WO2022152835A1

WO2022152835A1 - High molecular weight triethylene-glycol polyorthoester iv (teg-poe iv) polymers and compositions for drug delivery and medical implants applications

Info

Publication number: WO2022152835A1
Application number: PCT/EP2022/050726
Authority: WO
Inventors: Fei Liu; Jian-feng ZHANG; Thomas Endres; Maria MONTERO MIRABET; Andrea ENGEL; Marshall Scott Jones; Donghui Wang; Krystal R. FONTENOT; Bruce C. Johnson
Original assignee: Evonik Operations Gmbh
Priority date: 2021-01-18
Filing date: 2022-01-14
Publication date: 2022-07-21

Abstract

The present invention discloses high molecular weight TEG-POE IV polymers. The present invention also discloses a method to synthesize series of TEG-POE IV polymers of various molecular weights without altering the diols (triethylene glycol, triethylene glycol-glycolide) in the polymerization reaction. These polymers exhibit surface eroding biodegradation properties and superior mechanical strength. The present invention also discloses a composition comprising TEG-POE IV polymer and a biologically active additive such as collagen.

Description

High Molecular Weight Triethylene-glycol Polyorthoester IV (TEG-POE IV) Polymers and Compositions for Drug Delivery and Medical Implants Applications

Field of invention

The present invention relates to triethylene-glycol polyorthoester IV (TEG-POE IV) polymers and compositions. The present invention also relates to a novel synthetic process of preparing polyorthoester IV (POE) with high molecular weight for biomedical applications. Instead of varying co-monomer composition to achieve high molecular POE, adjustment of reagent stoichiometry allows precise control over the molecular weight. The method can be used to obtain high molecular weight POE for drug-eluting implants, medical devices, and particles for orthopedic, tissue engineering, or dental applications.

Background of the Invention

Polyorthoester polymers represent a family of bioerodible polymers developed by Heller et al. for controlled drug delivery (J. Heller etal. Advanced Drug Delivery Reviews 54 (2002) 1015-1039). The hydrophobicity of the orthoester functional groups hinders water penetration in combination with fast hydrolytic degradation. These properties result in surface erosion rather than a bulk degradation (S. Einmahl et al. Advanced Drug Delivery Reviews, 2001 , 53, 45 -73). Four generations of POE are known from literature, with different applications for drug-delivery purposes. Polymers are typically used for injectable depot dosage forms, which require a comparably low weight average polymer molecular weight (Mw) and preferably semi-solid material properties.

Currently, the only POE used in a commercial drug formulation is triethylene glycol (TEG) in combination with triethylene glycol-glycolide (TEG-GA) containing POE IV (TEG-POE IV). Brand name of the drug product is Sustol® for controlled release of Granisetron. (T. Ottoboni et al. Journal of Experimental Pharmacology 2014, 6, 15-21). The Mw of POE IV utilized in this product is reported approximately 6 kDa. Glycolide building blocks incorporated into the polymer structure play a key role in increasing the acidity to control the degradation rate. Typical degradation time for the sustained release application is approximately 7 days. In US. Patent 5968543, the demonstrated zero-order drug release profile of low Mw TEG-POE IV renders this polymer applicable for drug delivery systems, especially for injectable depot dosage forms. POE IV has not been used for commercial medical device applications so far, due to fast degradation and limited mechanical strength of the low Mw polymer.

