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Recent Patents on Regenerative Medicine 2014, 4, 40-51
Biomedical Applications of Poly(Lactic Acid)
Rajendra P. Pawara, Sunil U. Tekalea, Suresh U. Shisodiaa, Jalinder T. Totrea and
Abraham J. Dombb,*
a
Department of Chemistry, Deogiri College, Station Road, Aurangabad Maharashtra 431 005, India; bDepartment of
Medicinal Chemistry and Natural Products, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem91120, Israel
Received: February 24, 2014; Accepted: March 20, 2014; Revised: April 2, 2014
Abstract: Polylactic acid (PLA) is a biodegradable, biocompatible, non-toxic and eco-friendly polymer. PLA and its
composites are currently used in medical implants, tissue engineering, orthopedic devices, drug delivery systems, etc. The
present review highlights recent research and patents for the utility of PLA based polymers and their blends in biomedical
applications.
Keywords: Biomedical applications, medical implants, PLA.
INTRODUCTION
Polylactic acid or polylactide (PLA) is a thermoplastic
and biodegradable aliphatic polyester derived from naturally
occurring organic acid (lactic acid). PLA is inexpensive,
dimensionally stable and harder than Polytertafluoroethylene
(PTFE). It melts at a lower temperature (in the range of 180220°C) with glass transition temperature 60-65°C. Furthermore, PLA and its composites are biodegradable in nature;
they degrade easily in physiological conditions as shown in
animal model by simple hydrolysis of the ester backbone
resulting in the formation of non-harmful and non-toxic
compounds. Their degradation products are easily excreted
through kidneys or eliminated in the form of carbon dioxide
and water through metabolic processes in animals. PLA can
also be recycled to its monomer by thermal depolymerization
or hydrolysis. It can be processed by injection molding, extrusion, spinning film and casting, providing easy access to a
wide range of materials. High molecular weight polylactides
are absorbed completely and their rate of absorption depends
on molecular weight, morphology, and enantiomeric purity
of the polylactides.
Thus, due to its biocompatibility, complete biodegradability and non-toxic nature of degradation products, PLA
based polymeric materials are ideal for the preparation of
various polymeric devices used for different practical applications all over the world.
Due to their excellent biocompatibility and mechanical
properties, PLA and its copolymers have been used extensively in different fields such as polymer engineering, tissue
engineering, drug delivery systems and various medical
*Address correspondence to this author at the Department of Medicinal
Chemistry and Natural Products, School of Pharmacy, The Hebrew
University of Jerusalem, Jerusalem- 91120, Israel; Tel: 972-2-6757573;
Fax: 972-2-6757076 E-mails: [email protected]; [email protected]
2210-2973/14 $100.00+.00
implants of paramount significance. As per the consumption
rate in 2010 PLA was regarded as the world’s second most
important bioplastic.
PLA is a promising, eco-friendly biopolymer for use in
the human body. The use of degradable materials for medical
implants has been of great interest for many years. The loss
or malfunctioning of tissues or organs provides an impetus
for the development of novel biomaterials and techniques for
their synthesis. Among the different biopolymers used, PLA
has attracted significant attention. The safety of PLA based
implants is depending also on the solvents or compounds
incorporated in the polymer during processing. The elimination of any toxic solvent or agent from the final implantable
PLA product should be confirmed.
PLA is the polymeric form of lactic acid, and as such it is
the natural product of fermentation of sugars in sugarcane
and corn by microorganisms. It is a biodegradable thermoplastic with good mechanical strength and excellent biocompatibility. Being a thermoplastic and biodegradable, PLA has
become attractive material for biological and medical applications. It can be spun into fibers which can be used for implants and other surgical applications such as sutures. Its
composites find many applications in biomedical devices
from fibers to subcutaneous sutures and to regenerative surgery implants.
PLA is widely used in tissue engineering, and it finds a
wide spectrum of applications in the medical field. PLA and
its copolymers are used in the form of implants or devices
due to their biodegradability. PLA and lactide copolymers
can be produced from renewable resources; they are biodegradable and nontoxic to humans as well as to environment.
They are being extensively used as biomedical materials in
the fields of controlled drug delivery systems, tissue regeneration and as alternatives for other ceramic based polymeric
materials which reduce impact on environment. Being a bio© 2014 Bentham Science Publishers
PLA Applications
Recent Patents on Regenerative Medicine 2014, Vol. 4, No. 1
degradable material, it avoids surgical procedures to remove
the devices of which it is comprised.
PLA and its composite polymeric materials have the following striking characteristic features:
•
Biodegradability
•
Good biocompatibility
•
Good process ability
•
FDA approved synthetic degradable polymers.
The present review provides a compilation of significance of PLA and PLA based biodegradable polymeric materials for medical implants and an insight into recent patents
and their applications in medical implants.
BIOMEDICAL SIGNIFICANCE OF
COMPOSITES AND COPOLYMERS
PLA,
PLA-
Polylactide (PLA) and its copolymers are the aliphatic
polyesters possessing different properties such as good biocompatibility, biodegradability by enzyme and hydrolysis
under physiological conditions, low immunogenicity, etc.
Thus they are therapeutically safe. Due to such features they
have attracted attention and great interest as innovative materials for a wide range of applications in biomedical and
pharmaceutical applications, e.g. drug delivery systems, sutures, implants for bone fixation, etc. They are widely used
in orthopedic medicine, soft tissue repair, synthetic grafts,
etc. The first report on PLA as bio-absorbable surgical devices was by Kulkarni, et al. [1]. The present review provides an overview of scientific articles and patents on approaches for use of PLA towards medical applications.
A comprehensive literature search reveals the applications of PLA and its polymeric composites in medical fields
such as:
1.
Orthopedics
2.
Drug carriers
3.
Facial fracture repair
4.
Tissue engineering
5.
Antimicrobial agents
6.
Antitumor
7.
Ureteral stents
8.
Biomaterials
9.
Miscellaneous applications
41
(PLA-PGA) have been used extensively in orthopedic applications such as tissue growth implants and fracture fixation devices.
Bioabsorbable fixation devices are extensively applicable
in orthopedic and craniomaxillofacial surgery. Such devices
and ultra-high-strength implants are mainly composed of
PLA and/or PGA polymers. They are commonly used for the
stabilization of fractures, bone grafting, reattachment of
ligaments, tendons, etc. PLA polymers reduce risks during
pre-implant osteoporosis and risks arising due to infections.
The intrinsic nature of PLA/PGA copolymers renders promising application for slow release of bioactive agents in the
field of orthopedics. These materials eliminate osteopenia
occurring due to stress shielding or additional surgery, but
they also suffer from the drawback of reduction in cell proliferation. They may also be used not only to minimize the
problem of osteochondral repair particularly in soft tissues,
but also to enhance fixation and repair processes in tendons
and ligaments [2].
PLA-calcium-phosphate-glass-fiber composites used as
orthopedic implants are reported to degrade faster as compared to PLA or glass fibers (GF) [3]. PGA (Polyglycolic
acid)-fiber-reinforced-PLA can be effectively used as implant material during bone surgery. These composites are
completely bioabsorbable. Their degradation rate can be
modulated depending upon stereocopolymer configuration,
crystallinity and PLA/PGA matrix ratio. Such material has
been used successfully and employed for 3 years in maxillofacial surgery [4].
Zhou reported the use of PLA/chitosan composite materials in bone tissue scaffolds. The chitosan material significantly neutralizes acidity caused by PLA degradation. The
composite has sufficient strength and shape of tissue to remain for longer time [5].
1. ORTHOPEDICS
The combination of PLA with carbon fiber, hydroxyapatite (HA) ceramic and aluminum-calcium-phosphorous oxide
ceramic significantly enhances the mechanical properties of
these blends; use is in the repairing and replacement of both
soft and hard tissues. The bone plate of carbon fiber reinforced PLA can be used in bone fracture repair. PLA/HA
foam fabricated by a phase separation technique is used for
controlled release of bone morphogenic proteins (BMP)
through highly porous foams. It also facilitates the regrow of
tissue and thus helps in ectopic induction of bone and cartilage [6]. Absorbable self-reinforced fibrillated PLA
(96L/4D)/ a (SR-PLA96) rod has been successfully used for
the healing of bones during the treatment of osteotomies in
rabbits [7].
