Flowable placental connective tissue matrices for tendon repair: A review

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Introduction/background
Tendon disorders have become increasingly common and account for a substantial portion of musculoskeletal injuries [1][2][3][4].The number of people affected by tendinopathies and subsequent tendon tears is rapidly increasing [5].This is attributed to the combined effects of population growth and aging as well as increased participation in extreme/competitive sports.The magnitude of treating these injuries presents a major clinical and fi nancial burden to modern medicine [6].
After the injury, the mechanical competence of the native tendon is never restored.The healed tissue is burdened by the formation of adhesions, which disrupt the Extracellular Matrix (ECM) and increase the risk of further degeneration and rupture [7].Even after surgical repair, the tendon is predisposed to re-rupture [8].Thus, researchers and clinicians are interested in new methods to augment tendon repair.While exogenous scaffolds have shown promise [9][10][11], Flowable Placental Connective Tissue Matrices (FP-CTMs) have gained increasing interest [12].Like non-fl owable scaffolds, FP-CTMs provide structural and biochemical ECM components.In contrast with their non-fl owable counterparts, FP-CTMs offer the added benefi ts of minimal invasiveness and the capacity to fi ll irregular spaces.Clinicians are considering the use of FP-CTMs for the treatment of tendinopathy/tendinitis [13][14][15] as well as the surgical repair and reconstruction of periarticular soft tissues [12].Within, tendon biology, pathology, healing, and current treatment modalities are presented, followed by a review of the clinical application of FP-CTMs for tendon repair.A comprehensive literature search was performed to identify the available clinical evidence.Specifi cally, the PubMed database was queried for the terms: "placental tissue matrix," "micronized," "human," and "tendon."Inclusion criteria included studies reporting on the use of FP-CTMs for tendon repair, clinical outcomes, and human subjects.Exclusion criteria included animal data, basic science studies, review articles, and non-English language literature.A date range was not defi ned.This review uniquely demonstrates the gaps in the literature as well as potential directions for future work relative to the application of FT-CTMs for tendon repair.

Tendon structure and function
Tendons are comprised of dense fi brous connective tissue, which connects muscle to bone.The interface where the tendon attaches to the muscle is known as the myotendinous junction, and the interface where it attaches to the bone is known as the osteotendinous junction or enthesis (Figure 1).The primary function of a tendon is to transmit forces produced by a muscular contraction to the skeletal system to enable movement.Tendons have higher tensile strength compared with muscle, which enables them to withstand signifi cant amounts of tension and protect the muscle from external forces [16].The ECM of tendons is composed of collagen, elastin, proteoglycans, and glycoproteins (Figure 2) [17].Collagen is the most abundant molecule in the ECM, accounting for 60% to 85% of the dry weight of the tissue [18].Type I collagen fi bers are organized along the long-axis of the tissue, which affords tendons excellent uniaxial mechanical strength [19], although there are small amounts of type II collagens in the epitenonium/ endotenonium and type III collagens in the fi brocartilaginous areas of the osteotendinous junction [16].The organization of the tendon is hierarchical; collagen fi brils join together to form collagen fi bers, which join together to form bundles, the bundles join together to form fascicles, and fi nally, the fascicles join together to form the whole tendon (Figure 1).The epitenon and endotenon are connective tissue sheaths, which permit smooth movements against adjacent structures and provide blood vessels, lymphatics, and nerves.The epitenon surrounds each tendon, and the endotenon encloses fi bers.The elastic fi bers contain elastin, which is responsible for the extensibility of the tendon [20].Interspersed throughout the collagen hierarchy, there are non-collagenous matrix components, commonly grouped into proteoglycans, glycoproteins, and glycoconjugates [19].Proteoglycans are responsible for the viscoelastic properties of the tendon.There are two predominant proteoglycans in tendons: decorin, a member of the small leucine-rich proteoglycan (SLRP) family accounting for approximately 80% of the total proteoglycan content in tendons, and versican, a large aggregating proteoglycan [21].
There are two specialized fi broblast cells in tendon tissue: tenoblasts and tenocytes.They comprise 90% to 95% of the cells within the tendon.Chondrocytes, synovial cells, and vascular cells make up the remaining 5% to 10% [24].
Tenoblasts are immature tendon cells with an ovoid shape.As they mature, they transform into tenocytes with an elongated spindle shape [16].Tenocytes are responsible for maintaining and synthesizing the components of the ECM and are intimately involved in tendon repair.Tenocytes respond to mechanical loading through the modulation of the ECM [25].Loading, therefore, is essential to tendon homeostasis, but can also readily promote remodeling or degeneration [26].Exposure to elevated mechanical stresses can place tendon tissues at risk of damage, and overloading is widely considered a causative factor in the onset of tendon injuries [26].