Several studies have been reported regarding the synthesis of high Mw POE to enhance mechanical properties. Two techniques have been reported so far. The first method is to include high Mw diol linkers, i.e. 1 ,10-decanediol or 1 ,6-hexaendiol, to increase the chain length. (A. Dove etal. Angewandte Chemie, 2017, 129 (52), 16891-16895; R. Gurny etal. Journal of Biomaterials Science, Polymer Edition, 1999, 10 (3), 375-389). Gurny etal. have synthesized POE with 1 ,10-decanediol and 1 ,10-decanediol- lactate resulting in a polymer with a molecular weight of 28 kDa. By adjusting the ratio between 1 ,10- decanediol and 1 ,10-decanediol-lactate, the Mw could be increased up to 50 ~ 60 kDa with 5 mol% of lactate. Notably, these polymers have a different co-monomer composition than the POE IV used in the commercial Sustol® formulation. Therefore, the degradation is different compared with the reference listed drug. Schwach-Abdellaoui et al. developed another technique to adjust the Mw POE by addition of a monofunctional monomer, 1 -decanol, to regulate the polymer growth. (International Journal of Polymer Analysis and Characterization, 7(1-2), 145-161). By addition of 15% of 1-decanol, POE-lactide polymer molecular weight was 6.1 kDa whereas it can reach 9.7 kDa with only 5% of 1- decanol.

Even though efforts have been made to synthesize high Mw POE IV, there seems to be no successful synthesis route for high Mw TEG-POE IV without altering the co-monomer composition. The composition of TEG-POE IV is used in an U.S. FDA approved drug product and has a history of safe use in an injectable depot dosage form. From that standpoint it is desirable to maintain the POE IV composition, while at the same time increasing the molecular weight to reach the mechanical strength needed for use in medical device and other drug delivery applications, such as drug eluting implants and particles. Medical device applications for this surface eroding flexible polymer are, but are not limited to, soft tissue repair (such as barrier membranes), wound healing, cosmetic surgery, hemostasis (such as arterial embolization), dermal fillers. Flexible shapes made from surface eroding, high molecular weight TEG-POE IV can support the wound healing process of soft tissue. For polymers with bulk degradation mechanism, such as Poly lactide-co-glycolide polymers, the degradation occurs throughout the bulk of the specimen and acidic degradation products, such as lactic acid, can generate an acidic microenvironment. The local pH drop can cause side effects on the surrounding tissue and the specimen can lose integrity and mechanical properties. POE predominantly degrades via surface erosion. Water penetration is hindered during the hydrolysis process which impedes an acidic microenvironment. In addition, since the degradation only occurs on the surface, mechanical properties of materials are maintained during the degradation process. The synthesis of TEG-POE IV by polycondensation of diols (TEG and TEG-GA) and 3,9-diethylidene-2,4,8,10- tetraoxaspiro[5.5]undecane (DETUSO) up to kilogram scale is reported in the patent US 5968543. A 1/1 mol/mol stoichiometry of DETOSU and diols was used in these efforts. This is the theoretically expected ratio between the reactants from a mechanistic perspective. In the underlying invention a DETOSU excess was chosen rather than a 1/1 ratio. Surprisingly, it was discovered that Mw of TEG- POE IV can be controlled over a wide range by varying the ratio between DETOSU and diols. A polymer molecular weight beyond 30 kDa can be reached by variation of the stoichiometric ratio of DETOSU/diols between 1 .2 and 1 .7. A maximum Mw of 60 kDa was reached for a reactant ratio of 1 .3. Synthesized high Mw TEG-POEs were characterized and exhibited a co-monomer composition comparable to TEG-POE IV. At the same time the high Mw significantly increased the mechanical strength of the materials. The present invention discloses a method that enables the synthesis of high Mw POE with superior mechanical properties without major changes in co-monomer composition in the polymer. Collagen has been used prevailing in resorbable dental membranes. However, its rapid degradation has stimulated the need for degradation tunable synthetic polymers for such application. No report has been found for the inclusion of hydrophilic collagen into hydrophobic polyorthoester yet. The present invention discloses TEG-POE IV compositions that comprise collagen.