The investigation of bio-absorbable implants for fixation in orthopedics is rapidly growing. PLA and its copolymers with glycolic acid and other hydroxy acids are
materials of prime importance for orthopedic applications.
The use of absorbable materials instead of traditional metallic devices has been prominent since 1965. First PLA
suture used for fracture fixation plates and screws was patented in 1973. Recently, polylactic acid-polyglycolic acid
Classical PLGA (1:1) copolymers are not strong enough
to carry loads for longer times before there is sufficient
growth of bone to replace the eroded prostheses. Poly butylene terephthalate polymers provide a suitable alternative in
such cases [8]. These copolymers are safe and effective for
use in foot and ankle in case of syndesmotic, Lisfrancinjuries, osteochondral defects and tendon transfers [9]. In vivo
and in vitro studies of biocompatible PLA with good me-
42 Recent Patents on Regenerative Medicine 2014, Vol. 4, No. 1
chanical strength show retention of sufficient strength after a
period of 8-12 weeks following implantation to be useful as
internal bone fixation devices [10].
PLA (D, L)-polyethyleneglycol (PEG) block copolymer
can be used as a carrier for bone morphogenetic proteins
(BMPs) in the orthopedic field. However, from reports on a
mouse model of ectopic bone formation it was observed that
the ectopic bone formation is possible only in higher dosages
[11]. The stiffness, radiolucent behavior, biocompatibility
and bio-absorbable nature of PLAs made them attractive
materials for bone healing. PLA combined with a proteo
lipid (mucopeptide N-acetyl muramoyl hydrolase phosphatidylinositol 3,4-diphosphate) have been documented for bone
healing in rats and dogs [12]. Biodegradable composites of
PCL and PLA matrix reinforced with phosphate-based glass
fibers have been employed as bone regenerative implants.
Nano-HAP/collagen/PLA (nHAC/PLA) composites have
been reported as bone tissue engineering scaffolds. These
composites were successfully used in clinic trials for more
than hundred patients of bone defects [13]. A PGA- PLA
composite with a typical structure of cartilage lacuna was
developed as an artificial cartilage. The material becomes
more mature 6 weeks after in vivo implantation [14].
2. FACIAL FRACTURE REPAIR
Cranio-maxillofacial (CMF) surgery may be considered
as a part of fracture fixation that involves synthesis and investigating applications of bioabsorbable materials in facial
fracture repair. It involves safe clinical applications and biochemical property studies of bioabsorbable polymeric materials. The application of bioabsorbable materials in craniomaxillofacial surgery has ushered in a new era in fracture
fixation. Such materials are similar to metal devices, safe in
clinical applications, and easy to handle. These materials
have proven to be safe in clinical applications. Currently,
many polymeric materials such as PLA, PGA, and poly dioxanone, are being used in orthognathic surgery, followed by
treatment of fractures of the upper facial skeleton. Polymers
and copolymers of lactide and glycolide are used as fixation
materials in cranio-maxillofacial surgery, because these materials are biocompatible and gradually lose strength. With
such materials secondary treatment for removal of the material (often resulting in discomfort and pain) is not required
[15]. Hence, these find applications in maxillofacial fractures.
Osteotomies may be adequately fixed with bioabsorbable
materials. Resorbable PLGA in the form of plates and screws
can be used for facial fractures in children [16].
Self-reinforced (SR) technology based on reinforcing the
elements in the same materials helps in manufacturing these
implants of ultra-high strength. Recently, copolymeric SR
devices of P(L/DL)LA, PLGA and BioSorb PDX, have become more popular in CMF surgery [17]. Due to the resorbable nature and biocompatibility of the constituent polymeric
materials, for the past two decades devices comprised of
PLA, PGA and their copolymers have been recognized as
safe materials compared to routine metallic plating systems
Pawar et al.
in different craniofacial surgical operations, including Le
Fort osteotomies, midface/monobloc internal distraction, etc.
Furthermore, these materials portend a bright future in the
refinement of new medical devices in craniofacial surgery
[18]. The use of bioabsorbable devices particularly in children avoids problems associated with conventional bio stable
devices [19].
DRUG CARRIERS
Controlled drug delivery of hydrophilic and lipophilic
drug substances has received significant attention in the development of pharmaceutical dosage forms. These substances have been used for the past 40 years due to good
bone-compatibility, biodegradability and physico-chemical
properties of PLA and co-polymers with glycolic acid
(PLCG). They are also used as effective drug delivery systems with various small molecular weight therapeutic agents,
high molecular weight chemotherapeutic drugs, antibiotics
and peptide hormones. Several biodegradable nanoparticles
are available for cytosolic delivery of therapeutic agents.
PLGA and PLA-based nanoparticles have also been investigated for the efficient intracellular delivery of drugs and
genes. The biodegradability of polymer and other solvents as
matrix-forming agents is also an important factor in controlling the release time of drugs. Local delivery of drugs is affected by several factors such as monomer composition,
polymer molecular weight, implant size, fabrication technique, hydrophilicity and physiochemical properties, etc.
[20].
Currently, research is in progress to develop novel local
drug delivery devices using biodegradable polymers, particularly PLA and PLGA, due to good biocompatibility, biodegradability and good processability. Chitosan microspheres,
prepared in combination with PLA and PLGA, act as effective adjuvants for the controlled release of several antigens.
This is because chitosan exhibit an important fraction of
primary amino groups. These amino groups are easily coupled with bioactive protein ligands. Positive charge of chitosan promotes the ionic binding of chitosan microspheres and
controls the rate of antigens nucleic acids release. Thus they
act as complementary materials for existing aluminum salts
for vaccine potential. The stereo complex formation between
enantiomeric PLA, poly(L-lactide) induces structure with
mechanical properties and degradation. It finds many applications in medical devices. It also increases the thermal and
hydrolysis-resistance of PLA-based materials and thus can
be used as hydrogels and particles for drug delivery systems.
The mixing ratio and the molecular weight of L-lactide and
D-lactide units control the properties of such materials [21].
A biodegradable copolymer of PLA and PGA has been used
for the prolonged release of growth factors and other bioactive agents from porous coated prostheses. There is a possibility of water to permeate throughout the material at a fast
rate on account of the low thickness of the polymer layer and
intertwining metal fibers [22].
Degradable thio-acrylate monomer with three lactide
units on each side has been synthesized and used as photo
polymeric material in tissue engineering and drug delivery
PLA Applications
scaffolds. The degradable thio-acrylate mixtures can photo
polymerize in the absence of photo initiator [23]. Chitosan
and PLGA microspheres can control the rate of release of
entrapped antigens [24].
The release of vancomycin is possible from a bioresorbable -tricalcium phosphate (-TCP) and biphasic CaP
(BCP)-based composites containing 30 vol. percent polycaprolactone (PCL) or PLA. Studies reveal that -TCP-30
vol. percent PLA composites function as the best combination in terms of compression strength and drug release.
Complete drug release is achieved with a negligible material
dissolution. The use of such materials in the release of antimicrobial agents reduces the chances of implant infections
[25].
Osteoarthritis is an illness of the joints that affects cartilage and subcondral bone. HA is a commonly used material
in such cases due to its bone microstructure and tissue compatibility. Due to its short degradation time and good biocompatibility, PLA is used for implant applications. A
PLA/HA (9:1 wt. percent) hybrid composite has also been
successful for such use [26].
The release of proteins from degradable polymer matrices, typically composed of PLLA and its composites is being
investigated. Protein release is achieved primarily through
matrix erosion. PLA/Pluronic blend films show a considerable decrease in the “burst” release of proteins. In comparison to delivery profiles of gamma-globulin and hemoglobin
through aluminum-calcium-phosphorus oxide (ALCAP) capsules and (PLA)-impregnated capsules, it is clear that the
amount of proteins released through non-impregnated capsules was higher than the amount released from PLA [27].
