regional or centralized regulatory bodies like the European
Medicines Agency (EMA) in the European Union (EU) are the most used. They are
responsible for the development, assessment, and supervision of medicines [10].
Beyond this fact, it is also important to point out that the translations of the medical
technologies into the clinic also rely on its nature, because cellular and acellular
devices face different regulatory scrutiny in each country [11].
This chapter covers the general cares required for manufacturing tissue engineer-
ing and regenerative medicine (TERM) products. Particularly, it is focused the
existing marketed products for OC tissue engineering and regeneration.

19.2  ood Manufacturing Practices and Regulatory Hurdles

G
in Tissue-Engineered Products

Over the recent years, TERM has witnessed a rapid development that has motivated
the marketing of novel products and with it some quality control procedures, and
consistency and reproducibility guarantees. To assure that these conditions are
being implemented, the FDA, EMA, and other world organizational committees are
responsible to inspect the developers of commercial products. These organizations
allow the implementation of standard procedures that extend away from individuals,
research groups, and organizational procedures. It is their intention to have proto-
cols in place that are independent of the operators and/or equipment guaranteeing
uniformity of the data [12].
Good manufacturing practices (GMP) are a series of regulations that ensure that
diagnostics, the production of pharmaceutical and medical devices, are controlled
according to defined quality standards. GMP refers to all up-to-date aspects of the
production from materials and equipment to the training staff and hygiene [13].
Moreover, the use of cells and tissues of human origin for TERM products also need
to answer the good tissue practices (GTP). Particularly, GTP focuses its require-
ments on the prevention of the initiation, diffusion, and spread of contagious dis-
eases besides ensuring uniformity, consistency, reliability, and reproducibility [14].
Following these lines, the description of a task or operation has to be performed in
an identical manner and in compliance with appropriate regulation, as an approved
standard operation procedure (SOP). Highly specific SOPs are usually required dur-
ing all phases of a manufacturing process, and therefore are used to control the
manufacturing of TERM products. Companies must agree to operate under
­harmonized guidelines across different geographic locations to assure that the best
practices exist in every corner of the world. For instance, regarding TERM products
using patient samples, companies need to pay attention to the appropriate ways to
418 D. Bicho et al.

transport them once the classification of the shipment is the key in defining the level
of containment required [13]. Fortunately, the TERM field is at the front line in
terms of harmonization of international regulatory agencies, mostly because of the
use of human cells in therapy, which has lead a worldwide joint effort [15].
Nevertheless, it should be kept in mind that the introduction of cells in tissue-­
engineered materials has associated hazards such as teratoma formation, contami-
nation, immunogenicity, and insufficient cell adaptation. Thus, even though the
materials used for tissue engineered strategies affect the regulatory process, cellular
scaffolds pass through more regulatory hurdles to assure their safety.

19.3 Challenges in Clinical Translation and FDA Regulation

The programs for safety regulation vary widely by the type of product, its potential
risks, and the regulatory powers granted to the agency. For example, the FDA regu-
lates almost every facet of prescription drugs, including testing, manufacturing,
labeling, advertising, marketing, efficacy, and safety, yet FDA regulation of cosmet-
ics focuses primarily on labeling and safety. The FDA regulates most products with
a set of published standards enforced by a modest number of facility inspections
[16]. Each type of material is subjected to a different type of regulation based on its
classification. Therefore, it is possible to characterize devices as “substantially
equivalent” to currently accepted devices, allowing them to be more easily commer-
cialized [17]. Contrariwise, when using novel bioactive scaffolds it is necessary to
deeply describe their degradation and safety profile in preclinical and clinical stud-
ies, which normally results in a 30% of the costs increment [11]. However, if possi-
ble, new materials with more refined features should be created for TERM
applications despite the innumerous hurdles that ought to be addressed for eventual
clinical success. The first aspect to keep in mind is the scientific basis and the patent-
ability of the technology. Furthermore, clinical studies should be carefully con-
ducted. Then, the company where the product has been developed needs to assure
not only enough financial support but also the regulatory requirements for GMP in
order to have reproducible products [12]. Finally, the market potential of the thera-
peutic solution, possible competitors, and target audience may be considered.
Nevertheless, even with these concerns, TERM is experiencing a boost in the devel-
opment of new therapies for the treatment of chronic diseases and damaged tissues.