Summary of the Invention

The present invention is directed to high molecular weight TEG-POE IV polymers and TEG-POE IV compositions. The present invention also directed to a method to synthesize series of TEG-POE IV polymers of various molecular weights without changing the type or co-monomer ratio of the diol building blocks (triethylene glycol, triethylene glycol-glycolide). This was achieved by controlling the feeding ratio between DETOSU and diols. A molar formulation curve of the reactants was developed to control the molecular weight of the resulting polymer. This method enables the synthesis of TEG- POE IV up to a Mw of 60 kDa. This polymer exhibits surface eroding biodegradation properties and superior mechanical strength. For example, polymer with Mw of 46 kDa has 292 kPa loss modulus and 274 kPa storage modulus at 37 °C. Thermo-responsive modulus and high flexibility is especially suitable for applications in medical devices for soft-tissue repair. Potential applications are, but are not limited to, dental applications, scaffolds for wound healing, organ gels, combination products, drug delivery systems, such as drug eluting implants and particles and other biomedical applications.

The present invention is also directed to a composition comprising TEG-POEIV and a biologically active additive.

Brief Description of Drawings

The above and other objects, features and advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

FIG. 1 is a reaction scheme showing the synthesis of DETOSU monomer,

FIG. 2 is a reaction scheme showing the synthesis of glycolic acid-diol linker,

FIG. 3 is a reaction scheme showing the synthesis of TEG-POE IV,

FIG. 4 depicts the molecular weight control of TEG-POE IV,

FIG. 5 depicts the dynamic rheological analysis of high MW TEG-POE IV(46 kDA),

FIG. 6 depicts the dynamic mechanical analysis of TEG-POE IV polymer (44 kDA),

FIG. 7 depicts the dynamic rheological properties of polyorthoester with recombinant collagen at percentage by weight of 10%, 20%, 30%, 40%, and 50%. In all the composition, the storage modulus is less than 10 MPa in a temperature range between 20 and 40 °C., FIG. 8. depicts the water contact angle of the polyorthoester and its composition with recombinant collagen. The inclusion of recombinant collagen reduced water contact angle indicated the materials become less hydrophobic,

FIG. 9. depicts the fourier-transform infrared spectra of neat polyorthoester, the neat recombinant collagen, the polyorthoester with 30% recombinant collagen, and

FIG. 10. depicts the dynamic rheological properties of polyorthoester with two molecular weights mixing with 10% recombinant collagen, respectively. The POE with molecular weight of 33k Dalton and 10% recombinant collagen were non-sticky. The POE with molecular weight of 8k Dalton was sticky. The POE with molecular weight of 8k Dalton and 10% recombinant collagen was flowable within the investigated temperature range 20 - 40 °C.

Detailed Description of the Invention

Before the present compounds and processes are disclosed and described, it is to be understood that the aspects described herein are not limited to specific processes, compounds, synthetic methods, articles, devices, or uses as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.

Definition of Terms

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

The conjunctive term “or” includes any and all combinations of one or more listed elements associated by the conjunctive term. For example, the phrase “an apparatus comprising A or B” may refer to an apparatus including A where B is not present, an apparatus including B where A is not present, or an apparatus where both A and B are present. The phrases “at least one of A, B, . . . and N” or “at least one of A, B, . . . N, or combinations thereof’ are defined in the broadest sense to mean one or more elements selected from the group comprising A, B, . . . and N, that is to say, any combination of one or more of the elements A, B, . . . or N including any one element alone or in combination with one or more of the other elements which may also include, in combination, additional elements not listed.

The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 1 1 %, and “about 1 ” may mean from 0.9-1 .1 . Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1 ” may also mean from 0.5 to 1 .4.

The term “wt. %” means weight percent.

The term “w/w” means weight per weight.

The term “weight-average molecular weight (M_w)” means measuring system that includes the mass of individual chains, which contributes to the overall molecular weight of the polymer.

The term “latent acid” means short acid segments in the polymer backbone, such as glycolic acid, lactic acid et al.

The term “anti-solvent precipitation” means a purification process by mixing the polymer solution and the antisolvent.