TISSUE ENGINEERING
Tissue engineering is the medical technology that involves the use of cell combination, engineering and materials
methods and suitable biochemical and physio-chemical factors to improve or replace biological functions. It provides an
alternative to the treatment of malfunctioning or lost organs.
Patients are treated with their own cells that are grown on a
polymer support so that a tissue part is regenerated from the
natural cells. PLA composites constitute effective scaffolds
that stimulate cells/tissues for proliferation and osteogenic
differentiation in bone tissue engineering.
A
biomimetic
recombinant
collagen,
nanoHA/recombinant human-like collagen (RHLC)/PLA, was
synthesized and studied to improve its osteoinductive property. BMP-2-derived peptide increases the osteoinduction of
nHA/RHLC/PLA scaffolds and the P24 peptide induced new
bone formation depending on its dose. It works as an ideal
material for bone tissue engineering [28]. Cells can be
seeded onto bioresorbable PLA and PGA scaffold materials.
The seeded scaffolds are then cultured for tissue growth
which is dependent upon polymer type and bioreactor fluid
dynamics [29].
Intestinal crypt cells transplanted as epithelial organoid
units on PGA-PLA tubular scaffolds can survive, reorganize
and regenerate complex composite tissue. These cells exhibit
Recent Patents on Regenerative Medicine 2014, Vol. 4, No. 1
43
organ morphogenesis, cyto differentiation and phenotypic
maturation, which show resemblance to small intestines [30].
Poly-L-lactic acid can be applied in the successful management of soft-tissue augmentation. Several non-toxic porous
phosphate glass particles incorporated into PLA (95L/5DL)
and its composites have been used in bone-tissue engineering.
The introduction of glass particles into such polymer affords
good mechanical properties and biological response [31].
BIOMATERIAL
Biodegradable implants of PLA/PGA (1:1) materials are
stiff and can sustain external stress. PLA can be used as a
scaffold on which cultured osteoblasts can grow and mineralize [32]. In vitro and in vivo degradation of poly (lactic
acid) (PLA) in rats and the femur of rabbits shows that PLA
functions as an effective degradable and absorbable biomaterial [33].
ANTIMICROBIAL AGENTS
Antimicrobial polymers (polymeric biocides) are the
polymers with antimicrobial activity or the ability to inhibit
the growth of microorganisms such as bacteria, fungi or protozoans. Currently polymers are being invented to mimic
antimicrobial peptides that are used by the immune systems
of living things for killing bacteria. In general, such polymers are synthesized by attaching or inserting an antibacterial drug onto a polymer backbone via an alkyl or acetyl
linker. Antimicrobial polymers increase efficiency and selectivity of antimicrobial agents together with decreasing
environmental hazards. These are also useful in water sanitation to inhibit the growth of microorganisms in potable
water. Poly (lactic-co-glycolic acid) (PLGA) and poly (lactic
acid) (PLA) based polymers have been used as effective antimicrobial polymers.
PLA provides promising results for the local drug delivery of linezolid in cases of chronic osteomyelitis [34]. The
antimicrobial effect of olive leaf extract can be incorporated
into PLA films. These films have been found to be effective
in cases of Staphylococcus aureus bacterial strains [35]. PLA
antibacterial coatings can be used to reduce the pathogens on
fruit surface such as apples [36].
Although titanium is commonly used in dental implants
due to its favorable biological response, it may be accompanied by microbial infection. Chlorhexidine (CHX) works
against different bacterial microbes. Hence, attempts are
being carried to release slowly CHX from CHX-containing
polylactide (PLA)-coated titanium for better dental implants
[37-39].
URETERAL STENTS
Ureteral injury is a serious clinical problem. Search for
the discovery of biodegradable ureteral stent is an active and
ongoing research. Biodegradable PLA and its composites
find extensive application as ureteral stents for the treatment
of ureteral injury. A biodegradable SR-PLA 96 stent possessing effective expansion capacity can be used for stenting
after ureteral repair [40]. Studies have been focused on
44 Recent Patents on Regenerative Medicine 2014, Vol. 4, No. 1
screening the usage of poly-L, D-lactide copolymer (SRPLA 96; L/D ratio 96/4) device for ureteral stenting in kidney functioning [41].
Pawar et al.
ment portion in the bladder wall following partial cystectomy. This patch makes autologous fibrous capsule cells,
generated by tissue reconstruction, where they grow thereon
after insertion inside the patient [48].
MISCELLANEOUS APPLICATIONS
The in vitro and in vivo degradation of PLA braided multifilament yarns produced by melt spinning as models of
synthetic bioabsorbable ligaments is well studied. PLA is a
useful material for bioabsorbable implants due to its hydrolytic degradation product, lactic acid, which is a normal intermediate of carbohydrate metabolism.
PLA devices can be used as micro-coded controller systems, accomplishing different tasks at different times based
on control signals. Such devices are better than the conventional ones in terms of mutual compatibility, space, power,
reliability and modularity [42].
Lactic acid / trimethylene carbonate (PLA/TMC) polymer has great strength that can maintain vessel patency to
resist acute vasoconstriction. Furthermore, no inflammatory
effect during the biodegradation of this material in the vessel
wall has been observed [43]. Chitosan-collagen-soybean
phosphatidylcholine (SPC) complex film impregnated with
Mitomycin C (MMC)-PLA- nanoparticles was used for the
treatment of hepatocellular carcinoma in rats. The system
worked as an effective delivery system for MMC [44]. A bio
absorbable three-dimensional micro porous L-PLA polymer
was developed for coronary occlusion during catheterization
and cardiovascular interventions. When implanted into porcine, coronary arteries reproducibly results in the development of a chronic total occlusion (CTO) at day 3 [45].
Filamentous carbon and PLA polymer composite have
been used for the repairing of tendon and ligament injuries.
The filamentous carbon provides scaffold for the formation
of new tissues. Geometric configuration and surface characteristics significantly affect the properties and applications of
these composites [46].
Three-Dimensional Fibrous Scaffolds for Cell Culture
(2013)
US20130224860 discloses a three dimensional fibrous
polyethylene glycol-polylactic acid block copolymer (PEGPLA) and a poly (lactic-co-glycolic acid) (PLGA) based
scaffold for cell culture. The scaffold consists of fibers
which are randomly oriented [49].
Buprenorphine Nanoparticle Composition and Methods
Thereof (2013)
WO2013126552 relates the synthesis of PLA nanoparticles containing buprenorphine with average loading efficiency of 70.69%. The material is useful in controlling pain
in animals and development of methods for treating addiction in humans. Due to the biodegradable nature of the polymeric material used, the chances of excreting toxicity in
human body are reduced. The degraded products secrete in
the urine of the animal during metabolic processes of animal
body. Furthermore, no additional surgery is required to remove the implanted matrixes after depletion of the drug [50].
Scaffolding Biomaterials Based on Polymer-Coated
High-Stiffness Particles (2013)
WO2013116736 explains the construction of stiff particles of materials such as hydroxyapatite, tricalcium phosphate, CaCO3, TiO2, etc. which are coated with shells of biocompatible polymer like (PLA), (PLGA), poly (glycolic
acid) (PGA), etc. Such particles are useful in the delivery of
bioactive agent insulin-like growth factors TGF-beta1, TGFbeta3, a bone morphogenetic protein, BMP-2, BMP-7, etc.
[51] Fig. (1).
For past few years the animal health industry has paid
more attention to the development of long-term drug delivery for companions and farm animals. For this purpose the
PLA/PLGA, PEG-PLA-PEG and sucrose acetate isobutyrate
(SAIB) polymeric materials have been of increasing interest
in the controlled release of drugs, more so than slow release
technologies such as microspheres or standard implants [47].
RECENT PATENTS ON MEDICAL APPLICATIONS
OF PLA / PLA BASED COPOLYMERS
This part of the review focuses on recent patents dealing
with inventions made by the scientific community on applications of PLA based polymeric devices in biomedical applications.
