Kinetic degradation and biocompatibility evaluation of polycaprolactone‐based biologics delivery matrices for regenerative engineering of the rotator cuff

Abstract

Whereas synthetic biodegradable polymers have been successfully applied for the delivery of biologics in other tissues, the anatomical complexity, poor blood supply, and reduced clearance of degradation byproducts in the rotator cuff create unique design challenges for implantable biomaterials. Here, we investigated lower molecular weight poly‐lactic acid co—epsilon‐caprolactone (PLA‐CL) formulations with varying molecular weight and film casting concentrations as potential matrices for the therapeutic delivery of biologics in the rotator cuff. Matrices were fabricated with target footprint dimensions to facilitate controlled and protected release of model biologic (Bovine Serum Albumin), and anatomically‐unhindered implantation under the acromion in a rodent model of acute rotator cuff repair. The matrix obtained from the highest polymeric‐film casting concentration showed a controlled release of model biologics payload. The tested matrices rapidly degraded during the initial 4 weeks due to preferential hydrolysis of the lactide‐rich regions within the polymer, and subsequently maintained a stable molecular weight due to the emergence of highly‐crystalline caprolactone‐rich regions. pH evaluation in the interior of the matrix showed minimal change signifying lesser accumulation of acidic degradation byproducts than seen in other bulk‐degrading polymers, and maintenance of conformational stability of the model biologic payload. The context‐dependent biocompatibility evaluation in a rodent model of acute rotator cuff repair showed matrix remodeling without eliciting excessive inflammatory reaction and is anticipated to completely degrade within 6 months. The engineered PLA‐CL matrices offer unique advantages in controlled and protected biologic delivery, non‐toxic biodegradation, and biocompatibility overcoming several limitations of commonly‐used biodegradable polyesters.

Pegylated insulin‐like growth factor‐1 biotherapeutic delivery promotes rotator cuff regeneration in a rat model

“…Our engineered PLA‐CL matrices demonstrated controlled release of a structurally preserved model protein over the target period of 4 weeks, while simultaneously undergoing controlled degradation as reported in our earlier work 25 . The degradation byproducts or the dispersion of lyophilized protein into the organic polymer‐dissolved solvent phase did not result in significant polymer or solvent‐induced structural perturbations of our model protein as noted by CD spectroscopic observation.…”

“…Hydrolytic breakdown of the polypeptide in the matrix interior may also be catalyzed by carboxylate or other acidic degradation products (low pH) 36 . However, the lower LA content and the controlled degradation of the PLA:CL matrix enabled by slow degrading caprolactone may have resulted in less accumulation of acidic products and thereby helped maintain the protein conformation 25 . The tested matrices rapidly degraded by 4 weeks (~30%) due to preferential hydrolysis of the lactide‐rich regions within the polymer, and subsequently maintained a stable molecular weight due to the emergence of highly crystalline caprolactone‐rich regions 25 .…”

“…For more information about water absorption, weight loss and model protein BSA release across a range of mol. Wt and casting concentrations, the reader is directed to our previous report 25 …”

“…Protein-encapsulated PLA-CL matrices were fabricated using a solvent-casting process using previously optimized methods. 25 For assessing protein encapsulation and release, pulverized lyophilized protein, Bovine Serum Albumin (BSA) was dispersed at 5 wt.% protein vs. polymer in pre-dissolved PLA-CL solutions in dichloromethane (DCM) and vortexed and sonicated at 4 C for approximately 5 min each until uniform dispersions were obtained. Protein-dispersed polymer solutions in dichloromethane (DCM) at 5, 10, and 20 wt./vol.% polymer concentrations were poured on to 60 mm diameter Teflon evaporation dishes (Fisher Scientific, Hampton, NH) and placed under vapor saturated conditions on a leveled platform at 4 C for 2 days.…”

“…This molecular weight and higher CL ratio were chosen to allow faster water penetration (from increased rubbery domains of CL) and thereby faster hydrolytic degradation without acidic degradation product accumulation; a higher CL ratio would also help minimize burst release and generate pliable elastic matrices that supports surgical implantation in the rotator cuff. 25 Histology and microCT of the isolated tissues were used to assess tissue microstructure and uniaxial tensile test was used to assess tissue biomechanical function. We found that pegylated-IGF-1 mimic (PEG-IGF-1m) biotherapeutic delivery showed structural regeneration of the tendon-enthesis with improved collagen organization and maturity, columnar arrangement of fibrochondrocytes with significant recovery of the tendon failure mechanics and tensile properties within 8 weeks of repair.…”