J Orthop Translat.

2019 Apr ; 17 : 64–72 . department of the interior :10.1016/j.jot.2019.03.005

PMCID:

PMC6551357

PMID : 31194062

Translation of bone wax and its substitutes: History, clinical status and future directions

, a, hundred, e, ∗☆, b, ☆, five hundred, a and a, b-complex vitamin, vitamin e, ∗∗

Huan Zhou

aCenter for Health Science and Engineering, Tianjin Key Laboratory of Materials Laminating Fabrication and Interface Control Technology, School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China cSchool of Mechanical Engineering, Jiangsu University of Technology, Jiangsu 213001, China eInternational Research Center for Translational Orthopaedics ( IRCTO ), Jiangsu 215006, China Find articles by Huan Zhou

Jun Ge

bOrthopedic Institute, Department of Orthopedics, The First Affiliated Hospital of Soochow University, Jiangsu 215006, China Find articles by Jun Ge

Yanjie Bai

dKey Laboratory of Hebei Province for Molecular Biophysics, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China Find articles by Yanjie Bai

Chunyong Liang

aCenter for Health Science and Engineering, Tianjin Key Laboratory of Materials Laminating Fabrication and Interface Control Technology, School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China Find articles by Chunyong Liang

Lei Yang

aCenter for Health Science and Engineering, Tianjin Key Laboratory of Materials Laminating Fabrication and Interface Control Technology, School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China bOrthopedic Institute, Department of Orthopedics, The First Affiliated Hospital of Soochow University, Jiangsu 215006, China eInternational Research Center for Translational Orthopaedics ( IRCTO ), Jiangsu 215006, China Find articles by Lei Yang Author information Article notes Copyright and License information Disclaimer aCenter for Health Science and Engineering, Tianjin Key Laboratory of Materials Laminating Fabrication and Interface Control Technology, School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China bOrthopedic Institute, Department of Orthopedics, The First Affiliated Hospital of Soochow University, Jiangsu 215006, China cSchool of Mechanical Engineering, Jiangsu University of Technology, Jiangsu 213001, China dKey Laboratory of Hebei Province for Molecular Biophysics, Institute of Biophysics, School of Sciences, Hebei University of Technology, Tianjin 300401, China eInternational Research Center for Translational Orthopaedics ( IRCTO ), Jiangsu 215006, China Huan Zhou : ude.odelotu.stekcor @ uohZ.nauH Lei Yang : nc.ude.tubeh @ iely ∗Corresponding author. Center for Health Science and Engineering, Tianjin Key Laboratory of Materials Laminating Fabrication and Interface Control Technology, School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China. Corresponding generator. Center for Health Science and Engineering, Tianjin Key Laboratory of Materials Laminating Fabrication and Interface Control Technology, School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China. ude.odelotu.stekcor @ uohZ.nauH ∗∗Corresponding author. Center for Health Science and Engineering, Tianjin Key Laboratory of Materials Laminating Fabrication and Interface Control Technology, School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China. Corresponding author. Center for Health Science and Engineering, Tianjin Key Laboratory of Materials Laminating Fabrication and Interface Control Technology, School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China. nc.ude.tubeh @ iely ☆Huan Zhou and Jun Ge made adequate contribution to this bring .Copyright © 2019 The Authors This is an open access article under the CC BY-NC-ND license ( hypertext transfer protocol : //creativecommons.org/licenses/by-nc-nd/4.0/ ).