Improved Absorbable Patch, in Reinforced PGA, for the
Replacement of a Portion of Bladder Wall Following Partial Cystectomy (2013)
WO2013135544 deals with the development of an absorbable patch in reinforced PGA, applicable as a replace-
Fig. (1). Time released biodegradable or bio erodible microspheres
or micro particles suspended in a solidifying depot-forming injectable drug formulation (2013).
US20130189369 deals with composite drug delivery material comprised of micro particle biodegradable material
such as PLA or PLGA, helpful for drug delivery into the eye
of a person or other mammal during the treatment of ocular
disease. The composite drug delivery material may be in-
PLA Applications
jected to provide sustained delivery of the drug. The media
component may gel or solidify upon injection into the eye
[52].
Elastomeric and Degradable High-Mineral Content
Polymer Composites (2013)
WO2013044078 invents novel materials of hydroxyl
apatite and block copolymers of PLA and PELA such as
elastomeric and degradable polymer composites with highmineral content. The presence of degradable hydrophobic
blocks and hydrophilic blocks affords high stability to the
polymer-hydroxyapatite suspensions. However, the HA-PLA
composites are better than the HA- PELA composite in
aqueous media due to difference in hydrophilicity giving rise
to mechanical integrity [53].
Recent Patents on Regenerative Medicine 2014, Vol. 4, No. 1
45
Orthopedic Cage Comprising Device for Adjusting Positions of Implant Body Relative to Bone (2012)
WO2012075349 concerns a joint implant composed of
PGA/PLA copolymers, stainless steel, titanium, hydroxyapatite-coated titanium and CoCr alloy. It is a V-shaped body
consisting of an adjustment device for changing positions of
the body relative to a bone. The adjustment device consists
of a slotted cylinder with a deformable neck. This implant
has been used especially in veterinary medicine [58] Fig. (3).
Composite PLA/Alginate Surgical Barrier (2013)
US20130052236 is related to the preparation of medical
assembly comprising a surgical barrier aspect, a short term
mucoadhesive aspect, an intermediate term protein polymer
adhesive aspect, and a long term tissue in growth implant
localization aspect. The composites may be provided as layered sheet structures [54].
Drug Elution Endoprosthetic Medical Device Comprising
Biodegradable Polymer Layers (2013)
US20130018258 deals with a medical device comprising
biodegradable polymer layers of poly-DL-lactide for the
delivery of therapeutic agents to vascular dissections or perforations. In this device a mask layer of an extruded poly
(glycolide-lactide) copolymer is formed [55] Fig. (2).
Fig. (3). Implantable polymer for bone and vascular lesions (2012).
WO2012054742 deals with a bone implant of PLA-PGA
copolymer with glycerol cross linker used for shoring up
bone structure with good load-bearing ability assisting the
healing small fractures. A solidifying implant has a composition of a polymer mixed with a bio absorbable solvent to
solidify. It also helps devascularizing and treating a tumor or
vascular lesion, and treating vascular disease [59].
Three-Dimensional Scaffolds, Methods for Fabricating
and Treating Peripheral Nerve or Spinal Cord Injury
(2011)
Fig. (2). Pharmaceutical composition of nanoparticles for the treatment of cancer (2012).
WO2011123798 concerns thin polymeric films by casting PLA solution in 1:1 DCM: CHCl3 on glass cover-slips
followed by spinning on grounded aluminum target using an
electro spin technique to afford a three-dimensional scaffold
including at least one layer of highly-aligned fibers. Threedimensional scaffold is useful for the treatment of nerve or
spinal cord injury [60] Fig. (4).
US8318198 deals with liposome nanoparticles prepared
from - PGA-PLA block copolymers used in cancer therapy
for the delivery of anticancer drug paclitaxel at the infected
tissue. The drug delivery was studied on tumors implanted in
mice. Around 20% of release of paclitaxel was observed
during the first hour [56].
Hemisphere for Bladder Expansion in Patients with Low
Compliance (2012)
WO2012123272 deals with an implant composed of PLA
and silicone coated with pyrolytic turbostratic carbon or with
amorphous diamond-like carbon. It is useful for bladder expansion in the case of patients with low compliance [57].
Fig. (4). Thick foam preparation for biomedical application (2010).
46 Recent Patents on Regenerative Medicine 2014, Vol. 4, No. 1
WO2010117824 deals with the development of a novel
method for thick foams, which can be used for tissue scaffolding and other medical devices. The thin foams are prepared from a thermo-reversible polymer solution using 95/5
poly (lactide-glycolide) (PLA/PGA) and 1, 4-dioxane. The
solvent is removed by lyophilization to afford thick dry foam
with uniform pore morphology and size [61].
Antibacterial Hydrogel and use Thereof in Orthopedics
(2010)
WO2010086421 is related to the invention of antibacterial hydrogels used in damaged bones in human or animal
bodies. PLA is activated with NHS followed by reaction
with tetrabutylammonium salt of hyaluronic acid (HA-TBA).
Thus the formed HA-PLA product is dispersed in water until
a transparent viscous gel forms before mixing of a solution
of Vancomycinn. Drug release is possible with antibacterial
hydrogel coated on titanium prostheses [62].
Biocompatible Fiber Based Device for Guided Tissue
Regeneration (2010)
WO2010077520 discloses a biocompatible fiber tissue
engineering device for tissue regeneration in the pelvic floor
[63].
Copolymer Including PLA, Acrylic Acid, and Polyethylene Glycol Processes (2010)
WO2010056421 explains the development of copolymers
of acrylic acid, and polyethylene glycol having a PLA backbone in their structures. Such materials have good toughness,
modulus, and mechanical strength [64].
A Peripheral Nerve Growth Scaffold which Includes
PCL (2010)
UK patent GB 2463861 concerns a poly-caprolactone
(PCL) based scaffold containing PLA and used for peripheral nerve growth in a human or animal body. The scaffold is
internally coated with alkaline compounds [65].
Medical Device (2010)
WO2010029295 provides a peripheral growth conduit for
the growth of peripheral nerves. The implant is composed of
PCL which may also include PLA [66].
Implantable Medical Device Coatings with Biodegradable Elastomer and Releasable Taxane Agent (2010)
WO2010021757 deals with the preparation of medical
device which is capable of eluting taxane e.g. paclitaxel. The
device consists of a layer of bioabsorbable elastomer. Its
stents are over coated with PLA in acetone [67].
Manipulating Electro Processed Scaffold Material Properties Using Crosslinking and Fiber Tertiary Structure
(2009)
WO2009149181 describes the method, development and
tuning the properties of electro processed materials such as
Pawar et al.
collagen and fibrin using PLA and PGA. The properties of
such materials can be manipulated by crosslinking and fiber
tertiary structure [68].
Corneal Onlay Devices and Methods for Vision Correction (2009)
WO2009146151 deals with the configuration of an onlay
device for replacing the exposed surface of eye cornea, thus
inhibiting epithelial growth under the onlay. Such structures
can be provided on the onlay to adhere the onlay to the eye.
To achieve the vision correction effectively in using this
approach, the anterior side of onlay can be designed with a
degradable water inhibiting layer comprising PLA and PGA
copolymer [69].
Optimum Density Fibrous Matrix for Tissue Engineering
Scaffolds (2009)
US20090148495 is related to the development of implantable and biodegradable porous fibrous matrices that can
comprise a biological agent such as a growth factor or cell
adhesion protein. The fibrous matrix can be composed of
90% PGA and 10% PLA copolymer arranged in a non
woven array with optimum density and used in repairing
and/or regeneration of mammalian tissue [70].
Osteogenic Lactam Compounds for Bone Repair (2009)
WO2009016333 relates a method for the development of
lactam compounds with good osteogenic properties promoting bone regrowth and repair. A PLA/PGA matrix was used
as a loaded barrier membrane for these osteogenic lactam
compounds. These materials are studied for their applications in the development for guiding bone regeneration applications [71].