The term “biological tissues” include, but are not limited to, human soft tissues, skin, subcutaneous layer, mucous membranes, cartilage, ligaments, tendons, muscle tissues, blood vessels, human organs, cardiac muscle tissues, heart valves, nervous tissues, pericardium, pleurae, and peritoneum.

The term “reaction feeding ratio” means the the molar ratio of used DETOSU monomer to the total of triethylene glycol and triethylene glycol-glyolic acid or triethylene glycol-lactic acid.

The term “storage modulus” relates to a material’s ability to store energy elastically in an oscillatory experiment.

The term “loss modulus” represents the viscous part or the amount of energy dissipated in the sample through heat.

For the purposes of the present invention, the term “biodegradable” refers to polymers that dissolve or degrade in vivo within a period of time that is acceptable in a particular therapeutic situation. Such dissolved or degraded product may include a smaller chemical species. Degradation can result, for example, by enzymatic, chemical and/or physical processes. Biodegradation takes typically less than five years and usually less than one year after exposure to a physiological pH and temperature, such as a pH ranging from 6 to 9 and a temperature ranging from 22°C to 40°C. TEG-POE IV is synthesized in a step-growth polymerization. The molecular weight of the polymer from step-growth polymerization is typically dependent on the stoichiometric balance, the purity of chemicals, and the degree of polymerization. Especially monomer impurities are known to limit the degree of polymerization. In the present invention, all monomers were purified by recrystallization to ensure quality. The ideal stoichiometric balance for two bifunctional monomers, A-A and B-B, is 1.0. There are special cases documented in literature where a stoichiometric imbalance can significantly speed up the step-growth polymerization rate (Macromolecules 32.15 (1999): 4776-4783; Polymer Chemistry 11.1 (2020): 125-134). Excess monomer is consumed by side reactions that can impact the kinetic and equilibrium of the polymerization, resulting in a higher molecular weight polymer. However, this phenomenon has not been reported for TEG-POE IV polymer synthesis so far. In the present invention, the stoichiometric imbalance of bifunctional monomers enables a high degree of polymerization resulting in a high molecular weight POE IV.

Synthetic Methods

The disclosed polymers may be prepared by synthetic processes typically known by those skilled in the art. In certain embodiments, oxygen and water are excluded via inert gas purging or vacuum or both. The diol linkers are mixed and dissolved in organic solvent followed by addition of monomer solutions which have also been separately dissolved prior to the addition. Typical preferred reaction temperature ranges are from room temperature 25 °C to about 35 °C over a time necessary for complete conversion of monomer to polymer. Product is achieved after filter- and precipitationpurification process.

Weight-average molecular weight of synthesized polymer was characterized by Gel Permeation chromatography (GPC). The test was performed on an Agilent system with a differential refractive index detector utilizing one PLgel 5 pm MIXED-D 300x7.5 mm column (elution range 0.2 to 400 kDa). OmniSolve TX0282-1 stabilized HPLC grade THF was used as the eluent at a flow rate of 1 mL/min at 25 °C. The molecular weight calibration was performed with monodisperse linear polystyrene (0.58 to 400 kDa). For weight-average molecular weights, the entire signal of a major peak including its shoulder at a lower retention volume was integrated.

Disclosed herein are medical applications of high molecular weight POE IV polymers. The disclosed forms for medical applications include pastes, gels, granules, films, patches, etc. The disclosed medical applications include, but not limited to, guided tissue regeneration, guided bone regeneration, wound healing, trauma, cosmetic surgery, bone void fillers, chin augment, antiadhesion, barrier membrane, tissue engineering, and drug delivery systems, etc.

Ingredients

Suitable biologically active additives include, but are not limited to animal derived collagen, and recombinant collagen. Examples

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

The following examples are provided to illustrate the preparation of the invention. They are intended solely as possible methods described by way of examples without limiting the invention to their contents.