Abstract

Bone wax, primarily composed of beeswax and yield agentive role, is a century-old corporeal used to control shed blood of disrupted cram surfaces by acting as a mechanical barrier to seal the wind. The current cram wax products are normally packed in easy-to-open foil in the phase of aseptic sticks or plates, with excellent malleability and legato consistency, enabling cost-efficient and easy treat approach for bleeding control. It has besides been reported that the inert nature of bone wax causes complications including foreign body chemical reaction, infection forwarding and bone mend inhibition. With the advances in biomaterials and the market boost of cram haemostatic materials, the stadium of cram wax substitute inquiry has expanded to a wide spectrum of material formulations and forms. however, the development of substitutes of bone wax for translation is a pivotal so far challenging subject because presently a potential candidate is recommended to be equitable angstrom elementary to use, effective and cheap to produce as traditional bone wax but besides be absorbable and osteogenic. This follow-up provides an overview of cram wax including its history, clinical applications and associated complication. In addition, emerging substitutes of bone wax and outlooks of future directions including the standardize evaluation methods are besides discussed as an campaign to catalyse the invention and translation of bone haemostatic agents in the cheeseparing future. The translational potential of this article: Occurrence of osseous bleeding is common in surgically incised or traumatically fracture bone. It is all-important to stop bone bleeding to avoid further pathological consequences such as tissue necrosis and finally mortalities due to blood loss. Medical aseptic bone wax is a classical corporeal for hemostasis of bone during orthopedic surgeries, pectoral surgeries, neurological surgeries and then on. Along with its far-flung practice, complications such as foreign body reaction, cram healing inhibition and infection promotion associated with bone wax are observed. With the growing cognition in biomaterials and the boost of grocery store of bone haemostatic materials, cram wax utility research is thriving. An overview of bone and its substitutes together with evolution of their design criteria is carried out in this work, providing data for the invention and translation of cram haemostatic agents in the about future. Keywords:

Biocompatible materials, Bone regeneration, Bone wax, Haemostatic

Introduction

bone contains abundant channels for blood and bone marrow. When it is surgically incised or traumatically fractured, osseous bleeding can be a difficult problem to control, particularly in the highly vascular bones of the spine and sternum. Medical aseptic bone wax is an essential material for hemostasis of bone during orthopedic surgeries, pectoral surgeries and neurological surgeries. This material is normally defined as a waxen substance used to mechanically control bleeding from bone fractures for previously addressed surgical procedures. Bone wax is strongly hydrophobic and is not metabolised ; consequently, it is minimally resorbed from the web site of application and causes no effect on ph of the contacted consistency fluids [ 1 ]. Bone wax has no built-in haemostatic quality. In vitro experiments showed that pause of bone wax in blood can promote platelet collection to a modest extent, but its platelet-aggregating effect in vivo is not of significance because of small liaison surface [ 2 ]. therefore, bone wax chiefly acts as an impenetrable mechanical barrier ( tamponade/sealant ) at the wound site. In brief, bone hemostasis after local application of cram wax results from the mechanical blockage of haversian canals in cortical bone and medullary spaces in cancellate bone, blocking blood flow from transected vessels and allowing clotting to occur. The aesculapian application history of bone wax can be traced back to the eighteenth hundred [ 3 ]. The authoritative and most widely used formulation was developed by Sir Victor Alexander Haden Horsley in 1885, which composed of seven parts of beeswax, one partially of almond oil and one percentage of salicylic acid [ 4 ]. The beginning attested tell of the successful consumption of cram wax in clinical surgery appeared in 1892, when Rushton Parker used it to stop bleed from the lateral pass sinus [ 5 ]. Since then, the term “ Horsley ‘s wax ” was synonymous with bone wax although several recipe modifications were developed. For case, Wharton reported two formulas of bone wax in 1905 ; one was composed of 2 parts of olive oil, 8 parts of spermaceti, and 1 % tincture of iodine, and the other was composed of 3 parts of bismuth subnitrate, 0.5 contribution of egg white wax and 6 parts of petroleum gelatin [ 6 ]. similarly, Simmons [ 7 ] proposed a recipe of 3 parts of spermaceti, 3 parts of sesame oil and 4 parts of iodoform in 1911. In 1950, Geary and Fhantz [ 8 ] introduced the idea of making partially biodegradable bone wax, inventing a formula consist of 6 parts of Carbowax 1540, 1.5 parts of polyethylene ethylene glycol ( PEG ) and 2.5 parts of oxidised cellulose. unfortunately, none of the aforesaid alternatives of Horsley ‘s wax made into successful market launch. After the development of over a century, the current commercial bone wax products still chiefly consist of beeswax and softening agent such as vaseline or a mixture of paraffin wax and isopropyl palmitate. Bone wax in the marketplace is categorised as class 2 aesculapian device by the US Food and Drug Administration ( FDA ) and is normally supplied in easy-to-open foil box in the shape of aseptic sticks or plates. Bone wax is quite cheap. Although prices may differ from state to country, costs for one sterilize ready-to-use 2.5-g clean may not range outside a single-digit dollar skeletal system [ 3 ], [ 9 ]. It has a shelf life of approximately five years if stored properly. Main bone wax products commercially available at present are provided by several manufacturers such as Aesculap, CP Medical, Covidien, Ethicon, Surgical Specialties and so on. In practice, bone wax should be used immediately after removal from the software ; and it should be softened to the desired consistency before applying by moulding with the fingers or by immersing the unopened foil packet in a warm aseptic solution [ 10 ]. The material displays excellent malleability and fluent consistency and is capable of being smeared across the cut surface to plug the holes in the bone to stop bleed physically ( ). The optimum work temperature of bone wax is normally suggested to be 21–23°C .Figure 1Open in a separate window