Biodegradable Bone Plates and Bonding Systems (2008)
Bone plates of pure PLA are brittle with lesser mechanical properties that undergo fractures. The mechanical
strength of these plates can be significantly enhanced with
the material blend of PLA with Ecoflex, making the plates
stronger. US20080234754 concerns the development of bone
plates and a novel hot-melt adhesive polymer blend useful in
cranio-maxillofacial surgery. These plates are designed from
the polymer blend of PLA (80%) and Ecoflex (20%) [72].
Compositions Such as Cell Substrate Coated with PLGA,
and Methods for the Repair and Regeneration of Cartilage and/or Bone (2008)
WO2008086147 discusses synthesis of materials composed of a copolymer of PLA and PGA, which is useful for
the repair of bone and defects in cartilage. A chondrocyte
implant prepared on a smooth substrate yields chondrocytes
cultured to produce their own extracellular matrix. The
smooth substrate is sorbable substrate that can be molded to
fit the size and shape of the cartilage defect [73].
Stents Having Biodegradable Polymeric Layers (2008)
WO2008086369 describes the preparation of a laminate
coronary stent. In this stent bioabsorbable polymers such as
PLA Applications
Recent Patents on Regenerative Medicine 2014, Vol. 4, No. 1
47
PLA and PGA in the form of layers one above the other are
spread onto a biosorbable metals such as magnesium. The
stent is sintered to form a trilayered structure consisting of a
metal-polymer composite. Drugs such as rapamycin or Taxol
or other antirestenotic agents can be coated on any given
polymer layer or on the metal base stent itself [74].
of a polymeric matrix. A thin coating of DL-PLA (mol. wt. =
65K) is combined with everolimus at a drug-to-polymer ratio
of 1:1 in acetone [80].
Intraocular Drug Delivery Systems (2008)
US20070281117 documents the treatment of metallic
stents with gaseous species in a plasma state. The species are
polymerized and deposited in polymeric form on the metallic
stent surface. A polylactide (PLA) mixture is then applied to
the stent by conventional non-plasma deposition methods.
After applying the drug-polymer mixture on the stent, it
forms a coating and then releases the drug in a time-release
manner [81].
US20080131484 is related to PLA-based microspheres
consisting of methoxyestradiol and poly (D, L) lactide polymer, which can be administered through injection into various intraocular locations of rabbit eyes for drug delivery.
The microspheres were found to be well tolerated. Furthermore, from studies on rats, eye redness (ocular surface hyperemia) disappears within one-week after intraocular administration [75].
Sustained Release Formulations Comprising Very Low
Molecular Weight Polymers (2008)
WO2008049631 describes a semi-solid formulation
comprising of 10% BIM51077 and PLA ended with C5 alkyl-group, used for drug carrying [76].
Multilayered Composite for Organ Augmentation and
Repair (2008)
US20080081362 describes a device and methods for tissue
regeneration. The device is comprised of a bioabsorbable
scaffold of natural polymer material, bioactive glasses, ceramics, hydrogels, etc. and a pharmaceutical agent such as
analgesic, antibiotic or other anti-inflammatory. This implant
can be implanted in tissue or organs. A PGA/PLA (9:1)
composite scaffold disk is used for seeding porcine bladder
smooth muscle cells (SMC). Urothelium and smooth muscle
cells are retained in their respective scaffolds and retain their
phenotypes [77].
Method of Polishing Implantable Medical Devices to
Lower Thrombogenicity and Increasing Mechanical Stability (2008)
US7329366 patent deals with the invention of a method
for polishing an implantable medical device. It also describes
the positioning of an implantable medical device on a support. It reports the use of poly (lactic acid) (PLA) stents
without coating and with a PLA coating to check its utility
for blood compatibility [78].
Subcutaneous Implants Comprising Glycolic Acid-lactic
Acid Copolymer (2008)
WO2008015236 deals with the construction of subcutaneous implants composed of an active ingredient dispersed
in a PLGA matrix, obtained by grinding an extruded product
consisting of a blend of at least two PLGAs having different
lactic acid/glycolic acid molar ratios [79].
Use of Plasma in Formation of Biodegradable Polymeric
Stent Coating (2007)
Calcium Phosphate Polymer Composite for Bone Repair
(2007)
US20070255422 deals with the invention of a calcium
phosphate polymer composite for repairing of bone.
In this composite calcium phosphate is deposited on hydrolyzed poly (lactic acid) (PLA) yarn soaking in calcium
nitrate and ammonium orthophosphate solution at p H 12. The
yarn obtained is then coated with PCL (MW = 43 kDa) solution and finally air dried. The bone-repair composite thus
obtained functions as a mimic of bone with bending modulus
similar to that of natural mammalian bone [82].
Oil-in-oil Emulsified Polymeric Implants Containing a
Hypotensive Lipid and Related Methods (2007)
US20070224246 deals with the preparation of an intraocular implant containing bimatoprost (400 mg) and PLA
(600 mg). This implant can be inserted into the vitreous of
the eye of a glaucoma patient to reduce the symptoms of an
ocular condition of glaucoma [83].
Toughened PLA/Polyhydroxybutyrate Blends (2007)
US20070182041 is related to the fabrication of a PLA or
PLA copolymer blend with 4-hydroxybutyrate polymer
(PHB) or copolymer. This polymeric blend is tough enough
and can be easily processed into films, fibers, extruded articles, etc. It is useful as a biocompatible and biodegradable
material for various medical applications [84].
Modification of Chemical Forces of Bone Constructs for
Implants (2007)
US20070173950 deals with a method for increasing in
growth of host bones. It involves modification of a bone
graft creating an ionic gradient to form a modified bone graft
structure. It helps in enhancing the binding of growth factors
and cell cultures to the bone graft structure. The composite
comprising of PLA (50%), demineralized bone (30%) and
bone particles (20%) is modified by an oxygen plasma treatment [85].
Morphology Profiles for Control of Agent Release Rates
from Polymer Matrixes (2007)
Bioabsorbable Polymeric Drug Delivery Devices (2007)
WO2007146049 describes a method for creating a medical device having controlled release rate, which is composed
US20070162110 deals with the preparation of a bioabsorbable drug delivery device. The device is prepared using a
48 Recent Patents on Regenerative Medicine 2014, Vol. 4, No. 1
bioabsorbable polymeric material PLA/PGA using low temperature fabrication process by which bio-active agents or
drugs are incorporated into the device. The device is frequently a tubular helical stent. The delivery device thus
formed consistently releases drugs and bioactive agents
throughout its length [86].
Implanting a Disc Stabilization Device Combined with
Therapeutic Agents for Treating Degenerative Spinal
Disorders (2006)
WO2006138690 deals with implanting a disk stabilization device to administer a therapeutic agent for promoting
the healing of damaged intervertebral disks. The device not
only decreases load of the disk but also inhibits any inflammatory process. The disk stabilization device is extradiscal
stabilization or an intradiscal stabilization device. The intradiscal implant is composed of biomaterials such as PLA,
PGA, cellulose, etc. [87].
Implantable Device Comprising Amorphous Poly (D, Llactide) Coating (2006)
US20060246108 provides the preparation of an implantable device comprising of amorphous PLA (D, L) and zinc
oxide. These implantable devices can be used for multiple
applications such as treatment in hemorrhage, restenosis,
thrombosis, vascular dissection or perforation, ureter obstruction etc. [88].
Polymer Biodegradable Medical Device Formed by
MEMS Technology (2006)
US20060193892 discloses a medical device composed of
biodegradable polymer PLA, poly(butyl methacrylate,
parylene, chitosan etc. obtained by MEMS technology. The
device consists of one or more microstructures which can be
used for controlled and / or uncontrolled release of bioactive
agents like rapamycin, trapidil, taxol etc. [89].
Drug-Containing Implants and Methods of Use Thereof
(2006)
US20060159721 is related with drug containing medical
implants composed of therapeutic drug and polymer PLA or
PGA. It also provides methods for maintaining a therapeutic
level of a drug and its release at substantially linear rate.
These implants were successfully used in the treatment of
schizophrenia and other disorders [90].