19.4  ommercially Available Products for Osteochondral

C
Regeneration

The commercialization process of the scaffolds for implantation involves multiple

stages of R&D replications before reaching the final approval from the government.
R&D stages ensure safety and efficacy of the implants, which involve the produc-
tion of medical grade scaffolds followed by animal testing, under regulatory
19 Commercial Products for Osteochondral Tissue Repair and Regeneration 419

approved conditions. Over the recent years, the concentrated research on TERM has
resulted in few clinically approved therapeutics. Biomaterials applied in tissue
regeneration are normally composed of a temporary three-dimensional (3D) sup-
port for the growth of cells that will regenerate a given injury, being then biode-
graded and substituted by the new tissue. In OC regeneration, different materials
have been employed as templates for cell interactions and formation of ECM to
support the newly formed tissue. However, the most commonly used technique con-
sists in designing bilayered scaffolds able to regenerate both cartilage and subchon-
dral bone [18]. Normally, autologous chondrocytes are seeded at the top of the
scaffold and allows the application of a cell–scaffold implantation [19]. An alterna-
tive approach to this procedure uses two scaffolds from cartilage and bone assem-
bled either before or during implantation to assure OC regeneration [20].
At the present time, some commercial products have appeared. For example,
Collagraft® (Nuecoll Inc.) consists of a mixture of collagen with HA and β-TCP in
the form of granules. In previous studies, this product was used as subchondral sup-
port using chondrocytes harvested from rabbit articular cartilage. The animal model
used survived through the regenerative process which occurred after 6 months pre-
senting the adequate features for bone integration, but not for cartilage [21]. On the
other hand, the treatment of small OC defects is also possible with the collagen-­
based implant ChondroMimetic™ (TiGenix NV). This product is an off-the-shelf
bilayer implant launched in the European market. The chondral layer is made of
collagen and glycosaminoglycan while the osseous layer is composed of calcium
phosphates. It showed to support the simultaneous natural repair mechanism of both
articular cartilage and bone, following by implantation in patients [22]. Another
collagen-based 3D scaffold to treat knee chondral or OC defects is MaioRegen®
(Med&Care). This matrix mimics the entire osteo-cartilaginous tissue and is com-
posed of deantigenated type I equine collagen that resembles the cartilaginous tis-
sue, and magnesium enriched-HA for the subchondral bone structure [23].
Preclinical studies using 12 sheep proved that this biomaterial is able to promote
bone and hyaline-like cartilage tissue restoration. Quantitative macroscopic analy-
sis showed absence of inflammation with some hyperemic synovium, but no syno-
vial hypertrophy or fibrosis was noted. The histological score evaluations confirmed
the presence of a newly formed tissue and a good integration of scaffolds [24]. Also,
clinical evaluation of knee chondral and OC lesions in 27 patients, during a 5-year
follow-up scored clinical improvements. Magnetic resonance imaging (MRI) results
demonstrated a complete graft integration in 78.3% of patients offering a good clini-
cal outcome for MaioRegen®. However, in another clinical investigation using knee
and talar OC injuries, the biological response in vivo evaluated over 2.5 years show-
ing no improvements after the implantation of MaioRegen®. Radiographic results
of computed tomography and MRI presented a complete defect filling, integration,
and an intact articular surface after 2.5 years of implantation [25].
One of the products used as an injectable material, in the treatment of OA of the
knee, is the Gel-One®, which is composed of a cross-linked hyaluronic acid hydrogel
through a photo-gelation process [26]. This product was applied in a clinical study
using 379 patients with OA, and a single injection allowed both the relief of the pain
associated to this condition for 13 weeks, as well as physical improvements [27].
420 D. Bicho et al.