Tendon pathology
Tendon injuries are common disorders of the musculoskeletal system that are associated with considerable pain and disability, affecting both the athletic and general populations [27][28][29][30][31]. Tendon injuries often occur secondary to overuse, traumatic injury, or intrinsic age-related degeneration.Tendon injuries can be classifi ed into one of two groups: acute or chronic.Acute injuries occur instantaneously, whereas chronic injuries develop over time.
The terminology and defi nitions relating to tendon injury are ever-changing [32].Generally, the term "tendinopathy" describes a broad spectrum of tendon pathologies that are associated with pain, swelling, and impaired function [33][34][35].
It is often used to describe a chronic tendon injury in the absence of a partial or complete tear.The term "tendinitis" describes tendon pathology that has an infl ammatory component [32].
The term "tendinosis" describes a tendon with impaired tendon healing, devoid of infl ammatory cells.Tendon "tears" or "ruptures" refer to the separation of the tendon from the tissue to which it is attached.Spontaneous tendon tears occur without prior symptoms.
Tendinopathy has a multifactorial etiology, arising from biological and lifestyle-related factors as well as the use of pharmacologic agents.Like others, Steinmann and colleagues [36] grouped risk factors for chronic tendon pathology into three buckets: 1) mechanical overuse; 2) intrinsic factors (i.e., acting from within the body); and 3) extrinsic factors (i.e., acting on the body) (Figure 3).The onset of tendinopathy is often associated with a mechanical event, such as overuse or overloading.However, there is variation in how much load an individual can endure before developing tendinopathy.
Likewise, the treatments required for recovery vary by individual.Identifying and understanding the risk factors may assist in understanding the progression of this multifaceted disease.
In a 2009 review, Cook and Purdam introduced a continuum model of tendinopathy [37].This model suggests that in response to an excessive load (i.e., volume, intensity, frequency), tendons enter a pathologic continuum that consists of three continuous stages: 1) reactive tendinopathy; 2) tendon disrepair (i.e., failed to heal); and 3) degenerative tendinopathy.
According to Cook and Purdam, adding or removing load moves  [36] suggest that risk factors can act as triggers, predisposing the tendon to injury and impairing proper tendon healing.In their model, a tendon in the early reactive tendinopathy stage still possesses the capacity for healing.However, as risk factors increase, the tendon enters a state of disrepair, and eventually, tendon degeneration occurs.The tendon undergoes structural and compositional changes with alterations in biology and biomechanics.Cell-to-cell and cell-to-matrix communication are distorted, disrupting the organization of the ECM, making the tendon prone to further injury and tendon rupture [36].The rate of progression through the various stages of tendinopathy is unknown and is likely infl uenced by various risk factors, such as age, gender, biomechanics, activity level, and nutritional habits [36].

Incidence of tendon tears
Although there are almost 4,000 tendons in the human body, certain tendons are more prone to rupture than others (Table 1).
The rotator cuff experiences more tendon tears than any other tendon in the human body [38].Rotator cuff tears are multifactorial in origin, often a combination of age-related and degenerative changes from micro-and macro-trauma [39].For example, 13% of individuals in their fi fties [40] and 50% of individuals in their eighties experience a rotator cuff tear [41].The Achilles tendon, the largest and strongest tendon in the human body, is the most common tendon to rupture in the lower extremity [42].Rupture of the Achilles tendon most commonly affects middle-aged men, who participate in sports [43][44][45].The third most common group of tendons to rupture are the fl exor and extensor tendons of the hand and wrist.Injury to the fl exor and extensor tendons of the hand and wrist most commonly occurs in males between the ages of 20-29 years of age.Twenty-fi ve percent of these injuries are work-related, most commonly occurring in construction and extraction occupations [46].