Polymeric Multi-Compartment Delivery System (2006)
US20060153894 discloses the invention of a PGA/PLA
copolymer based polymeric multi-compartment delivery
system for the delivery of various bioactive agents in tissue
engineering. In addition, the delivery system may also be
used for the delivery of cells or their clusters. The devices
contained at least two compartments which were designed
independently and processed separately. The adjustment of
the compartments was done in such a way that therapeutic
released from one compartment provides some benefit to
cells hosted by another compartment to promote different
Pawar et al.
cell activities such as survival, proliferation, differentiation
etc. [91].
A Biocompatible Polymer Material and a Prosthetic Device Made Thereof for the Replacement, Repair and Regeneration of Meniscus (2006)
WO2006064025 is related with the development of biocompatible material consisting of polymer matrix of
hyaluronic acid derivatives and PLC. It also provides a process for the preparation of a prosthetic device of biocompatible material. Meniscus prosthesis was composed of a matrix
of HYAFF 11/PLC (40:60) reinforced with PLA fibers [92].
Cells (2006)
New bone or teeth are formed in vivo from a growth factor and/or stem cells contained within a hollow and porous
biocompatible vehicle. Patent WO 2006047310 is related
with microspheres of poly (DL-lactic-co-glycolic acid)
(PLGA) of 50:50 PLA/PGA ratios containing recombinant
human TGF and loaded into hollow cylindrical titanium implants capable of controlled release of biological agents [93].
Implants Made of Bioresorbable Polymeric Materials
(2006)
US20060009844 is related with an elastic implant having
a fluid-tight layer made from PLA, possessing many cavities
in fluidic connection with one another. The implant acts as a
bone replacement implant for insertion into a bone cavity or
an intervertebral implant to insert between two adjacent vertebral bodies of human or animal spine [94].
Hybrid Biologic-Synthetic Polymer Bio Absorbable Scaffolds (2005)
EP1593400 provides a method for making a threedimensional composite tissue implants. The bio prosthetic
device comprises a coating of synthetic layer of bioabsorbable fibrous material such as PLA, PGA, PCL etc. and their
polymeric blends [95].
Sustained Release Intraocular Implants Containing Tyrosine Kinase Inhibitors for Treatment of Eye Disorders
(2005)
US20050244470 deals with a medical device for the controlled release of tyrosine kinase inhibitor into eye for an
extended period of time. The implant consists of tyrosine
kinase inhibitor (TKI) and a biodegradable polymer PLGA
or PLA. The implants can be placed within eye for the treatment of ocular disorders [96].
Compressed Porous Materials Suitable for Implant
(2005)
US20050246021 is related with the manufacture of porous polymer of different PLA materials that permit the access for fluid migration through them. The material consists
of interconnected collapsed pores with good compressive
strength and permeability Fig. (5) [97, 98].
PLA Applications
Recent Patents on Regenerative Medicine 2014, Vol. 4, No. 1
49
REFERENCES
[1]
[2]
[3]
[4]
Polylactic Acid Stent Ref. No. [98]
Fig. (5). Polylactic acid stent.
CURRENT & FUTURE DEVELOPMENTS
PLA is the material of choice for the design and clinical
use of biodegradable implants. Due to its over 40 years of
safety history in various implantable devices, PLA is expected to remain the polymer of choice for future applications as long as it can fit in the application at hand. Copolymers of PLA with hydroxy alkanoic acids, predominantly
glycolic acid and caprolactone, and polyethylene glycol have
been and will be tailored for emerging applications. The review provides a brief overview on the use of PLA as biodegradable material for various implantable devices as reflected by the numerous patented inventions.
[5]
[6]
[7]
[8]
[9]
[10]
CONFLICT OF INTEREST
[11]
The authors confirm that this article content has no conflict of interest.
[12]
ACKNOWLEDGEMENTS
Declared none.
ABBREVIATIONS
[13]
[14]
PLA
=
Poly (Lactic Acid)
PGA
=
Poly (Glycolic Acid)
PCL
=
Poly Capro Lactone
[16]
PDO
=
Poly Dioxin One
[17]
PTFE
=
Poly Terta Fluoro Ethylene
GF
=
Glass Fibers
HA
=
Hydroxy Apatite
PLGA
=
Poly Lactic-co-Glycolic Acid
PEG
=
Polyethylene Glycol
[15]
[18]
[19]
BMP-2 =
Bone Morphogenic Proteins
[20]
RHLC =
Recombinant Human-like Collagen
[21]
BLM
=
Bleomycin
MMC
=
Mitomycin C
PLCG
=
PLA and Co-polymers with Glycolic Acid
[22]
Kulkarni RK, Moore EG, Hegyeli AF, Leonard F. Biodegradable
poly(lactic acid) polymers. J Biomed Mater Res 1971; 5: 169-81.
Agrawal C, Mauli, Athanasiou KA, Niederauer GG. Sterilization,
toxicity, biocompatibility and clinical applications of polylactic
acid/polyglycolic acid copolymers. Biomaterials 1996; 17(2): 93102.
Alexander H, Bajpai PK, Guastavino TD, Jenei SR. Degradation
analysis of polylactic acid (PLA)-glass fiber composites. Bioengin
Proc Northeast Conf 1987; 300-03.
Audion M, Chabot F, Christel P, Garreau H, Vert M. PGA (polyglycolic acid)-fiber-reinforced-PLA (polylactic acid) as an implant
material for bone surgery. Int Conf: Composites in Bio-Med Eng
1985; 11:1-11.
Zhou CR, Li LH. Application of novel PLA/chitosan composite
materials on bone tissue scaffolds. Aus Soc Biomater 2004; 8:
1572.
Kadiyala S, Leong KW, Lo H, Ponticiello MS, Reddi AH. Bone
induction achieved by controlled release of BMP from
PLA/hydroxyapatite foams. Trans Annu Meet Soc Biomater Int
Biomater Symp 1996; 1: 289.
Saikku-Baeckstroem A, Tulamo RM, Raeiha JE, Kellomaeki M,
Toermaelae T, Toivonen P, et al. Intramedullary fixation of cortical
bone osteotomies with absorbable self-reinforced fibrillated poly96L/4D-lactide (SRPLA96) rods in rabbits. Biomaterials 2001;
22(1): 33-43.
Vaidyanathan R, Hecht B, Studley A, Phillips T, Calvert PD, Tellis
B, et al. Resorbable polymer-ceramic composites for orthopedic
scaffold applications. Ceramic Engin Sci Proc 2004; 25(4): 529-36.
Raikin SM, Ching AC. Bio absorbable fixation in foot and ankle.
Foot Ankle Clin 2005; 10(4): 667-84.
Jadhav B, Kummer F, Lehman WB, Rohovsky MW, Strongwater
A, Tunc DC. Evaluation of body absorbable bone fixation devices.
Polymeric materials science and engineering, Proc. ACS Div Polym Mater 1985; 53:502-4.
Nanno K, Sugiyasu K, Yoshikawa H, Myoui A, Daimon T, Myoui
A. Synthetic alginate is a carrier of OP-1 for bone induction. Clin
Ortho and Rel Res 2009; 467(12): 3149-55.
Hollinger JO. Effects of a biodegradable copolymer-proteolipid on
osseous healing in rats and dogs. Trans Annu Meet Soc Biomater
Int Biomater Symp 1984; 7: 5.
Cui FZ, Zhang W, Liao SS. Hierarchical self-assembling of nanofabril of mineralized collagen for bone graft. Transactions 7th
World Biomaterials Congress, Sydney, Australia May 17-21, 2004.
Cao YL, Liu W, Cui L. Advances in cartilage engineering research.
Transactions 7th World Biomaterials Congress, Sydney, Australia
May 17-21, 2004.
Lindqvist C, Suuronen R, Haers PE, Sailer HF. Update on bioresorbable plates in maxillofacial surgery. Fac Plas Surg 1999; 15(1):
61-72.
Eppley BL. Use of resorbable plates and screws in pediatric facial
fractures. J Oral Maxillofac Surg 2005; 63(3): 385-91.