BST-Cargel® (Piramal Life Sciences) has emerged as an advanced biodegradable

and injectable chitosan hydrogel mixed with glycerophosphate and autologous
blood to improve cartilage regeneration [28]. This off-the-shelf product can be used
in conjunction with bone marrow cell stimulation by directly mixing blood from the
patient with the biopolymer. This product has proved to be efficient in the initiation
and amplification of the intrinsic wound healing processes of subchondral bone, as
well as of the cartilage repair [28, 29]. An international randomized controlled trial
with 80 patients was performed to compare the BST-Cargel® treatment with micro-
fractured untreated patients. The results showed to be effective in the mid-term car-
tilage repair, and after 5-year follow up the treatment resulted in a sustained and
significantly superior quantity and quality of repaired tissue against the microfrac-
ture alone [30]. Another commercial approach used in the treatment of cartilage
defects, consists of a resorbable and textile polyglycolic acid–hyaluronan (PGA/
hyaluronan) implant named Chondrotissue® (Biotissue). In preclinical studies with
an ovine animal model it has shown improved tissue formation [31]. Clinical results
with 5-year follow-up registered that this product had a good safety profile and pro-
vided a good filling of the chondral defects of the knee [32]. The effects of
Chondrotissue® in patella defects of the cartilage were also evaluated by first debrid-
ing the damaged cartilage down to the subchondral bone. Then, the immersion of
the implant in venous blood allows an enhanced MSC recruitment and integration
leading to the improvement of the symptoms and no intraoperative or postoperative
complications [33]. Chondrocushion (Advanced Bio Surfaces, Inc) made of bipha-
sic polyurethane cylinders is a synthethic product evaluated for cartilage applica-
tion. This biomaterial presents some potential disadvantages related with the lack of
porosity which impedes tissue ingrowth and replacement [34]. Other drawbacks of
this type of product include the displacement of the implant site and the release of
potentially toxic by-products that can cause inflammation and cell death [22, 35].
Another product within this category is SaluCartilage™ (SaluMedica), a biocom-
patible and hydrophilic cylindrical device consisting of a polyvinyl alcohol hydro-
gel. This material mimics human cartilage in terms of water proportions and has
been evaluated as a synthetic surface for the replacement of damaged cartilage.
There is no evidence of inflammatory reaction or osteolysis associated with this
implant [35]. Correspondingly, clinical results showed improvement of the chondral
defects, but the hydrogel showed inadequate connection to the bone and risk of
dislocation [36].
TruGraft™ (Osteobiologics) is a poly(lactic-co-glycolic) acid (PLGA) granulate
used as a bone void filler, and has shown to support osteoblast proliferation and dif-
ferentiation proved by high alkaline phosphatase activity and deposition of a miner-
alized matrix used in OC repair [37]. Bioseed®-C (Biotissue Technologies GmbH)
is a bioresorbable scaffold for OC composed of fibrin, PLA and polyglycoic acid
(PGA) copolymer, and polydioxanone embedding chondrocytes [38]. This product
was preclinically evaluated on an equine animal model of full thickness cartilage
defects and showed capacity to be integrated while promoting the formation of car-
tilaginous tissue [39]. These promising results made the testing of this product pro-
ceed into humans with posttraumatic and degenerative cartilage defects of the knee
19 Commercial Products for Osteochondral Tissue Repair and Regeneration 421

Fig. 19.1 Commercial biphasic scaffolds for osteochondral repair/regeneration: (a) Agili-C™
(reprinted with permission from [50]); (b) HYAFF™ (reprinted with permission from [51].
Copyright© 2015, Springer Nature) and (c) Trufit™