Tendon healing
The natural process of tendon healing is slow and ineffective.The hypovascular and hypocellular nature of tendons limits their intrinsic capacity for healing [47].Existing degenerative pathology and repetitive injury cause excessive infl ammation, further impairing the healing process [48].Even when a tendon successfully progresses through the healing cascade, the result is a mechanically and histologically inferior tendon compared with its native counterpart [11].
The initial infl ammatory stage begins with a vascular and cellular response to injury.Vascular permeability increases, followed by an infl ux of red blood cells, white blood cells, and platelets.The invading infl ammatory cells secrete a variety of cytokines and growth factors throughout the healing cascade.Initially, proinfl ammatory InterLeukin-6 (IL-6) and Interleukin 1 Beta (IL-1) are released, and later, in the reparative stage, Transforming Growth Factor Beta (TGF-), Platelet-Derived Growth Factor (PDGF), Vascular Endothelial Growth Factor (VEGF), and basic Fibroblast Growth Factor (bFGF) are released [50].During the infl ammatory stage, macrophages and tenocytes are recruited to the site of injury.Macrophages digest necrotic materials, and tenocytes are activated and begin proliferating.The release of angiogenic factors also initiates the formation of a vascular network in the healing tissue [51].In normal healing, the infl ammatory phase lasts between 3 and 7 days.During the proliferative stage, also known as the reparative stage, tenocytes synthesize ECM components, including proteoglycans and collagen.The collagen is primarily type III collagen in random organization [52].The formation of granular tissue, neovascularization, and epithelialization are the notable characteristics of the proliferative stage, which lasts for several weeks.
The remodeling stage begins 6 to 8 weeks after injury and can take more than a year to complete [52].During the remodeling phase, the collagen reorganizes along the longitudinal axis of the tendon, thereby restoring tendon stiffness and tensile strength.In addition, tenocytes synthesize and degrade the ECM, replacing the mechanically inferior type III collagen with type I collagen.The ECM continues to mature as collagen fi bril crosslinking occurs, and the tissue gains biomechanical strength.However, successful restoration of native tendon structure and function does not occur due to the formation of scar tissue.
Previous reports have suggested that there are two cellular mechanisms of tendon healing, known as intrinsic and extrinsic healing [49].Intrinsic healing occurs with the proliferation and migration of tenocytes from the epitenon and endotenon, preventing the formation of adhesions [53].Extrinsic healing, on the other hand, occurs with the invasion of cells from outside the tendon [53].Although these mechanisms were once believed to be independent of one another, researchers now believe that they must be balanced to optimize tendon healing [53].

Treatment of tendon injuries
The treatment of tendon injuries is conservatively focused.
Although both NSAIDs and corticosteroid injections provide short-term pain relief, long-term NSAIDs are discouraged, due to the associated risks, including gastrointestinal toxicity, renal damage, and increased cardiovascular risk [56,57], and corticosteroid injections have shown no intermediate or longterm benefi t [58,59].Additionally, there is evidence to suggest that corticosteroids may predispose tendons to rupture, especially in weight-bearing joints [60].Surgical intervention is often not recommended until conservative treatment options have been exhausted [61].Even with surgical repair, however, clinical outcomes are less than optimal with reported re-tear rates as high as 94% [8].
For this reason, many biological treatments have been suggested for the management of tendon injuries (Table 3) [61].Flowable placental connective tissue matrices represent a promising solution.The fl owable ECM-like material is designed to fi ll the defi cits within the tendon, facilitate cellular attachment and proliferation, attenuate the infl ammatory response, and limit adhesion formation [12].