Ashammakhi N, Toermaelae P, Gonzalez AM, Jackson IT. New
resorbable bone fixation. Biomaterials in craniomaxillo facial surgery: Present and future. Eur J Plast Surg 2004; 26(8): 383 -90.
Cohen SR, Holmes RE, Cornwall GB, Kleinhenz KK, Thomas KA,
Beckett MZ. Macro pore resorbable devices in craniofacial surgery.
Clin in Plast Surg. 2004; 31(3): 393-406.
Peltoniemi HA, Kontio R, Salo A, Waris T, Lindqvist C, Graetz K,
et al. The use of bio absorbable osteofixation devices in craniomaxillofacial surgery. Oral Surg, Oral Med, Oral Patho, Oral Radio,
and Endodon 2002; 94(1): 5-14.
Khang G. Drug delivery system using polymers (lactide-coglycolide). IFMBE Proc IFMBE; 2013; 40: 258-61.
Tsuji H. Poly(lactide) stereo complexes: Formation, structure,
properties, degradation, and applications. Macromolecular Bioscience 2005; 5(7): 569-97.
Agrawal CM, Pennick A, Schenck RC, Shen X, Szygenda DM.
Protein release kinetics of a porous coated implant impregnated
with a biodegradable delivery system. Trans Annu Meet Soc Biomater Int Biomater Symp 1996; 2: 151.
50 Recent Patents on Regenerative Medicine 2014, Vol. 4, No. 1
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
Rydholm AE, Reddy SK, Bowman CN, Anseth KS, Bowman CN,
Anseth KS. Fundamental studies of degradable thiol-acrylate photopolymeric biomaterials as tissue engineering and drug delivery
scaffolds. AIChE Annual Meeting, Conf Proc 2004; 89B: 6365-7.
Saravana KR. Chitosan microspheres as potential vaccine delivery
systems. Int J Drug Del 2011; 3(1): 43-50.
Makarov C, Gotman I, Gutmanas EY, Radin S, Ducheyne P. Vancomycin release from bioresorbable calcium phosphate-polymer
composites with high ceramic volume fractions. J Mat Sci 2010;
45(23): 6320-4.
Carbajal-De LT, Espinosa-Medina MA, Ibarra-Bracamontes LA,
Perez-Reyes JC. Villagomez-Galindo M, Rubio-Rosas E. Synthesis
of biodegradable composite for knee cartilage prosthesis joint. Mat
Res Soc Sympo Proc 2011; 1376: 32-8.
Bajpai PK, Benghuzzi HA. Effect of molecular weight on the release of proteins from ALCAP ceramic capsules. Bioengin, Proc of
the Northeast Conf 1988; 96-9.
Wu B, Zheng Q, Guo X, Wu Y, Wang Y, Cui F. Preparation and
ectopic osteogenesis in vivo of scaffold based on mineralized recombinant human-like collagen loadedwith synthetic BMP-2derived peptide. Biomedical Mat 2008; 3(4): 044111.
Barker M, Bull A, Carter A, Dootson G, Fidler E, Heskin K, et al.
Development of tissue engineered meniscal cartilage implants. Annual Int Conf IEEE Engin Med and Bio - Proc 1999; 1: 111.
Vacanti JP, Choi RS, Kim BS, Riegler M, Pothoulakis C, Vacanti
M, et al. Martin Studies of brush border enzymes, basement membrane components, and electrophysiology of tissue-engineered neo
intestine. J Pedi Surg 1998; 33(7): 991-7.
Ginebra MP, Navarro M, Planell JA, Ambrosio L, Zeppetelli S.
Development and cell response of a new biodegradable composite
scaffold for guided bone regeneration. J Mat Sci: Mat in Med 2004;
15(4): 419-22.
Bakhru H, Bizios R, Ricci JL, Supronowicz PS. Analysis of osteoblast mineral deposits on three-dimensional, porous, polylactic
acid scaffolds. Trans Annu Meet Soc Biomater Int Biomater Symp
1996; 2: 848.
Zhu W, Peng Q, Qiou S, Liou Y, Zhu W. The poly(lactic acid)
degradation in vitro and in vivo and tissues responses after implanted. Transactions 7th World Biomaterials Congress, Sydney,
Australia May 17-21, 2004.
Efstathopoulos N, Giamarellos BEJ, Lazarettos J, Nikolaou V,
Tsaganos T, Koutoukas P, et al. Elution of linezolid by a polylactic
acid local antimicrobial delivery system. J Bone Joint Surg Br
2009; 91B, Supp I 129.
Erdohan ZO, Cam B, Turhan KN. Characterization of antimicrobial polylactic acid based films. J Food Engin 2013; 119(2): 30815.
Jin T, Niemira BA. Application of polylactic acid coating with
antimicrobials in reduction of Escherichia coli O157: H7 and Salmonella stanley on apples. J Food Sci 2011; 76(3): M184-8. doi:
10.1111/j.1750-3841.2011.02052.x.
Kyoung-Nam K, Woo-Hyun K, Sang-Bae L, Seung-Kyun M,
Kwang-Mahn K, Kyoung-Nam K, et al. The release behavior of
CHX from polymer-coated titanium surfaces. Surf Interf Ana 2008;
40(3-4): 202-4.
Araki H, Tani T, Kodama M. Antitumor effect of into polylactic
acid. Artif Organs 1999; 23(2): 161-8.
Aikou T, Fukuzaki H, Kumanohoso T, Nakamura K, Natsugoe S,
Sagara M, et al. Drug distribution and antitumor effect of bleomycin incorporated in poly DL-lactic acid in rats. Jap J Can and Chemoth 1994; 21(13): 2248 -50.
Juha L, Antero H, Virpi T, Martti ALA-Opas, Martti T, Tero V,
et al. New bioabsorbable polylactide ureteral stent in the treatment
of ureteral lesions: An experimental study. J Endouro 2009; 13(2):
107-12.
Martti A-O, Antero H, Juha L, Virpi T, Martti T, Pentti T, et al.
New bioabsorbable polylactide ureteral stent in the treatment of
ureteral lesions: An experimental study. J Endouro 1999; 13(2):
107-12.
Subbarao WV. Multipurpose microcoded controllers for implanted
electronic systems. Southcon Conf Record 1986; 7(2): 1-7.
Pawar et al.
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
Sasken HF, Thatcher GL, Yoklavich MF. Vessel healing response
to bioabsorbable implant. Trans Annu Meet Soc Biomater Int Biomater Symp 1996; 1: 589.
Feng M, Han J, Sun Q, Hou Z, Zhang Q. Preparation and evaluation of implantable chitosan-collagen-soybean phosphatidylcholine
film impregnated with mitomycin C-PLA-nanoparticles. 3rd International Conference on Bioinformatics and Biomedical Engineering Sydney, Australia June 11-13, 2009.
Prosser L, Agrawal CM, Polan J, Elliott J, Adams, DG, Bailey SR,
Bailey SR. Implantation of oxygen enhanced, three-dimensional
microporous L-PLA polymers: A reproducible porcine model of
chronic total coronary occlusion. Catheter Cardio Interven 2006;
67(3): 412-6.
Alexander H, Gona AG, Parsons JR, Ricci JL. Dynamics of tendon
cell growth on synthetic fiber materials in vitro. Trans Annu Meet
Soc Biomater Int Biomater Symp 1984; 7: 298
Isele U, Matschke C, Van HP, Fahr A; Matschke. Christian sustained-release injectables formed in situ and their potential use for
veterinary products. J Control Rel 2002; 85(1-3): 1-15.
Sambusseti, A. Improved absorbable patch, in reinforced PGA, for
the replacement of a portion of bladder wall following partial cystectomy. WO2013135544 (2013).
Mohapatra, S., Mohapatra, S.S., Davis, Y.K., Wang, C. Threedimensional fibrous scaffolds for cell culture. US20130224860
(2013).
Ravis, W.R., Lin, Y.-J. Buprenorphine nanoparticle composition
and methods thereof. WO2013126552 (2013).