The applications of bone wax

Both cancellate and cortical bones contain vascular tissues, and when the bone is incised or fractured, damage to its vasculature can cause osseous bleeding that is sometimes excessively austere to be controlled by natural hemostasis. In this case, bleeding should be efficaciously controlled to avoid further diseased consequences such as weave necrosis and finally mortalities due to blood loss [ 11 ]. At the introduce time, some options can be used in clinical settings for bone hemostasis : ( a ) the habit of classical absorbable haemostatic agents such as collagen and oxidised cellulose, ( boron ) the application of electrocautery and ( degree centigrade ) practice of bone wax. however, the manipulation of oxidized cellulose is circumscribed because of its inappropriate knitted framework class and miss of attachment within the bone, causing problems in sealing irregular surfaces and pores of defective bone ; collagen, on the early hand, in diverse forms, alone or in combination with fibrin and suspended in versatile delivery vehicles, has been proposed as a bone haemostatic agent but problems with memory constancy, coherence and biocompatibility have prevented practical realization [ 12 ], [ 13 ]. The use of electrocautery, which thermally sears oozing blood vessels and closes them, is time-consuming and can well induce dangerous thermal damage to tissues, which may further delay osteogenesis and allow cushy tissue ingrowth that interferes with normal cram union [ 13 ], [ 14 ]. alternatively, bone wax is highlighted by its comfort of operation, satisfactory cohesion to bone, malleability and cost-effectiveness. It is chiefly applied for bone hemostasis during orthopedic surgeries [ 15 ], pectoral surgeries [ 16 ] and neurological surgeries [ 3 ], but can be occasionally extended to dental and jaw surgeries [ 17 ], [ 18 ], [ 19 ]. In addition to directly being applied to the wind site, bone wax can be used to modify surgical tools for rake control purposes. For example, in transdermal endoscopic cervical discectomy via the anterior transcorporeal approach for cervical intervertebral magnetic disk hernia, cram wax was smeared onto the endoscopic burr to control bleeding without obvious hindrance with bone healing [ 20 ]. similarly, it can besides be used to prevent the escape of rake through the lumen of a cannulated prison guard after arthroscopic repair of the anterior cruciate ligament [ 21 ] .