FP-CTMs
Flowable placental connective tissue matrices are sourced from various placental tissues, such as the amniotic membrane, the chorionic membranes, the umbilical cord, or a combination of these sources.Placental tissues possess anti-infl ammatory [62][63][64][65], anti-bacterial [66][67][68][69][70], anti-viral [68,69], antifi brotic [62,68,71], and immunomodulatory properties [72,73] that are innate to healing (Table 4).In addition to their wellrecognized biological properties, placental tissue also has notable mechanical properties, including elasticity, stiffness, and tensile strength [74].The placenta has a collagen-rich ECM and contains key bioactive molecules, such as fi bronectin, laminin, Glycosaminoglycans (GAGs), and elastin, which contribute to its biomechanical properties [75].The presence of elastin and type III collagen gives the tissue its elasticity; the presence of elastin and interstitial collagens (types I and II), its stiffness; and the lattice-like orientation of collagen bundles, its mechanical strength.The structure of the placental ECM is presumed to promote cell attachment, proliferation, differentiation, epithelialization, and other aspects of healing [76][77][78].Despite extensive research documenting the inherent ability of placental tissue to aid in healing, the acquisition and processing of the tissue are constantly evolving, and differences in tissue source and processing have the potential to infl uence both the biological and mechanical properties of the tissue.
Following stringent donor screening and selection, the tissue is procured and processed.Manufacturers sterilize and preserve the tissue to minimize the risk of disease transmission and to allow prolonged storage, respectively.Tissue preservation is often achieved using one of several preservation methods, most commonly through cryopreservation, drying, or lyophilization [66].Although these conventional preservation techniques render the amniotic epithelial cells nonviable, the sterilization process is incomplete as evidenced by immunogenic responses in non-decellularized AM [79,80].Consequently, removing the cellular content from natural tissue-derived matrices has been suggested to promote healing, and integration with host tissues, and to avoid rejection [81].
Endogenous cells are a contaminant and have the potential to induce host reactivity, including an immune reaction and infl ammation, leading to implant rejection.Decellularization is a process whereby endogenous cells, cell debris, and Deoxyribonucleic Acid (DNA) remnants are removed to prevent an immune response while retaining the natural structural and chemical elements of the ECM [82].Decellularization occurs through mechanical, enzymatic, and chemical means, although it is not rigidly defi ned [81].As with the preservation of tissue, decellularization can also affect the structures and entities within the ECM.Therefore, a successful preservationdecellularization protocol must be designed to delicately balance the removal of cellular material as well as retain the innate properties and functional characteristics of the ECM [81][82][83].This balance, however, is particularly elusive and is dependent upon tissue source and application.

Commercially available FP-CTMs
Commercially available FP-CTMs are sourced from various placental tissues and are subjected to different processing methodologies (Table 5).The products listed in Table 5 4A).AmnioFix® is a micronized dehydrated human amnion/chorion membrane allograft that also retains ECM proteins, growth factors, cytokines, and other specialty proteins of the placenta.Both products are manufactured using a selective membrane of reparative and reconstructive tissue (SMR 2 T™) technology and patented PURION® processing.
According to the manufacturer, the PURION® process involves the gentle separation of placental tissue layers, cleaning, and tissue reassembly, followed by dehydration of the tissue [86].During this process, blood components are removed, and the ECM remains intact [86].BioRenew TM (B-CTM) is an all-natural placental tissue treatment that retains powerful growth factors, cytokines, collagens, tissue inhibitors of metalloproteinases, and bioactive molecules known to modulate the immune system [87,88] (Figure 4B).Interfyl® (I-CTM) is an allogenic decellularized particulate human FP-CTM consisting of natural human structural and biochemical ECM components [12,62] (Figure 4C & 4D).Contrary to the other FP-CTMs, the decellularization process removes residual cells, cell debris, growth factors, and cytokines, while retaining an ECM structure with high collagen content and key bioactive molecules, such as fi bronectin, laminin, GAGs, and elastin [75].

In vitro research supporting FP-CTMs in tendon repair
In 2022, Moreno and colleagues [64] conducted an in vitro investigation to evaluate the effects of micronized dehydrated Human Amnion/Chorion Membrane (μdHACM, MiMedx, Marietta, GA) on the infl ammatory environment and hypervascularity associated with tendinopathy.Treatment with μdHACM was found to neutralize proinfl ammatory cytokines and proteases and regulate angiogenesis.These fi ndings suggest that μdHACM may reduce the infl ux of infl ammatory cells, attenuate infl ammation, and improve ECM restoration, • Dried • Terminally sterilized with e-beam irradiation Yes, using an osmotic shock followed by a mild detergent treatment [62] Citation: Protzman  which may give rise to a more structurally sound tendon.While encouraging, additional in vivo study is necessitated.
Our research group recently published an in vitro investigation, evaluating the direct interaction between tenocytes and FP-CTMs.The study compared three human FP-CTMs to determine which interacted more favorably with human tenocytes [20].The FP-CTMs included 1) A-CTM, a minimally manipulated, non-viable cellular particulate; 2) B-CTM, a liquid matrix; and 3) I-CTM, a decellularized fl owable particulate.Readouts included tenocyte adhesion and proliferation, cell migration, phenotype maintenance, and infl ammatory response.In line with the hypothesis, the study demonstrated that I-CTM, the decellularized FP-CTM, provided a more cell-friendly matrix to support tenocyte function.Although tenocyte attachment was signifi cantly higher on A-CTM, I-CTM supported greater tenocyte proliferation.In addition, I-CTM signifi cantly increased tenocyte migration, whereas A-CTM was comparable to the control.The presence of I-CTM also prevented the loss of the tenocyte phenotype and attenuated the infl ammatory response [20].These fi ndings demonstrate that the direct interaction of tenocytes with FP-CTMs positively modulates the tendon repair environment.
Collectively, the results from these two in vitro reports show promise for the use of FP-CTMs in the treatment of tendon injuries.However, the latter report also suggests that the decellularization of placental tissue may enhance the regulation of infl ammatory processes by human tenocytes.Although decellularization is performed to reduce immune response, the process of removing the cellular components can affect the structures and entities within the ECM, disrupting its functional characteristics [1,6,17].However, it appears as though the decellularization of I-CTM balances the removal of cellular content with the retention of necessary regulatory proteins.This is evident based on I-CTM attenuating the infl ammatory response beyond that of other non-decellularized FP-CTMs [62].More research is needed to determine if the observations are in fact due to decellularization or to other differences in tissue processing.Moreover, the clinical translation of these fi ndings remains to be understood.