Example 1 : TEG-POE IV (TEG: TEG-GA, 4:1)

Preparation of the DETOSLI monomer

Scheme 1 depicted in FIG. 1 refers to the synthesis of the DETOSU monomer. In a jacketed reactor purged with nitrogen, 300 grams of ethylene diamine was added into the reactor. 87 grams of potassium tert-butoxide was weighed out and added into reactor with a positive nitrogen flow while stirring. Mixed solution was kept stirring for 1 hour to dissolve all solutes. 54 grams of 3,9-Divinyl- 2,4,8, 10-tetraoxaspiro[5.5]undecane (DVTOSU) monomer was weighted and added into the reactor. Reaction solution stirred for overnight at 100 °C. Reacted solution was cooled to room temperature after 12 hours. A clear brown solution was formed.

Crude reaction solution was mixed with hexane (1 :4, v/v) for 2 hours to complete extraction. Organic phase (hexane) was collected and concentrated after rinsing with water twice to remove impurities. Concentrated solution was re-dissolved in hexane and crystallized at -20 °C for 20 minutes. Purified material was isolated by filtration through a filter funnel. The off-white solid product was dried in an oven overnight with a yield of 93%.

Preparation of latent acid diol linker

Scheme 2 depicted in FIG. 2 refers to the synthesis of the glycolic acid-diol linker. Glyolide is used as representative latent acid source for the linker. In a round bottom flask, 3.5 grams of glycolide and 4.5 grams of triethylene glycol were dissolved and purged under nitrogen for at least 1 hour. Solution was stirred for at least 18 hours at 180 °C. A transparent off-white liquid was formed. Material was cooled and stored in freezer. Preparation of POE IV with high Mw

Scheme 3 depicted in FIG. 3 refers to the synthesis of POE IV with high Mw. In a jacketed reactor at 30 °C, 1 .6 grams of triethylene glycol and 0.7 grams of triethylene glycol-glycolic acid were weighted and dissolved in 10 mL THF. In parallel, 5.0 grams of DETOSU were weighed accurately and dissolved in 25 mL THF. DETUSO solution was added dropwise into the reactor containing the solution of the diols. Reaction was stirred under anhydrous conditions for 2 hours at 30 °C. Subsequently, reaction mixture was cooled to room temperature and filtered through 0.45 pm PTFE membrane. Filtered solution was precipitated in hexane. The final purified polymer was dried under vacuum overnight. Yield was 95%.

Preparation of POE IV films

2 g of TEG-POE IV (44 kDa) was placed in the between of two stainless stain plates and loaded on to a compression molding machine (AUTOSERIES, Carver, Inc). Four pieces of shim sheets with the same thickness were also placed in the between of stainless stain plates. The plates were heated and hold at 60°C for 5 min under 3000 lbs. Plates with the polymer were cooled down to room temperature. After removing the plates, the films maintained their dimensions, for example, using shim sheets with 0.25 mm thickness, the transparent film had and maintained thickness about 0.3 mm.

Characterization

Molecular weight of synthesized polymer was characterized with gel permeation chromatography (GPC). Test was performed on an Agilent system with a differential refractive index detector utilizing one PLgel 5 pm MIXED-D 300x7.5 mm column (elution range 0.2 to 400 kDa). OmniSolve TX0282- 1 stabilized HPLC grade THF was used as the eluent at a flow rate of 1 mL/min at 25 °C. The molecular weight calibration was performed with monodisperse linear polystyrene (0.58 to 400 kDa). For molecular weights, the entire signal of a major peak including its shoulder at a lower retention volume was integrated.

Dynamic rheological behavior of the materials was evaluated by a rotational rheometer (AR 2000ex, TA Instruments). 1 g of the material was loaded onto the plate. The top Peltier plate was lowered until a gap of 1.05 mm was reached. After trimming the polymer edge the Peltier plate was further lowered until a gap of 1.0 mm was reached. A temperature ramp method with 1 Hz and 1 % shear strain at a rate of 5°C/min was used.