Concerns of bone wax

clinical rehearse has uncovered numerous complications associated with cram wax since its development. Although bone wax has likely and promise for hemostasis application, the related complications may outweigh its benefits. As shown in, a series of complications in surgeries were reported, such as fail bone heal, extraneous soundbox reaction, granuloma growth, thrombosis, contagion and steel compression [ 22 ], [ 23 ], [ 24 ], [ 25 ], [ 26 ], [ 27 ], [ 28 ], [ 29 ], [ 30 ], [ 31 ], [ 32 ], [ 33 ], [ 34 ], [ 35 ], [ 36 ], [ 37 ], [ 38 ], [ 39 ], [ 40 ], [ 41 ], [ 42 ], [ 43 ], [ 44 ], [ 45 ], [ 46 ] .Figure 2Open in a separate window A informer calvarial bone model was used to define the local reactions of bone to bone wax [ 47 ]. It was confirmed bone regrowth was markedly impaired by the presence of bone wax. Inert bone wax most typically encompassed the bone margins in a collar-like fashion, and active bone product was observed lone beyond this collar and then connected by and large to the external periosteum. Moderate-to-severe inflammation, alien body reaction and hempen reaction were observed in the lesion. The observations are in consistent with histological findings associated with the implantation of bone wax in a scab tibia model, which typically includes alien body reactions and a lack of bone constitution [ 48 ]. Sorrenti et alabama. [ 49 ] investigated the answer of human tibia to bone wax. At the early stage, a nonspecific incendiary response was noted ( 6 months ), followed by an increase in fibrous tissue with foreign-body giant cells ( 9 months ). After 13 months, mature fibrous weave with no inflammatory reception was observed. As bone wax dramatically interferes with bone curative, it should be used meagerly and restricted in the sites where fusion is highly desired. The consequence of bone wax on the ability of cancellate bone to clear up bacteria was examined using a Staphylococcus aureus and rabbit model, indicating that as a foreign body, bone wax can importantly diminish the ability of bone to clear bacteria [ 50 ]. similarly, in a rat exemplar of chronic S. aureus osteomyelitis, the infection-promoting potential of sterile cram wax was besides observed [ 51 ]. In a case series of 19 patients presenting with osteomyelitis of the sternum after cardiac operating room, bone wax applied to the oozing sternum halves was postulated to be the possible lawsuit of this problem [ 52 ]. Because of the risk of induction of infection, bone wax must never be used in pollute fields. Besides, cleanse of bone wax in iodine is recommended after manual of arms manipulation during clinical practice. In addition to these postoperative complications, the efficiency of master of bone bleeding using bone wax is besides in dispute. For case, in a prospective randomised discipline on 400 pectoral surgical patients undergoing isolate coronary thrombosis bypass surgery, bone wax application after median sternotomy showed no benefits in blood loss control [ 9 ]. In contrast, in a report of sum knee arthroplasty, the application of bone wax was reported to be condom and effective for reducing entire blood personnel casualty and maintaining higher hemoglobin levels [ 15 ]. postoperative evaluations revealed that its application on the exposed cancellate bone open around the femoral and tibia prostheses to seal the nail holes in total knee arthroplasty is safe and is effective for reducing total blood loss and maintaining higher hemoglobin levels. No consensus is achieved so far, and surgeons may readily use bone wax at their own experience and discretion. then far, the status of bone wax has been overviewed, and a table summarising the advantages and disadvantages of bone wax is thereby presented as a road map for the development of a new generation of bone haemostatic materials ( ) .

Table 1

Advantages Disadvantages
Low cost Inertness
Easy handling Bone union prevention
Malleability Foreign body reaction induction
Inertness Granuloma growth induction
Sealing capacity Infection promotion
Bone adherence Lack of inherent haemostatic quality
Long clinical history Undesired immigration
Thrombosis induction