In vivo application of FP-CTMs
A comprehensive literature search was conducted to identify studies evaluating the clinical application of FP-CTM for tendon repair [13][14][15] (Table 6).
In 2015, Lullove published a pilot study reviewing ten patients who received a fl owable placental tissue matrix injection (Human Regenerative Technologies LLC, Redondo Beach, CA) to treat tendon or muscular injuries of the lower extremity [13].These included posterior tibial tendonitis, peroneal tendonitis, anterior tibial tendonitis, extensor muscles of the foot, plantar musculature of the foot, excluding the plantar fascia, and Achilles tendonitis.Ultrasound guidance was used to target the site of injury when administering the injection.Outcome measures included pain and ultrasound evaluation of the tendon/muscle at four and six weeks.By week four, 8/10 patients reported no pain, and by week fi ve, all patients were pain-free.No adverse events or side effects were reported.No standard of the care treatment group was included for comparison.
In 2017, Gellhorn and Han reported a case series to evaluate the use of μdHACM allograft injection (MiMedx, Marietta, GA) for the treatment of tendinopathy or arthritis [15].Forty patients were included; 20 were treated for tendon pathology and 20 for joint pathology.All patients received an ultrasoundguided injection of μdHACM.Outcomes measures included pain and function, which were measured at 1, 2, and 3 months after the injection.Statistically signifi cant reductions in pain and statistically signifi cant improvements in function were observed.Localized pain at the injection site was common, but no other adverse events or side effects were reported.From this, the authors conclude that μdHACM injection is clinically effective in reducing pain and improving function.
And most recently, in 2020, a retrospective case series was published by Spector and colleagues evaluating μdHACM allograft injection (MiMedx, Marietta, GA) as a treatment for Achilles tendinopathy.Patients were seen twice after the injection within a 45-day observation window.The examined outcome variables included changes in the reported level of pain and treatment-associated adverse events.In the 45-day period, 66% of patients reported complete symptom resolution, while the remaining patients reported symptom improvement without complete resolution.After injection, there were two patients who reported muscle tightness.