Dynamic mechanical properties were measure by a Dynamic Mechanical Analyzer (DMA, Q-800, TA Instruments). Specimen was cut to straight rectangular shape (18 x 2 x 1 .5 mm) and mounted to the DMA with a pair of tensile clamps. The dynamic mechanical testing was performed by a multi- frequency-strain module at a heating rate of 37min from -40°C to 80°C. Table 1 depicts the molecular weight control of TEP-POE polymer by adjusting the feeding ratio of monomer DETOSU to Diol linker (TEG and TEG-GA). There is a clear dependency between feeding ratio and Mw. Surprisingly a maximum Mw is reached around a DETOSU/diol ratio around 1.3, whereas the stoichiometric ideal ratio is 1 .0.

Table 1. Optimization of the molecular weight control of TEG-POE IV with different feeding ratio

FIG 4. depicts the molecular weight control of TEG-POE IV as a function of feeding ratio. Molecular Weight increases from 28 kDa to 60 kDa maximum when the feeding ratio increases from 1.2 to 1.3. As the feeding ratio exceeds 1.3, a decrease of the molecular weight was observed reaching a minimum of 14 kDa for a ratio of 2.0. The formulation curve demonstrates the capability to control the molecular weight.

FIG. 5 depicts the dynamic rheological analysis of high Mw TEG-POE IV (46 kDa). A higher loss modulus (G”) than storage modulus (G’) over the entire investigated temperature range indicates that the polymer’s viscous contribution dominates the elastic characteristic. A storage modulus (G’) at body temperature (37 °C) of about 243K Pa enables maintaining the material’s shape.

FIG. 6 depicts the dynamic mechanical property of TEG-POE IV polymer (44 kDa) in a wide temperature range (-40 to 37 °C)..

PREPARATION OF EXAMPLE 2

Preparation of polyorthoester with recombinant collagen

Polyorthoester with molecular weight of 33k Dalton (Evonik Corporation) and recombinant collagen with various ratios were weighed depicted in Table 1. The weighed recombinant collagen were manually kneaded into polyorthoester for 2 minutes at room temperature to prepare a biologically active composition. 1 g of polyorthoester with recombinant collagen at each ratio was prepared. The kneaded mixtures had uniform dispersion examined by scanning electron microscope. Alternatively, the mixture of recombinant collagen and polyorthoester could be mixed in a container by high speed mixer at room temperature. Table 2. Ratio of polyorthoester and recombinant collagen by weight

PREPARATION OF EXAMPLE 3

Preparation of low molecular polyorthoester with recombinant collagen

Polyorthoester with molecular weight of 8k Dalton (Evonik Corporation) and recombinant collagen at a ratio of 90:10 by weight was kneaded manually at room temperature. This polyorthoester and the mixture with 10% recombinant collagen were flowable and sticky to everything they came to contact with.

Characterization

Dynamic rheological behavior of the materials was evaluated by a rotational rheometer (AR 2000ex, TA Instruments). 1 g of the materials was loaded onto the plate. Lowering the top Peltier plate until a gap of 1 .05 mm was reached. After trimming the polymer edge, the Peltier plate was further lowered until a gap of 1 .0 mm was reached. A temperature sweep method with 1 Hz and 0.5% shear strain at a rate of 5 °C/step was used. The testing was performed both in a cooling mode from 40°C to room temperature and a heating mode with freshly made samples from room temperature to 40°C to prevent denaturing the recombinant collagen or preserve the biological activities of the added additives.

Surface hydrophobicity of the materials was evaluated by a Drop Shape Analyzer (DSA100, Kruss GmbH). The materials were pressed between two clean glass slides into thin films with smooth surface for water contact angle measurement.

The materials were characterized using Nicolet iS 50 FTIR Spectrometer (Thermo Fisher Scientific) in a wavenumber range of 4000-500 cm^-1 at room temperature. The spectral resolution was 16 cm ¹.