[40, 41]. It was reported that most of the grafts were able of completely fill the
defects and formed tough hyaline-like cartilage, being well integrated into the tissue
with good connection with the articular cartilage and the subchondral bone.
Feeding the importance of subchondral bone in the maintenance of articular car-
tilage, researchers have been developing some biphasic products in order to mimic
both structures. These bilayered scaffolds have different characteristics to address
different biological and functional requirements of both bone and cartilage, which
are essential in the treatment of OC defects [23]. Accordingly, some commercial
biphasic scaffolds are available in the market. For example, a product derived from
natural sources for OC application, is Agili-C™ (CartiHeal) composed of calcium
carbonate for the bone region, and aragonite and hyaluronic acid for the cartilage
part (Fig. 19.1a). Results, after 12 months of implantation in a caprine animal
model, showed an improvement in terms of cartilage repair and osteointegration
with a reduction of the symptoms (limited motion, swelling of the joint, and pain).
The bone phase of the implant shows a structure similar to natural bone presenting
high pore interconnectivity essential for blood vessels [42, 43]. In contrast, the
chondral phase rich in hyaluronic acid helps the ECM of the cartilage to be main-
tained with their proper characteristics. Kensey Nash Corporation started develop-
ing an acellular Cartilage Repair Device (CRD) to tackle primary defects of the
articular cartilage in the joints, the OsseoFit® plug. This product was indicated to
support the regeneration of hyaline cartilage and subchondral bone by promoting
the correct cellular morphology, and structural organization during the healing pro-
cess. The OsseoFit® plug is composed of a bioresorbable biphasic scaffold of col-
lagen type-I fibrils, to simulate the cartilage, and 80% β-TCP + 20% polylactic acid
(PLA) for the subchondral bone phase. A study using OsseoFit® applied in 10 plugs
on the medial femoral condyle and on the lateral femoral condyle displayed a reduc-
tion in height of the material and the integration of the product on the surrounding
native cartilage [19]. HYAFF® (Fidia Advanced Biopolymers) is a biodegradable scaf-
fold used for repair of chondral and OC lesions. It is composed of purified hyaluro-
nan esterified in its glucuronic acid group with distinct types of alcohols (Fig. 19.1b).
422 D. Bicho et al.

In vitro degradation profile of HYAFF® 11 suggested that the hyaluronan esters

undergo spontaneous deesterification in an aqueous environment, meaning a good
integration in the biological tissues [44]. Also, in vivo studies showed a minimal
response after the first month of implantation, and no evidence of toxicity during the
1-year study following implantation. HYAFF® 11 scaffolds present the advantage of
having good cell adhesiveness even without coating and surface conditioning [45].
TruFit® (Smith & Nephew) is another product used in OC applications (Fig. 19.1c)
that consists of calcium phosphate and PLGA. This product presented good filling
of OC defects, good integration in the native cartilage, and histological assays that
showed a high percentage of hyaline cartilage formation, and good bone renovation
after implantation in the femoral condyles and trochleae of goat defects [46].
Originally, this plug was designed as an alternative treatment for OC autologous
transplantation, but in Europe has also been applied for acute focal articular carti-
lage and OC defects [47, 48]. Conversely, another work showed a comparative
study between patients undergoing mosaicplasty (harvest and transplant of plugs of
bone and cartilage from one place to another) and patients implanted with TruFit®
showed no improvement in applying this product in comparison to the other proce-
dure [49].
In order to establish a complete regenerative engineered strategy for TERM
application, the use of cellular scaffolds has been proposed. The inclusion of liv-
ing cells into the scaffolds enables real time growth factors, cytokines and matrix
proteins which will accelerate the regenerative process. However, this technology
also brings many complications besides the inevitable high costs, complexity of
manufacture, sterility, preservation and regulatory issues. Currently, the applica-
tion of cells without a scaffold has undergone several clinical studies showing that
integration with the host tissue remains a problem [52]. This fact had led to the
development of grafts combining living cells with biomaterials ex vivo allowing
the construction of a 3D structure to be implanted in the living organism.
Nevertheless, the type of cells and their quantity will help to set the mechanical
and biochemical characteristics of the graft [53, 54]. The marketed product
Osteocel® Plus (NuVasive®) is an example of a cell-based bone graft. It contains
native MSCs and osteoprogenitor cells combined with an osteoconductive demin-
eralized bone matrix (DBM), and cancellous bone, presenting osteogenic capac-
ity. Promising experiences with this material have been reported for several
applications, including lumbar [55], as well as periodontal [56], foot and ankle
defects [57].
On the other side, demineralized matrices from human donors are also applied
as optimal biomaterials. An example is Dynagraft®, a DBM combined with polox-
amer, the nonionic triblock copolymer (GenSci Regeneration Sciences). This graft
is moldable, packable and can be mixed with grafting materials being resistant to
irrigation. Additionally, hyaluronate (i.e., DBX®, Synthes), glycerol (Grafton®,
Osteotech, USA), and calcium sulfate (Allomatrix®, Wright Medical Technology)
have also been applied with DBM and are also being commercialized [58, 59].
19 Commercial Products for Osteochondral Tissue Repair and Regeneration 423