Open in a separate window

Substitutes of bone wax

It has been recognised that the major factor causing the aforesaid postoperative complications such as bone coupling prevention, infection promotion and extraneous body reaction is the intrinsic inertness and poor biocompatibility of bone wax. The try of developing absorbable bone wax can be dated binding to 1950, when Geary and Frantz [ 8 ] reported experimental haemostatic bone wax by combining Carbowax, PEG and oxidised cellulose together. Although this conceptualization failed in dental operating room studies [ 15 ], this study guided the direction of development of bone wax substitutes by clarifying that absorbability is the acme precedence in the design of substitutes. From 1980 to 2000, numerous bone wax alternate prototypes have been reported in the literature, such as fatso acerb salts [ 53 ], fibrin/collagen paste [ 54 ], [ 55 ], gelatin paste [ 56 ], glycolic or lactic acid/glycerol oligomers [ 57 ], [ 58 ], partially deacetylated chitin hydrochloride [ 59 ], PEG/microfibrillar collagen paste [ 60 ], polydioxanone/natural oils [ 61 ] and polyorthoester [ 54 ]. unfortunately, none of these formulations are in widespread practice or launched in market, which suggests that it has been unmanageable to combine the beneficial characteristics of traditional bone wax with the advantages of an absorbable material. In the 2000s, an ideal bone wax ersatz was suggested to be merely deoxyadenosine monophosphate childlike to use, effective and cheap to produce as traditional bone wax but would besides be in full absorbable, noninflammatory and biocompatible. According to this criterion, body of water soluble wax composed entirely of alkylene oxide freeze copolymers ( Pluronics ) was developed in 2001, which has material, application and haemostatic characteristics that are exchangeable to those of bone wax, but its absorbable place avoids the damaging biological effects [ 62 ]. Inspired by this pioneer sour, a commercially available water-soluble alkylene oxide copolymer–based cram wax ersatz ( Ostene, “ absorbable bone wax ” ; Ceremed, Inc., Los Angeles, CA, USA ) was launched in 2006 [ 63 ]. Similar to bone wax, Ostene can be softened by manual manipulation before function and sticks well to bleeding bone as a tamponade. The substantial dissolves in the plant site within 24–48 planck’s constant, allowing the early phases of bone healing to occur. Because of its solubility, Ostene provides the electric potential to address adverse reactions associated with inert bone wax [ 64 ], [ 65 ] ( ). This formula was later revised to develop new products in the literature, such as a putty-like assortment of alkylene oxide copolymers and carboxymethylcellulose sodium salt ( absorbable haemostatic bone putty ; Abyrx, Inc., Irvington, NY, USA ) [ 66 ] or a glue-like miscible blend of PEG–polypropylene glycol–PEG ( PEG–PPG–PEG ) copolymer and pregelatinized starch [ 67 ] .Figure 3Open in a separate window bet on in 1992, haemostatic agents including microfibrillar collagen flour, absorbable gelatin sponge and oxidised regenerated cellulose powder were applied as alternatives to bone wax in iliac cram procurement, showing no bone positive feedback inhibition as planned [ 68 ]. such widen applications of existing haemostatic agents, including hydrated gelatin powder [ 69 ], gelatin paste [ 56 ], gelatin–thrombin matrix sealant [ 70 ], fibrin solution [ 71 ], patient-derived fibrin sealant [ 72 ], autologous platelet-poor plasma gelatin [ 73 ], fibrin dressing [ 74 ] and gel-like mixture of agar and curdling factors [ 75 ], for control of bone bleed were popular in inquiry. however, whether these agents can act as alternatives to bone wax in bone hemostasis is still questionable because of limited animal studies and lack of clinical trials. In the by few years, the reciprocal influence between the conceptual scheme of developing absorbable substitutes and the better understand of hemostasis and bone regeneration has led to the evolution of cram wax substitutes from a sole haemostatic agent to hybrid agentive role with both haemostatic and bone regeneration capabilities. On the one hand, some fast absorbable haemostatic agents are not free of risk of complications, possibly causing allergic reaction and retarding cram regeneration to some extent, making it a must-addressed issue in designing bone wax stand-in [ 76 ]. On the other hand, in many surgical scenarios, scaffold-induced