Results

FIG. 7 depicts the dynamic rheological properties of polyorthoester with recombinant collagen at percentage by weight of 10%, 20%, 30%, 40%, and 50%. The loss modulus (G”) is greater than storage modulus (G’) within the investigated temperature range 20 - 40°C for the composition with 10%, 20%, 30%, 40% recombinant collagen. In all the composition, the storage modulus is less than 10 MPa in a temperature range between 20 and 40 °C.

FIG. 8. depicts the water contact angle of the polyorthoester and its composition with recombinant collagen. The inclusion of recombinant collagen reduced water contact angle indicated the materials become less hydrophobic.

FIG. 9. depicts the fourier-transform infrared spectra of neat polyorthoester, the neat recombinant collagen, the polyorthoester with 30% recombinant collagen. The recombinant collagen has characteristic absorbance bands at 1629 cm^-1 and 1521 cm ¹. The presence of these bands confirms the recombinant collagen in POE.

FIG. 10. depicts the dynamic rheological properties of polyorthoester with two molecular weights mixing with 10% recombinant collagen, respectively. The POE with molecular weight of 33k Dalton and 10% recombinant collagen were non-sticky. The POE with molecular weight of 8k Dalton was sticky, during mixing of 10% collagen and loading samples on the rheometer, about 30% of materials were lost and unable to recovery due to the stickiness. The POE with molecular weight of 8k Dalton and 10% recombinant collagen was flowable within the investigated temperature range 20 - 40 °C.

Claims

Claims What is claimed is:

1 . A polymer compromising following units:

x is between 0 and 10, preferably between 0 and 8, and more preferably between 0 and 4; y is between 0 and 10, preferably between 0 and 8, and more preferably between 0 and 4; x + y is between 1 and 20, preferably between 1 and 10, and more preferably between 1 and 8; m/n is between 1 and 100, preferably between 1 and 50, and more preferably between 1 and 5; m is between 20 - 140, preferably between 40 - 120, and more preferably between 80 and 100; n is between 5 and 35, preferably between 10 and 30, and more preferably between 20 and 25; and the polymer has a weight-average molecular weight (M_w) in the range of 10,000 - 70,000g mol^-1, preferably in the range of 20, 000-60, 000g mol^-1, and more preferably in the range of 40,000-50,000 g mor¹.

2. The polymer of claim 1 , wherein z is the ratio of n to m; and wherein z is between 0 and 1 , preferably between 0.1 and 0.5, and more preferably between 0.2 and 0.3.

3. The polymer of claim 1 , wherein reaction feeding ratio of DETOSU to the total of triethylene glycol and triethylene glycol-glyolic acid or triethylene glycol-lactic acid is between 1 .2 and 1 .7.

4. The polymer of claim 1 , wherein the DETOSU is 3,9-Diethylidene-2,4,8,10- tetraoxaspiro(5.5)undecane.

5. A composition comprising any one of the polymers in claims 1-4 and a biologically active additive.

6. The composition of claim 5, wherein the biologically active additive is an animal derived collagen, or a recombinant collagen.

7. A method for preparing any one of the polymers in claims 1 -4, wherein the method comprises the steps of:

(a) dissolving DETOSU monomers in an organic solvent to form a monomer solution; (b) mixing and dissolving triethylene-glycol with triethylene glycol-glycolic acid, ortriethylene glycol- lactic acid to form a diol solution;

(c) adding the monomer solution to the diol solution to start the polymerization reaction; and

(d) mixing the solutions to produce polymer.

8. The use of any one of the polymers of claims 1-4 in medical devices for soft-tissue repair, in dental applications, in scaffolds for wound healing, in organ gels, in combination products, and in other biomedical applications.

9. The use of any one of the compositions of claims 5-6 as dental membranes, craniofacial augment, bone void filler, hemostasis, sealants, soft tissue anti-adhesion, combination products, wound healing, dermal fillers, cosmetic surgery, chin augment, medical device coating, and scaffold applications.