Detamore, M., Berkland, C., Mohan, N., Gupta, V., Mchugh, P.,
Lohfeld, S. Scaffolding biomaterials based on polymer-coated
high-stiffness particles. WO2013116736 (2013).
Marsh, D.A., Rivers, H.M. Time released biodegradable or bio
erodible microspheres or micro particles suspended in a solidifying
depot-forming injectable drug formulation. US20130189369
(2013).
Song, J., Kutikov, A. Elastomeric and degradable high-mineral
content polymer composites. WO2013044078 (2013).
Tessmar, J., Esser, E., Bluecher, L., Milbocker, M. Composite
polylactic acid/alginate surgical barrier. US20130052236 (2013).
Folan, M., Horgan, F., Turkington, M. Drug elution medical device. US20130018258 (2013).
Sung, H.-W., Liao, Z.-X., Chung, M.-F., Chen, K.-J., Tu, H. Pharmaceutical composition of nanoparticles. US8318198 (2012).
Sambusseti, A. Hemisphere for bladder expansion in patients with
low compliance. WO2012123272 (2012).
Dejardin, L. Orthopedic cage. WO2012075349 (2012).
D’Agostino, J.A., Watterson, A. Implantable polymer for bone and
vascular lesions. WO2012054742 (2012).
Hurtado, A., Gilbert, R.J., Wang, H.B., Cregg, J.M., Mullins, M.E.,
Oudega, M. Three-dimensional scaffolds, methods for fabricating
the same, and methods of treating a peripheral nerve or spinal or
spinal cord injury. WO2011123798 (2011).
Shetty, D.S., Chun, I., Vyakarmam, M.N., Hyland, T.P. Thick
foams for biomedical applications and methods of making.
WO2010117824 (2010).
Giammona, G., Pitarresi, G., Palumbo, F., Romano, C.L., Meani,
E., Cremascoli, E. Antibacterial hydrogel and use thereof in orthopedics. WO2010086421 (2010).
Timmer, M., Yang, C., Volpe, C.G., Hammer, J.J., Shetty, D.,
Keeley, D.J. Donners: Biocompatible fiber based device for guided
tissue regeneration. WO2010077520 (2010).
Rasal, R.M., Hirt, D.E. Copolymer including polylactic acid,
acrylic acid and polyethylene glycol and processes for making the
same. WO2010056421 (2010).
Downes, S., Terenghi, G., Sun, M., Kingham, P. A peripheral nerve
growth scaffold which includes poly-epsilon-caprolactone (PCL).
GB2463861 (2010).
Downes, S., Terenghi, G., Sun, M., Kingham, P. Medical device.
WO2010029295 (2010).
Barnett, A.R., Gearhart, K.N., Lichti, J., Reyes, P.T., Sarasam,
A.R. Implantable medical device coatings with biodegradable elastomer and releasable taxane agent. WO2010021757 (2010).
PLA Applications
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
Simpson, D.G., Bowlin, G.L., Mahajan, R., Ayres, C., Bowman,
J.R., Newtom, D. Methods and compositions for manipulating electro processed scaffold material properties using cross-linking and
fiber tertiary structure. WO2009149181 (2009).
De, J.E., Reich, C.J., Boyd, S., Sierra, D., Alejandro, J.D. Corneal
on lay devices and methods. WO2009146151 (2009).
Hammer, J.J., Shetty, D.D., Sridevi, W.Z. Optimum density fibrous
matrix. US20090148495 (2009).
Chopra, B., McKenzie, G., Hardwick, B. Osteogenic compounds.
WO2009016333 (2009).
McCarthy, S., Weinzweig, J. Novel biodegradable bone plates and
bonding systems. US20080234754 (2008).
Pomahac, B. Compositions and methods for the repair and regeneration of cartilage and/or bone. WO2008086147 (2008).
McClain, J.B., Taylor, D., Rabiner, R. Stents having biodegradable
layers. WO2008086369 (2008).
Robinson, M.R., Blanda, W.M., Hughes, P.M., Ruiz, G., Orilla,
W.C., Whitcup, S.M. Intraocular drug delivery systems.
US20080131484 (2008).
Cherif-Cheikh, R., De Sousa, D.A.-P., Lacombe, F., Lachamp, L.,
Bourissou, D. Sustained release formulations comprising very low
molecular weight polymers. WO2008049631 (2008).
Keeley, D., Shetty, D., Dhanaraj, S., Wang, Z. Multilayered composite for organ augmentation and repair. US20080081362 (2008).
Gale, D.C., Hossainy, S.F.A. Method of polishing implantable
medical devices to lower thrombogenecity and increase mechanical
stability. US7329366 (2008).
Mauriac, P., Marion, P. Subcutaneous implants releasing an active
principle over an extended period of time. WO2008015236 (2008).
Syed, F.A.H., Fuh-Wei, T., Lothar, K., Thierry, G., Yiwen, T.,
Wouter, R., Stephen, P., Gina, Z., Yung-Ming, C., Andrew, F.M.,
Sean, A.M., Brandon, J.Y. Morphology profiles for control of agent
release rates from polymer matrices. WO2007146049 (2007).
Kaplan, S.L., Ruane, P.H., Lang, E.A., Kimura, T. Use of plasma
in formation of biodegradable stent coating. US20070281117
(2007).
Wei, M., Olson, J.R., Shaw, M.T. Calcium phosphate polymer
composite and method. US20070255422 (2007).
Hughes, P.M., Boix, M., Sarrazin, C., Do, M. Oil-in-oil emulsified
polymeric implants containing a hypotensive lipid and related
methods. US20070224246 (2007).
Recent Patents on Regenerative Medicine 2014, Vol. 4, No. 1
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
51
Rizk, S., Martin, D.P., Ho, K., Ganatra, A., Williams, S.F. Toughened poly lactic acid polymers and copolymers. US20070182041
(2007).
Zanella, J.M., Haddock, S.M., Taylor, C.E., Kitching, K.J. Modification of chemical forces of bone constructs. US20070173950
(2007).
Dave, V.B. Bio absorbable drug delivery devices. US20070162110
(2007).
Hunt, M.M., Hooper, D., Meunier, A., Jara-Alamonte, J. Improved
method of treating degenerative spinal disorders. WO2006138690
(2006).
Pacetti, S.D., Hossainy, S.F.A, Gale, D.C. Amorphous poly(D,Llactide) coating. US20060246108 (2006).
Furst, J.G., Brodbeck, W.G. Polymer biodegradable medical device. US20060193892 (2006).
Siegel, S., Winey, K. Drug-containing implants and methods of use
thereof. US20060159721 (2006).
Ghabrial, R., Fung, R., Rezania, A., Davis, J.E. Multi-compartment
delivery system. US20060153894 (2006).
Pastorello, A., Ambrosio, L., Tafuri, G., Pavesio, A. A biocompatible material and a prosthetic device made thereof for the replacement, repair and regeneration of meniscus. WO2006064025 (2006).
Mao, J. Hollow and porous orthopedic or dental implant that delivers a biological agent. WO2006047310 (2006).
Bloemer, W., Beger, J., Fink, U., Wagner, C. Implant for insertion
into a bone cavity or between vertebral bodies. US20060009844
(2006).
Malaviya, P., Orban, J.M., Jenks, P.J., Whalen, T. Hybrid biologicsynthetic bio absorbable scaffolds. EP1593400 (2005).
Hughes, P.M., Malone, T.C., De Vries, G.W., Edelman, J.L.,
Chang-Lin, J.-.E., Shiah, J.G., Nivaggioli, T. Sustained release intraocular implants containing tyrosine kinase inhibitors and related
methods. US20050244470 (2005).
Ringeisen, T.A., Turner, A., Demeo, J., Hearn, P.E., McDade, R.L.
Compressed
porous
materials
suitable
for
implant.
US20050246021 (2005).
Dissolvable
stents
from
Abbott
laboratories.
http://gizfactory.com/article/dissolvable-stents-from-abbottlaboratories (Accessed on: April 3, 2014).