Commercially available cartilage graft BioCartilage® (Arthrex) provides a simple

and inexpensive method to use extracellular cartilage matrix that has been dehy-
drated and micronized. It provides a proper scaffold to correct microfracture
defects of articular cartilage, providing the appropriate biochemical signals,
including collagen type II, cartilage matrix elements, and growth factors [60]. One
of the few FDA approved ACT products is Carticel® (genzyme), which a cellular
graft of autologous cultured cells derived from in vitro expansion of chondrocytes
of femoral articular cartilage from the patient. The application of Carticel® in
young patients has originated a cartilage tissue containing predominately collagen
type II but lacking total host integration and alignment with the surrounding car-
tilage [61]. Hyalograft® C is another commercially available matrix to assist chon-
drocyte implantation. This product is composed of a hyaluronic acid-based
cartilage graft in combination with autologous isolated and enriched chondro-
cytes. The clinical data of the application of this product showed improvements in
91.5% of the patients [62, 63]. The use of minced articular cartilage (autologous
or allogeneic) defects is being explored for cartilage repair in OC defects. The
off-the-shelf human tissue allograft DeNovo NT (Zimmer), consisting of juvenile
hyaline cartilage pieces with viable chondrocytes, has emerged. This commercial
product is intended to finds uses in lesions of articular cartilage. When implanting
DeNovo NT, the debridement of the fibrous and calcified tissue of the defect
should be performed without violating the subchondral bone layer. Then the
implant is added to the lesion site and using fibrin glue will help the tissue to be
maintained in place [64, 65]. Recently, this juvenile particulate cartilage has been
employed in patellar lesions with success. It has been demonstrated that the repair
hyaline cartilage is performed by integration with the surrounding tissue showing
a good recovery and improvement of the movements and reducing the pain associ-
ated with OC lesions [66]. Another alternative is the OC allograft Chondrofix®
(Zimmer®) composed of decellularized cadaveric human joints consisting of hya-
line cartilage and cancellous bone [67]. A case report of Chondrofix® implanted in
a large full-thickness OC defect demonstrated to be completely incorporated by
the bone without articular cartilage margins and restoring the native femoral con-
dylar radius of curvature [68]. Nevertheless, when working with these types of
materials, the risk of disease transmission or immunogenicity still remains.
Moreover, they can be quite brittle leading to the accumulation of microfractures
during the remodeling phase [69].
The available commercial products aforementioned show that there is still much
research that needs to be done to create new therapies to significantly increase the
regenerative capacity of OC structure. A summary of these commercialized prod-
ucts for bone, cartilage, and OC tissue regeneration is presented in Table 19.1.
424 D. Bicho et al.