Summary & next steps
Placental tissues offer vast clinical utility due to their unique structure, low immunogenicity, and biological properties.The amniotic membrane (AM) of the placenta was fi rst used as a biomaterial for surgical reconstruction in 1910 as a substrate for skin transplantation [89].However, only fresh AM was available at that time, which was diffi cult to obtain and carried a risk of disease transmission.Several decades later, with the introduction of better tissue processing techniques and preservation methods, placental tissue has regained popularity and is now used in several specialties, including wound and skin care [12], ophthalmology [90], gynecology [66], and orthopedics [91].
In this report, the literature was reviewed to better understand the clinical application of FP-CTMs in the setting of tendon repair.While the use of FP-CTMs is expanding [91][92][93][94], there is a paucity of clinical data evaluating its application in the treatment of tendon pathology.Three studies were identifi ed that used an FP-CTM injection for the treatment of tendonitis/tendinopathy [13][14][15].Although the results from these studies demonstrate the safety and effi cacy of FP-CTM injection, all three studies are retrospective case series (level IV) that reviewed the results of a single investigator.To systematically evaluate the safety and effi cacy of FP-CTMs in tendon healing, a prospective clinical trial is needed.
Prior evidence suggests that differences in processing methodology could infl uence the direct interaction between tenocytes and FP-CTMs [4,62], potentially causing variation in clinical outcomes.Two of the three clinical case series evaluated the injection of AmnioFix® for the of tendinopathy [14,15], whereas the pilot study from 2015 evaluated the use of PX50® (Human Regenerative Technologies LLC, Redondo Beach, CA).PX50® and DX100® are the fl owable forms of BioRenew® PTM TM therapy [95].All three studies reported statistically signifi cant reductions in pain [13][14][15], and the two studies evaluating AmnioFix® reported statistically signifi cant improvements in function [14,15].Both products evaluated are thought to retain ECM proteins, growth factors, collagens, and bioactive molecules found in human placental tissues [84,85,87].To date, no clinical research studies have evaluated the use of a decellularized FP-CTM to augment tendon healing.This is an important next step, as in vitro evidence suggests that decellularization of the placental tissue may improve tenocyte function and phenotype maintenance and also attenuate the infl ammatory response [62].
Two clinical applications have been suggested for the use of FP-CTM in tendon repair [12][13][14][15].The fi rst is for the treatment of tendinitis/tendinopathy with an ultrasound-guided injection [13][14][15].The second is an injection directly into the tendon or tendon sheath during the surgical repair of ruptured tendons.At this time, the available clinical evidence is limited to the former method.Additional clinical research is needed to evaluate the outcomes associated with the surgical repair of the ruptured tendon using FP-CTMs.

Figure 1 :
Figure 1: Tendon anatomy and organization.The interface where the tendon attaches to the muscle is known as the myotendinous junction, and the interface where it attaches to the bone is known as the osteotendinous junction or enthesis.Tendons have a hierarchical structure.As shown, collagen molecules assemble to form subunits of increasing diameter: tropocollagen, fi brils, fi bers, bundles, and fascicles.The fi gure is used with permission from the original publisher.'Drug Design, Development, and Therapy 2018 12 591-603' Originally published by and used with permission from Dove Medical Press Ltd [96].

Figure 2 :
Figure 2: Schematic representation of tendon extracellular matrix components.Tendon extracellular matrix components include collagen, elastin, and proteoglycans and glycoproteins, such as SLRPs and COMP.In addition, the interaction between the tendon extracellular matrix and cellular signal transduction is shown.The fi gure is used with permission from the original publisher.'Drug Design, Development, and Therapy 2018 12 591-603' Originally published by and used with permission from Dove Medical Press Ltd [96].Abbreviations: COL1A1, Collagen, type I, Alpha 1; COL1A2, Collagen, type I, Alpha 2; COMP, Collagen Oligomeric Matrix Protein; SLRP, Small Leucine-Rich Proteoglycan; TGFβ, Transforming Growth Factor Beta.

Figure 3 :
Figure 3: Schematic representation of tendinopathy pathogenesis.Individual risk factors may predispose a tendon to injury and impair tendon healing, resulting in degeneration and ultimately, tendon rupture.Tendons in the early reactive tendinopathy still possess the capacity to heal.Accumulation of risk factors leads to tendon disrepair and eventually tendon degeneration.Tendon degeneration is associated with structural and compositional changes, making the tendon more prone to further injury and rupture.The fi gure is adapted with permission from Steinmann et al. 2020 [36] and is based on the work of Cook & Purdham, 2009 [37], Shearn et al. 2011 [97], and Steinmann et al. 2020 [36].Abbreviations: MMPs, Matrix Metalloproteinases.

Figure 4 :
Figure 4: Commercially available FP-CTM products.Three commercially available human FP-CTM products are shown: (A) a minimally manipulated, non-viable cellular tissue matrix; (B) a liquid placental tissue treatment; and (C & D) a decellularized particulate.Abbreviations: FP-CTM, Flowable Placental Connective Tissue Matrix.
, additional clinical research is needed to more fully assess the safety and effi cacy of FP-CTMs in this application.Once the safety and effi cacy have been demonstrated, additional randomized, controlled trials are needed to determine if this treatment strategy improves clinical outcomes both in the treatment of tendinosis and tendon tears. 4

Table 1 :
Incidence of tendon tears.

Table 3 :
Biomaterials for the treatment of tendon injury.

Table 4 :
Innate healing properties of placental tissue.