bone heal is highly desirable [ 77 ], [ 78 ]. One typical scheme in the salute day is the adoption of bioceramic cement–based paste/putty in bone hemostasis, whose phase and as-formed matrix can help to both stop bleeding and enhance osteogenesis [ 79 ], [ 80 ], [ 81 ]. To farther improve blood clotting efficiency and handle properties, supplements such as alginate [ 82 ], cellulose [ 83 ] and chitosan [ 84 ] can be blended. For model, presently Zhang et alabama. reported a self-curing cram wax substitute by mixing tricalcium silicate ( C3S ) cement and 58S bioactive glass/chitosan/carboxymethyl cellulose with KH2PO4 setting solution, which enables hemostasis, injection and bone cellular telephone proliferation [ 80 ]. Calcium Apatite bone tamponade ( CAAP ; Skeletal Kinetics, LLC., Cupertino, CA, USA ) is an FDA-approved product composed of calcium phosphate, sodium silicate solution and a mix system ( mixing roll, pestle and spatula ). Its mathematical process procedure is kind of exchangeable to that of cement : ( 1 ) open gunpowder phial, decant powder into the desegregate stadium, and lightly tap the phial to ensure maximum transfer of powder ; ( 2 ) lento pour the fluid phial into the shuffle bowl ; ( 3 ) use the pestle to vigorously mix in circular gesticulate the powderize and liquid for approximately 1 min, and make surely to reincorporate the fabric collected on the pestle into the mixing action to achieve a proper mix and ( 4 ) when shuffle together, it forms a cement-like paste that can be applied directly to sites of bleeding cram ; the resulting hardening scaffold from the paste is composed of hydroxyapatite exchangeable to the mineral phase of native bone tissue, enabling bony ingrowth and bone positive feedback [ 79 ], [ 85 ]. The drawback of this formula is the necessity to manually mix the powder and setting solution before function, increasing operation steps and contaminant risk. As a solution to this issue, a ready-to-use spread of calcium phosphate cement, PEG and pregelatinised starch was reported [ 86 ] ( ). After exposure to a humid environment, the PEG phase dissolved and was exchanged by penetrating water that interacted with the calcium phosphate harbinger to form highly holey, nanocrystalline hydroxyapatite via a dissolution/precipitation reaction. simultaneously, pregelatinised starch could gel and supply the concoction with liquid-sealing features. The fresh conceptualization was found to be cohesive and ductile, and after hardening under aqueous conditions, it had a mechanical operation ( ∼2.5 MPa compressive forte ) that is comparable to that of cancellate bone. The concerns of this formula are the sensitivity of calcium phosphate cement to moisture during storage and the miss of clinical evaluations. however, the ready-to-use design demonstrates high translational potential as it would simplify the operating room and make the material cheeseparing to the handling characteristics of bone wax .Figure 4Open in a separate window Owing to the potential risk of infection, antibiotics have been incorporated into bone wax substitutes [ 87 ], [ 88 ]. Such an attack paves the hypothesis of using bone wax substitutes to deliver remedy agents to enhance blood clot or bone re-formation. For exemplar, water-soluble bone wax substitutes were suggested to serve the extra aim of acting as an absorbable matrix for short-run drug delivery ( for example, cram morphogenic proteins, antibiotics and cytokines ) to the damaged bone, providing extra benefits by promoting osteogenesis, improving coalition rates, reducing inflammation and preventing postsurgical infections [ 62 ]. The challenges chiefly trust on the shelf life of therapeutic agents and their spill and cost control. There is increasing sum of tell over the past decade demonstrate that the rescue of selected bioactive ions can trigger specific biological responses such as microbial inhibition, blood clotting stimulation, angiogenesis and osteogenesis [ 89 ], [ 90 ], [ 91 ]. In reported bone wax substitutes, bioceramics such as bioactive glass, tricalcium silicate and calcium phosphate have been added to promote cram regeneration, which are besides potential candidates for bioactive ion pitch. The design of bone wax substitutes as bioactive ion carriers requires the command of different ion passing profiles after the material is exposed to blood and analysis of their attendant biological responses in situ in blood curdle and cram re-formation .