Table 19.1 Commercial products for the repair and regeneration of bone, cartilage, and OC
defects
Product Manufacturer Composition Bioresorbable Applications
Chondromimetic™ TiGenix NV Collagen, GAG, and CaP ✓ OC
Trufit™ Smith & Calcium sulfate, PLGA/ ✓ OC
Nephew PGA
MaioRegen® Med&Care Collagen type I and ✓ OC
magnesium enriched-HA
OsseoFit® plug Type I collagen, and 80% ✓ OC
β-TCP + 20% PLA
BST-Cargel® Piramal Life Chitosan gel, n.d. OC
Sciences glycerophosphate, and
autologous blood
Bioseed®-C Biotissue PLA/PGA n.d. OC
Technologies
GmbH
Agili-C™ CartiHeal Calcium carbonate and ✓ OC
aragonite with hyaluronic
acid.
Collagraft® Nuecoll Inc Collagen with granules ✓ OC
of HA and β-TCP
Chondrotissue® Biotissue PGA/hyaluronan ✓ Cartilage
HYAFF® 11 Anika Hyaluronan ✓ Cartilage and
Therapeutics OC
Chondrocushion Advanced Bio Polyurethane No Cartilage
Surfaces, Inc
BST-Cargel® Piramal Life Chitosan with glycerol ✓ Cartilage
Sciences phosphate and
autologous blood
SaluCartilage™ SaluMedica Polyvinyl alcohol ✓ Cartilage
hydrogel
Gel-One® Zimmer Hyaluronic acid n.d. Knee OA
n.d not defined, GAG glycosaminoglycans, CaP calcium phosphates, OC osteochondral, PLGA
poly(lactic-co-glycolic) acid, HA hydroxyapatite, PLA polylactic acid, PGA polyglycolic acid, OA
osteoarthritis

19.5 Concluding Remarks and Future Trends

Several attempts are being made to mimic in vivo situations, and in fact enormous
advances as regards not only to OC tissues but also to other tissues of the human
body have been made. Herein, in this chapter we describe some commercial OC
approaches, particularly based on 3D scaffolds envisioned to support newly formed
tissues. The presented scaffolds are either biphasic, injectable hydrogels or decel-
lularized matrices, and their outcomes reinforce the ideal basic requirements for the
design of OC constructs aiming at tissue repair and regeneration. Such necessities
include porosity, mechanical strength, biocompatibility, bioactivity, biodegradabil-
ity, bio-integration, and proper cell proliferation and differentiation. Besides, due to
19 Commercial Products for Osteochondral Tissue Repair and Regeneration 425

its medical nature, new commercial products must undergo laborious testing, as
demanded by regulatory approval bodies, before their use in humans. Therefore,
some prospective improvements are under investigation to create better OC prod-
ucts. In this front, researchers are trying to enhance cell attachment to scaffolds
using cell-adhesive ligands, and changing cell morphology, alignment, and pheno-
type, by varying the topographic surface of the scaffolds or even by mechanobio-
logical stimulation of cells. Growth factors can also be incorporated directly into the
scaffolds to help cells to differentiate, but immunomodulatory molecules are also an
option to help to control inflammation towards the regenerative process. In the end,
the final purpose is to create a scaffold that entirely mimics the ECM of OC tissue,
having simultaneously proper mechanical properties, biochemical cues and the
appropriate degradation profile, providing the ideal conditions for tissue growth.

Acknowledgments The authors acknowledge the project FROnTHERA (NORTE-01-0145-­

FEDER-000023), supported by Norte Portugal Regional Operational Programme (NORTE 2020),
under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development
Fund (ERDF). The authors would also like to acknowledge H2020-MSCA-RISE program, as this
work is part of developments carried out in BAMOS project, funded by the European Union’s
Horizon 2020 research and innovation program under grant agreement N° 734156. The financial
support from the Portuguese Foundation for Science and Technology under the program
Investigador FCT 2012 and 2015 (IF/00423/2012 and IF/01285/2015) is also greatly
acknowledged.

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