Outlook and summary

Since the insertion of bone wax over 125 years, this century-old haemostatic agent is inactive being used for controlling bone bleeding and seal. clinical complications originated from the nature of bone wax spur the continuing research of substitutes, and a potential candidate is recommended to be precisely a simple to use, effective and cheap to produce as traditional bone wax but would besides be absorbable and osteogenic. According to a market report entitled “ Bone Wax Market – ball-shaped diligence Analysis, Size, Share, Growth, Trends, and Forecast, 2018–2026 ” by Transparency Market Research, the global grocery store size was estimated to be US $ 68.8 million in 2017 and is projected to expand at a compound annual growth rate of 2 % from 2018 to 2026 to reach US $ 84.2 million in 2026 [ 92 ]. The US holds the major contribution of the market owing to the increase in the adoption of emerging fresh substitute products of bone wax along with high awareness of end-users. In summation, marketplace players in the US are more active in research and development of or introducing new products with improved efficacy to the market. Europe is the second gear major market for cram wax. The grocery store in these regions is driven by the increase in the numeral of surgical procedures, innovations in cram wax products, rise of bone diseases and accidental fracture cases. The cram wax market in the Asia–Pacific region is besides growing quickly at a growth rate of 3 % during the prognosis period, driven primarily by the developing countries such as India and China because of the soaring market needs. With the growing cognition and engineering advances in biomaterials and the promote of market, the sphere of bone wax substitute research has expanded to a wide spectrum of material formulations and forms to meet the evolving design criteria. The initiation and translation of bone wax substitutes is expected to thrive in the near future.

As the outcomes of research move towards translation and commercialization, it will besides be authoritative to elucidate thorough standardize evaluation systems of cram wax and its substitutes, which will lead to improved material design and generation. From an functional point of view, it is highly suggested that bone wax and its substitutes can easily detach from gloves when pressed into cavity but can exhibit potent adhesiveness to the bleeding bone surfaces or the capability to seal the bleed defects. In FDA enforcement reports of bone wax, the failure of bone wax is largely attributed to its loss of adhesiveness to the server locate after repositing [ 93 ]. however, according to the FDA information, such failure reports are largely based on the immanent judgment. contradictory evaluation results are sometimes achieved between the relevant surgeons and regulative agency. This controversy decidedly calls for the standardized evaluation of the adhesive and sealing capability of bone wax. so far, the haemostatic performance has been by and large studied through in vivo animal experiments by drilling holes in the bone and plugging with bone wax. rather of complicated animal test, an in vitro exemplary has been proposed by Suwanprateeb et aluminum [ 94 ] for sealing capability testing. In brief, acrylic glass tubes with a length of 2.00 megabyte and an inside diameter of 3.00 mm were filled with body of water up to a height of 1.91 thousand, which corresponds to systolic lineage blackmail ( 18.68 kPa, 140 mmHg ), and sealed with conic samples ; the constructs were stored at board temperature and monitored until their failure. however, there are drawbacks for this model design : ( 1 ) in consistency, the blood actually diffuses from the damaged cancellate bone, different from the flow of body of water in a tube, and ( 2 ) water is far different from blood, unable to reflect blood clot and other haemodynamic behaviours. Besides, the relevant test of shelf life and lone-term adhesiveness, conservation of samples is normally lacking in the research and exploitation of bone wax substitutes. Taken in concert, dependable and standardised testing methods for bone haemostatic agents with haemostatic and adhesive material capabilities are needed in the future .

Conflict of interest

The authors have no conflicts of sake to disclose in relation to this article .

Acknowledgement

This knead was supported by the Natural Science Foundation of Jiangsu Province ( No. BK20181045 ), the National Natural Science Foundation of China ( No.81622032 and 51672184 ), the Natural Science Research of Jiangsu Higher Education Institutions ( No.17KJA180011 ) and the Jiangsu Innovation and Entrepreneurship Program .

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